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Full text of "Report of program activities : National Institutes of Health. Division of Research Resources"

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division of research and technology 

division of research grants;, 

. division of research resources 
division of research services 



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NATIONAL INSTITUTES OF HEALTH 
NIH LIBRARY 




BLDG10, 10 CENTER DR. 
BETHESDA, WSD 20892-1150 



ANNUAL REPORT 
OF 
PROGRAM ACTIVITIES 
k, MtfuMM. .w4tiTOtfc%"l DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY 

OF HdfttTM, J 

DIVISION OF RESEARCH GRANTS 

DIVISION OF RESEARCH RESOURCES 

DIVISION OF RESEARCH SERVICES 

Fiscal Year 1975 



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PUBLIC HEALTH SERVICE - NATIONAL INSTITUTES OF HEALTH 
DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY 
Report of Program Activities 
July 1, 1974 through June 30, 1975. 



— 



ANNUAL REPORT 

TABLE OF CONTENTS 

Page 

DIRECTOR'S SUMMARY 1 

Office of Scientific and Technical Communications ------- 8 

Summary of the Assistant Director --------------- 10 

Research Project Reports 

Automated Processing of Medical Language ---------- 12 

COMPUTER CENTER BRANCH 

Summary ---------------------------- 14 

COMPUTER SYSTEMS LABORATORY 

Summary ---------------------------- 25 

PHYSICAL SCIENCES LABORATORY 

Summary ---------------------------- 31 

Research Project Reports 

Theory of Biochemical Separation Technique --------- 33 

Theory of the Helix-Coil Transformation of Polypeptides 

in Solution ------------------------- 35 

Rapid Scan Nuclear Magnetic Resonance Spectroscopy ----- 36 

Cellular Motility and Chemotaxis -------------- 38 

Measurement of van der Waals Forces ------------- 40 

Physical Force Interactions Between Cell Membranes and 

Cell Membrane Analogues ------------------- 42 

Influence of Electric Forces on the Organization of Proteins 

and Model Systems --------------------- 44 

Correlation Function Spectroscopy /Laser Light Scattering - - 46 



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Page 
Consulting Services --------------------- 48 

Miscellaneous Studies -------------------- 50 

LABORATORY OF APPLIED STUDIES 

Summary ---------------------------- 53 

Research Project Reports 

Evaluation of Computer Systems for ECG Analysis ------- 56 

Computer Systems for Nuclear Medicine ------------ 58 

Investigations of Physiologic Signals and Simulation Models 

by Distributed Hybrid Computing --------------- 61 

Mathematical Modeling of Biological Processes -------- 64 

General Mathematical and Computational Collaborative 

Efforts 68 

Statistical Research in Clinical Pathology --------- 71 

DATA MANAGEMENT BRANCH 

Summary ---------------------------- 74 

LABORATORY OF STATISTICAL AND MATHEMATICAL METHODOLOGY 

Summary ---------------------------- 88 

Research Project Reports 

Pattern Recognition --------------------- 94 

Research Topics in Computer Science ------------- 96 

Nonlinear Equations --------------------- 93 

Discrete Mathematics and Applications ------------ 10O 

Visual and Biological Shape ----------------- 102 

Multivariate Statistical Methods --------______ iq4 



DCRT Annual Report 
July 1, 1974 through June 30, 1975 

OFFICE OF THE DIRECTOR 



This Director's Summary highlights some of the Division's FY75 activities, 
and provides a perspective in which to see the progress of computing at NIH, as 
you read the details of what the DCRT Laboratories and Branches did this year. 

Ten years ago the new Division of Computer Research and Technology was 
organized on the NIH campus. Today computing has become an integral part of 
the NIH scene, and literally involves and affects work of thousands of scien- 
tists and administrators. The key to this integration is the interaction be- 
tween those who provide computing capabilities and those who use these for 
biomedical research, health administration and program leadership at NIH. 

To be useful and successful any such interaction must involve: 

"a worthwhile information processing task 

"a successful computer system 

'a way to perform the task on the system. 

Successful Computer Systems 

NIH has successful computer systems, largely because NIH planned for and 
was willing to build its own centers of technical expertise. As a minimum, 
successful computer systems must be both reliable and accessible. This requires 
expertise in computer hardware, computer software, and electronic communications, 
plus an ability to combine all three appropriately for the tasks at hand. 

The DCRT Computer Center Branch continues to provide NIH with responsive, 
reliable computer services and facilities of an unexcelled quality and diver- 
sity. To provide computing power to some 5000 users is no trivial matter. 
The CCB success derives largely from recognition that the key to developing 
a good central computing utility is high quality system software expertise, 
(system programmers). 

The CCB report therefore emphasizes this competence and describes several 
improvements which balance an average of more than 10,000 computing tasks per 
day among several large, interlinked computer processors, while handling 80,000 
on-line data sets and archiving almost 30,000 reels of computer tape. In this 
context, one can see the importance of the implementation of the automatic data 
migration facility, the automatic tape inventory and registration, the "quick" 
and "discount" services, and various privacy protection facilities. 

These improvements carry forward the CCB philosophy of an integrated 
utility, based upon reliable commercially available hardware and accessible 
through reliable commercially available commmuni cations lines. Perhaps the 
greatest tribute to the CCB system teamwork is the recognition and emulation 
it receives by professionals outside the NIH, including those who provide 
commercial computing services. 



> 



The DCRT Computer Systems Laboratory must be viewed from another perspec- 
tive since its mission and activities focus on computing tasks of a different 
type. It develops systems tailored to needs that cannot be met by a central 
computing utility. These needs fall largely in biomedical research laboratories 
and in clinical care areas that have requirements for real-time data collection, 
analysis, display or process control, as well as an interactive computing capa- 
bility for research and clinical staff. 

As noted in previous annual reports these tend to be longer range projects. 
Indeed, two of the more significant CSL projects get little discussion this 
year because they are not "new." One is the continuing work on systems for 
fundamental biochemical and biophysical investigation among the NIAMDD labora- 
tories in Building 2. The other is the expansion and refinement of the system 
supporting the NHLI Intensive Care Unit. 

The CSL summary notes that in addition to software competence its work 
involves considerable electronic engineering expertise. The intricacies of 
computer hardware and of directly-wired communications lines are an inescapable 
part of specifying or designing CSL systems. Many of these involve the acqui- 
sition, conditioning, and preprocessing of complex signals from instruments in 
the laboratory or at the bedside. The CSL staff too has its share of recog- 
nition and emulation by professional colleagues outside of the NIH. 

Worthwhile Information Processing Tasks 

There are three salient facts about the value of information processing 
tasks at NIH. 

1. Judgements about, their value rests primarily with those persons, 
scientific or administrative, who use the information products as 
part of their work, and secondarily with those who must evaluate 
that work. 

2. The value of doing an information processing task on a computer 
involves a separate judgement but this also must rest with the 
same people who make judgements about the value of the task it- 
self, although DCRT often provides advice. 

3. Computing at NIH has flourished because there are large numbers 
of worthwhile information processing tasks at NIH and many of 
these are worth doing on a computer. 

Biomedical research is, after all , a matter of acquiring and evaluating 
new information in the light of existing knowledge, and health science admin- 
istration involves the evaluation processing of large amounts of information 
about research and training projects. Behind both NIH research and adminis- 
tration lies the considerable logistical and managerial infrastructure inherent 
in operating a complex organization consisting of thousands of people respon- 
sible for many hundreds of millions of dollars. 

The activities of three parts of DCRT provide examples of some worthwhile 
information processing performed on computers. 



The Physical Sciences Laboratory studies problems in physics and chemistry 
that relate to biological sciences. These investigations look at fundamental 
levels of biomedical phenomena. In general they entail theoretical studies and 
experimental work on interactions among molecules or the interactions of mole- 
cules or other small entities with a variety of physical force fields, e.g., 
centrifugal or electromagnetic. 

Like much of modern physical science, the PSL work uses the precision of 
mathematical forms for the theoretical studies. It uses the power of computers 
both for numerical evaluation of mathematical statements and in experimental 
work as part of sophisticated instrument systems that automatically measure the 
changing response of the material under investigation and in many cases auto- 
matically change the force fields. 

But significantly, the PSL has been rather frugal in its use of computers. 
In many instances it uses programmable calculators rather than full-blown com- 
puter systems because its competence in mathematics permits PSL to make appro- 
priate simplifying substitutions in place of more complex forms. As the PSL 
report indicates, this mathematical talent is applied in a variety of collab- 
orative studies with scientists outside of NIH, and the laboratory sponsors 
occasional meetings of experts on pertinent topics. 

The Laboratory of Applied Studies operates in a similar mode with respect 
to problems closely related to clinical research and care. Some studies in- 
volve mathematical theory and numerical analysis, or develop statistical theory 
and methods for analyzing clinical data. 

Others deal with complex clinical information forms such as electrocardio- 
grams and radionuclide scinti graphs, the X-ray like images produced by the 
radiation emitted from minute amounts of radioactive substances administered 
in diagnostic tests. 

Such statistical and clinical studies may involve a considerable amount of 
mathematical computing. They also make use of a computer's ability to organize, 
store, and retrieve sets of data precisely and efficiently, as well as to con- 
trol the acquisition and/or conditioning of the electronic signals from which 
the data are derived. 



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Hence, it is no surprise that both LAS and PSL work with the Computer Sys- 
tems Laboratory and other NIH institutes on projects which require the develop- 
ment of specialized computer systems and at the same time make use of the 
facilities of the Computer Center Branch for large scale data processing and 
computation. 

The DCRT Office of Administrative and Management Services contains examples 
of the value of computing in administrative data processing. Perhaps the best 
example is the DCRT Project Accounting System, which handles the accounts for 
all DCRT services that are billable through the NIH central accounting system 
under the NIH Service and Supply Fund (the Revolving Fund). The system was 
designed by members of the Computer Center Branch and Data Management Branch. 
It automatically collects data on all jobs run on the CCB computer utilities 
and is fed supplementary information on other billable personnel, rental and 
service charges. 



Those data are available at all times for "emergency" on-line queries. 
Each month's charg°- ir billed by transfer of data on magnetic tape to the NIH 
Office of Financial Management. The system also makes microfiche copies of the 
monthly bills for ready visual reference if questions arise. 

The information thus processed is absolutely essential for responsible 
fiscal management under the service and supply fund. Note that in this case 
the computer is essential for recording measurements of its own activities. It 
is also valuable for keeping files well organized for query and for easy trans- 
fer to other computer-based accounting systems. The microfilm records supple- 
ment and reduce the need for costly on-line inquiries. 

Performing Worthwhile Tasks on Successful Systems 

The mere existence of successful computer systems and worthwhile infor- 
mation processing tasks does not guarantee that the tasks will get done. 

The DCRT tasks mentioned above benefit from close proximity within DCRT 
to programmers and information specialists as well as to successful computer 
systems. 

But many computer users at NIH do not have all this talent available 
"down the hall." Their initial interaction with computers usually occurs first 
through DCRT staff and then directly through the variety of facilities which 
are provided and supported by the DCRT staff. 

These facilities are computer programs designed to make it easier to 
create new programs and to use them. Indeed, this very concept of computer 
programs interacting with each other as well as information and people and com- 
puter hardware is absolutely essential to an understanding of modern computing. 

The Data Management Branch uses many such facilities to provide practical 
solutions for the variety of data processing problems posed by NIH scientists 
and administrators. One key to the DMB success is its ability to employ, as 
needed, a full range of such facilities: conventional compiler-based languages, 
conversational programming systems and the data management program generators 
that DMB itself has created. During the past year DMB has improved its gene- 
rators and plans to have a completely revised system available early in FY1976. 

The Clinical Information Utility System segment of the DMB Clinical Center 
Project is an excellent example of the accomplishments which are possible 
through continuing interaction of knowledgeable staff in DCRT and other organi- 
zations. The CIU System addresses a long felt need for rapid, accurate and 
controlled retrieval of subsets from the wealth of data accumulated by the 
Clinical Center clinical laboratories over recent years. Development of the 
system involved resolution of many of the classic jurisdictional ard privacy 
issues which appear in articles about data management in large organizations. 

As in previous years, the DMB summary includes a number of projects in 
support of clinical research with the various NIH institutes. An excellent 
example is the retrospective NHLI study of pre and postoperative data on more 
than one thousand cases requiring surgical replacement of heart valves. 



( 



The DMB report also demonstrates a strong support for NIH laboratories 
and administrative areas. In the latter, a close look at the project list 
shows their work interacting productively with the central systems maintained 
and operated by the NIH Division of Research Grants and the NIH Office of 
Administration. 

The Laboratory of Statistical and Mathematical Methodology is a counter- 
part to DMB. It provides practical solutions for problems involving the sta- 
tistical analysis and mathematical evaluation of data. Like DMB, LSM uses a 
full range of facilities: compiler-based languages, interactive systems, a 
variety of statistical packages developed elsewhere and two facilities, MLAB 
and MODELAIDE, by DCRT staff members who are now part of LSM. 

Here again success is a result of the interaction between the expertise of 
LSM and the NIH scientists and administrators who have information processing 
problems. The examples listed in the LSM report show that these consultative 
and collaborative efforts have flourished during the first year of the labora- 
tory's activities. 

The close reader of the DMB and LSM reports may note that DMB has several 
projects involving statistical analyses. Some of these are projects started 
in DMB years ago and have built up a close working staff relationship. But it 
is more important to realize that information processing tasks associated with 
sets of data do not fall into two discrete classes. 

Thus, while LSM is a DCRT focus for certain statistical and mathematical 
disciplines, these are found elsewhere in DCRT. Similarly the research 
activities of LSM in size and shape and pattern recognition, computer science 
and various branches of mathematics have direct or related counterparts in 
DCRT. Without this commonality of expertise among the DCRT labs and branches 
much of the collaborative multi disciplinary work within DCRT would suffer. 

DCRT Training Courses and Seminars are another essential element in get- 
ting the worthwhile tasks done on the successful computer systems. In many 
ways it is useful to view the NIH Computing System (the machines, the software, 
the computer science and information science expertise and the NIH staff with 
information processing tasks) as a learning system. 

This view leads to two questions. Who needs to know what about the theory 
and practice of informationthandling and computer systems in order to achieve 
the best research, administration and program leadership? What kind of "educa- 
tional experiences" are needed to provide that knowledge and the skills and J 
attitudes which enable the knowledge to be used effectively? The first ques- 
tion tends to be answered throughout NIH by each person for his or her own 
perceived needs. The second is answered rather well for the specific DCRT 
supported programming languages and facilities by training courses given twice 
a year. 

Future Progress of Computing at NIH 

The progress of computing at NIH has followed the major outlines of the 
scenario envisioned in the early 1960s. Then, after a year long study (1962-63) 



in 



hr 1 



NIH opted for a new Division of Computer Research and Technology. This divi- 
sion was to be a strong central computing utility and programming resource, 
embellished with laboratories of excellence in computer systems engineering 
and mathematics. All of this came to pass. 

Socalled Data Base Technology has made slower progress. There was to be 
a Data Systems Analysis and Design Branch in the original DCRT. The Federal 
enthusiasm of the late 1950s and early 1960s for central pools of systems 
analysts separate from computer programmers never materialized at NIH. This 
was due in part to the nature of NIH and in part to the state of computing at 
NIH and elsewhere. 

There was no NIH centralization of administrative data processing systems, 
A group of systems analysts has functioned within the Division of Research 
Grants, Statistics and Analysis Branch, which operates its centralized data 
management systems for grants and lately for contracts. The Office (now 
Division) of Financial Management has in large measure obtained systems anal- 
ysis, design and implementation by contract. 

In spite of some promises of the late 1960s there never developed a good 
commercial general purpose information processing system to apply to data 
management. To fill the void the Data Management Branch developed a data 
management system for its customers in the various NIH Institutes and adminis- 
trative offices. 

More recently there have emerged on the market some data base management 
systems which begin to approach the facilities promised in the 1960s. It 
remains to be seen whether they will be suited to the NIH needs and whether 
the central NIH administrative data processing functions are suited to the 
concepts of integrated data base management. 

Federal Automatic Data Processing regulations (ADP) still haunt computing 
at NIH in the form of the GSA. The general problem was discussed obliquely in 
last year's Director's Summary, with a historical note to show recognition in 
1963 of the difference between NIH computing needs and those previously envi- 
sioned by Federal ADP philosophies. Whether or not current differences can 
be resolved is a matter of some concern for the future of the NIH central com- 
puter facilities. 

Several trends will affect computing at NIH . One is resource constraints. 
The last seven years brought tighter employment ceilings to most of NIH and a 
call for higher productivity throughout the Federal Government. To the extent 
that computers can increase the "efficiency and effectiveness" of NIH and 
other Federal employees, we are likely to see greater use of systems like the 
NIH Computer Center, which are reliable, accessible and relatively inexpensive. 
The ultimate limit on expansion will be economic, depending on the values 
placed on computing compared to other activities during a period of continuing 
inflation. 

Another trend appears in two areas which are not computers in the conven- 
tional sense. These are electric calculators and "word processing machines." 
The NIH property rolls currently list some 3200 "electric calculators" ranging 



from $35 manual calculators to $12,000 programmable calculator systems, and 
the NIH rents or leases some 390 magnetic card or magnetic tape typewriters. 

Programmable calculators are now available with cassette tapes and with 
alphabetic characters to put labels on printed results (and presumably on pro- 
gram statements). "Communicating" mag card and mag tape typewriters are avail- 
able which send and receive messages via telephone lines, linking to the NIH 
central computer (or in theory to any other compatible computer in the world 
with telephone posts). And new product lines are announced monthly. 

The significance of these trends to computing at NIH will be evolutionary 
rather than revolutionary. The need for a central NIH computer system will 
not disappear. Nor will every office and laboratory demand its own complement 
of number and word processing machinery and "intelligent terminals" linkable 
to a large computer. What will emerge is a more diverse information processing 
environment and a more sophisticated body of information processors (people) 
within NIH. 

The challenge to NIH and hence to DCRT a decade ago was to make computers 
available and reliable. This has been met. The challenge for the decade 
ahead is to help computing in its increasing variety become more effective and 
productive as part of the "information intensive" environment of NIH. To this 
end one can foresee increasing, not decreasing, interaction between DCRT exper- 
tise and scientific and administrative staff as well as with policy-making 
groups at NIH and elsewhere. 



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July 1, 1974 through June 30, 1975 

NATIONAL INSTITUTES OF HEALTH 
DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY 

1 . DCRT 

2. OFFICE OF SCIENTIFIC AND TECHNICAL 3. William C. Mohler 

COMMUNICATION Director 

This year DCRT established a new Office of Scientific and Technical 
Communications. The office formally brings together the DCRT Library and the 
Scientific and Technical Information Office and also is a locus of collabora- 
tive and research projects in information science and mathematics. 

One domain of the office is information about information processing. 
Its concern is the adequacy of information reaching NIH scientific staff about 
computers, about their applications to scientific and administrative problems 
and about the DCRT activities. Another domain is application of advanced in- 
formation science principles, including mathematics, to multidimensional infor- 
mation structures. 

The office is small as well as new. Its three areas are led by Judith 
Prewitt, mathematician and expert on image processing, Ruth Ketler, the DCRT 
Scientific and Technical Information Officer, and Ellen Chu, the DCRT Librarian. 
Two part-time staff members and two co-workers from the Data Management Branch 
constitute the rest of the group. The Chief of the office is the DCRT Associate 
Director in a dual position. 

The DCRT Library serves three functions. It is an integral working part 
of DCRT activities, a resource for the NIH staff, and an independent member of 
the network of special libraries in the Washington area. This is reflected in 
the 1974 circulation statistics. Some 60% of the books are borrowed by DCRT 
staff but over 60% of its more than 300 borrowers work outside of DCRT. 

To meet these needs the library added about 230 books, 100 technical 
reports and theses, and 25 new periodicals this year to its collection on com- 
puter science, mathematics, engineering and related topics. It also instituted 
a review of holdings and subscriptions to eliminate outdated and unused materials, 

As part of the library network, the DCRT library continued to include its 
catalog cards in the NIH Library catalog, to provide MEDLINE bibliographic 
services and to arrange for bibliographic searches through the NASA Scientific 
and Technical Information Facility and the Defense Document Center. 

During her first year as librarian, Mrs. Chu has made several changes to 
improve effective service and operating efficiency, based on her questionnaire 
survey of library users and on the advice of her ten member DCRT Library Com- 
mittee. For the coming year she ambitiously proposes: 1) a complete inventory 
of the collection, 2) an update of the catalog, shelf list and journal holdings 
list, 3) modifications to the automated circulation list, 4) improvements in 



the work area and library layout, 5) investigation of microform reading 
equipment, and 6) revision of the reference collection. She also plans fur- 
ther cooperative efforts with other local libraries. 



The Scientific and Technical Information Office began to enlarge its 
scope this year. It initiated new steps to analyze the needs of the NIH staff 
for information about computers, about their applications and about DCRT activ- 
ities. A questionnaire survey of some 500 NIH laboratory, branch and department 
chiefs and administrative officers disclosed a broad expression of interest in, 
or need for those three kinds of information. This response is indicative of 
the extent to which computing has generated application and interest in all 
parts of NIH. 

The new STI Officer, Mrs. Ketler, arrived in the midst of the DCRT prepa- 
rations for the Alumni Reunion, the Public Open House and the Bicentennial 
Exhibit. In conjunction with the Computer Systems Laboratory and other members 
of DCRT, she helped to implement an exhibit about computing at NIH incorpora- 
ting a slide show with sound track and a supplementary brochure. In addition 
to the exhibit DCRT presented five examples of computing via remote terminals 
to demonstrate the broad capability of human interactions with computers, by 
such means as graphic displays and audible responses including computer- 
generated speech. 






During the fall, the STIO assis 
preparation for a conference on Comp 
DCRT in conjunction with NHLI, The E 
American IEEE. 



ted the Computer Systems Laboratory in 
uters in Cardiology which was sponsored by 
uropean Congress of Cardiology and the 



As in previous years, the Scien 
answered many queries from both insi 
these requests were for technical re 
for information about computer appli 
a number of information reporting fu 



tific and Technical Information Office 
de and outside the NIH. The majority of 
ports, for specific software programs and 
cations. The office continued to handle 
nctions required by Federal regulations. 



In the coming year, the office plans both to better define the interests 
and needs expressed in this year's questionnaire survey and to develop a set 
of presentations to meet them. 

The work on multidimensional information structures has several dimensions. 



Mrs. Prewitt has been a leade 
divisions of the National Can 
techniques for diagnostic rad 
and analytic studies of subce 
types of neoplasms. On the N 
jects in data analysis with s 

Her active participation 
conferences. She was also an 
conferences, seminars, and wo 
These all related to her inte 
and effectiveness of both dia 



r as well as a collaborator in programs of three 
cer Institute. These include development of new 
iology, advances in automated clinical cytology, 
llular cell and tissue characteristics of several 
IH campus she has begun several collaborative pro- 
cientists in the National Heart and Lung Institute. 

in these programs entailed many site visits and 
invited speaker or participant at some two dozen 

rkshops in the United States, Europe and Japan. 

rests in development of rational bases for utility 

gnostic and therapeutic procedures. 



Summary of the Assistant Director 
July 1, 1974 through June 30, 1975 

The Office of the Assistant Director, DCRT, provides three basic capabilities: 

1. The Office serves NIH as the focus for coordination of ADP 
policy matters and thus also as a central point of NIH 
contact with PHS, the Office of the Secretary, other DHEW 
agencies, GSA and 0MB for NIH ADP policy questions and 
relative to NIH participation in the development thereof. 

2. The Office supports the Director of DCRT by providing a 
point of reference and coordination to insure that DCRT's 
own ADP activities are consistent with NIH, PHS, 0/S, 
GSA and 0MB policy directions, and 

3. The Office supports the Directors of DCRT and NIH by 
providing advice on ADP resource acquisition and allocation 
necessary for DCRT and NIH mission performance. 

During the year the role of the Office of the Assistant Director, DCRT, as 
the NIH-wide coordinator of ADP policy needs and its role as the central 
point of contact on ADP policy questions with PHS, OS, 0MB, GSA and other 
Federal Agencies was given added status by its formal recognition as the 
Office of ADP Policy Coordination. This change solidifies the role of the 
Director, DCRT, as the principal advisor to the Director of NIH on all ADP 
matters. This is also a first step in the implementation of the organiza- 
tional alignments recommended by the AMETA Study of 1973. 

A major continuing undertaking started during FY72 and continuing thereafter 
is the technical and management leadership in development of NIH's annual 
ADP Plan. This plan attempts to lay out a two year projection for ADP 
equipment, manpower and ADP support contracts for all components of NIH. 
This planning process creates an orderly opportunity for ADP users to take 
stock of their goals and accomplishments. The most recent annual plan 
covered NIH ADP efforts exceeding $34 million for FY75, $34 million for FY76 
and $38 million for FY77. Through extensive coordination with PHS and the 
Office of the Secretary, the office was able to integrate several GSA and 0MB 
reporting requirements into the NIH ADP planning process, thereby reducing 
the administrative burden which would otherwise be entailed in the current 
trend toward "overmanagement" of ADP. 

In serving as a central point of contact for NIH on ADP related matters with 
PHS, DHEW, GSA, 0MB, etc., a large number of NIH research and research support 
staff members are spared the agony of becoming expert in the many nuances of 
ADP related regulations. Since these regulations are generally written from 
a second generation business data processing point of view, a thorough 
understanding of their purpose and operation often allows beneficial 
interpretations of their application to the NIH research environment. 



10 



During FY75 the ever-increasing "overmanagement" of ADP by OMB and in 
particularly GSA, has resulted in the need for the Office of the Assistant 
Director, DCRT, to spend an ever-increasing percentage of available man- 
hours on the paper work associated with ADP procurements. Notwithstanding 
the increased burden of paper work, the office has been able to make 
technical contributions which have assisted the National Library of Medicine 
in making an orderly upgrade of the MEDLINE capabilities and assisted the 
Clinical Center in the installation of a new clinical chemistry system and 
in the selection of a total Hospital Information System. In addition, 
numerous small laboratory computer systems have either been installed or 
placed on order. In each case the office provided both advice and assistance 
with regard to procurement and policy considerations as well as technical 
advice. 



The NIH policy coordination role is exercised in part by review of all NIH 
proposals for contracts or procurement actions involving ADP equipment, 
services or programming which must all be cleared through this office prior 
to being executed. This provides a continuous opportunity to alert program 
or contract officials to opportunities to avoid duplications, reduce costs 
or, importantly, to avoid difficulties with higher echelons. 



*- 



With regard to the role of assisting the Director, DCRT, with technical 
coordination of internal DCRT operations, the office provided technical 
leadership with regard to two major physical plant undertakings initiated 
during FY75. The office coordinated an architectural and engineering study 
which will eventually result in the conversion of the second floor of 
Building 12 into space usable for computing equipment. This innovated 
approach to overcoming the natural limitations of the size of a building will, 
when brought to fruition, result in the novel but functionally effective 
concept of a twc-floor computer room. Secondly, during the year the office 
coordinated for Engineering Design Branch the ADP technical aspects of an 
entirely new building, 12B, which will allow for expansion of the computation- 
al functions of the Division. 






ii 



Serial No. Z01 CT 00001-04 DIR 

1. Office of the Director 

2. Medical Information Science 

3. Bethesda 



PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 



Automated Processing of Medical Language 

4.9 

A.W. Pratt, M.G. Pacak 

P. Graepel , G. Dunham, S. Harper, 
M. De Meyts-Graitson 



Project Title: 

Previous Serial Number: 

Principal Investigators: 

Other Investigators: 

Man Years: 

Total: 2.5 

Professional: 2.5 
Other: 

Project Description: 

Background: 

For the past several years, an effort has been underway to develop a 
linguistically-oriented system for automated processing of medical 
language, and the program for information storage and retrieval of 
pathology data. The system includes the acquisition of textual 
information, the interrogation of a medical dictionary (SN0P), a set 
of transformational morphosyntactic and morphosemantic rules which 
are required for the identification of the information content of the 
input messages. The system for automated indexing of pathology data 
became operational in 1971 and is going to be extended to other 
subfields of medicine. 

FY 74-75 Activities: 

Development of a procedure for automated morphosyntactic analysis of 
medical language. The program was written in RMAG and PL-1 and is 
fully operational . 

The model for the construction of a computer-oriented medical micro- 
glossary for cancers and the design of a semantic model for the 
interpretation of medical records are being tested. 

A program for automated encoding of French pathology data was developed 
and successfully tested. This program is compatible with the program 



12 



which was developed for the encoding of English pathology data which 
became operational in 1971. 

Preliminary design of lexical processor and manipulator for study, 

comparison and maintenance of medical lexical material. Feasibility 

trials for the implementation of the lexical processor indicate that 

NIH 370 system would serve as a base. 

A program was developed for the identification and transformation of 
terminal morphemes in medical French (M. Graitson) which became a 
part of the French medical encoder (see appendix). 

Analysis of a set of German language autopsy reports in preparation 
of an automated preprocessing method for medical German. Special 
attention was given to the problem of segmentation of compound words 
in German (Dr. Graepel). The preliminary results of the segmentation 
algorithm were used for the development of a statistical model for 
word segmentation by Dr. Mosimann and C. Clark. 

Future Efforts: 



L- 



Improvements of English and French encoders on the syntactic and 
semantic levels (development of paraphrasing rules, classification 
of semantic operators, etc.). 

Construction of computer-oriented microglossaries for tumors and 
cardiology. 

Application of statistical linguistics to medical data processing, 
and the construction of medical dictionaries. 



Publications: 

1. Pratt, A.W.: Medicine and Linguistics, MEDINFO 74 , North Holland 
Company (1974). 

2. Pratt, A.W.: Representation of Medical Language Data Utilizing 
The Systematized Nomenclature of Pathology, Proceedings of 
Symposium "Computers in Laboratory Medicine , Univ. of California, 
San Francisco, February 1975. 

3. Pratt, A.W.: Organizing the Medical Data for Pattern Generation, 
Proceedings of IRIA Medical Data Processing Symposium , Toulouse, 
France, March 3-5, 1975. 

4. Pratt, A.W.: Computer-Based Information System for the Research 
Environment, Proceedings of IRIA Medical Data Processing Symposium , 
Toulouse, France, March 3-5, 1975. 

5. Pacak, M.G.: Computational Linguistics and Information Handling, 
Management of Information Handling System , ed. P.W. Howe r ton, 
Hayden Book Co., New Rochelle Park, N.Y., 1974; pp. 19-47. 



1 

1 

1 

1 

1 


o 

73 
CO 











13 



July 1, 1971* thru June 30, 1975 



PUBLIC HEALTH SERVICE-NATIONAL INSTITUTES OF HEALTH 
DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY 



1. DCRT-2 



2. COMPUTER CENTER BRANCH 



Serial Number 

3. J. D. Naughton 
Branch Chief 



MISSION 

The Computer Center Branch design 
large general-purpose computer u 
the dynamic and diverse requlreme 
investigators and managers In 
This charge includes the origlna 
facilities to meet the unique req 
order to bring the full powe 
problems at every level of blomed 
locations. The core of this c 
computers and remotely located te 
modern communications network, ex 
directly into research laborato 
throughout N.I.I!. This provld 
computer thus minimizing delay 
making more efflcent use of 
traditional methods. An Inherent 
Center Is the continued research 
to extend the network even furthe 
wh i 1 e continually adapting to 
knowledge and program direction. 



s, Implements and operates a 
tlllty to meet most effectively 
nts of both N.I.H. research 
the support of modern medicine. 
1 development of new system 
uirements of the NIH mission in 
r of the computer to bear on 
ical research in many remote 
omputer utility is a network of 
rmlnals, which, by means of a 
tends the power of the computer 
rles and administrative offices 
es immediate access to the 
s In the research program and 
critical manpower than more 
responsibility of the Computer 
and development of new methods 
r Into the research environment 
the constant Impact of new 



A full spectrum of computational services is provided to all 
Institutes and Divisions of the NIH on a fee-for-serv Ice (cost 
recovery) basis. These facilities include conversational 
programming, graphics, microfilm output, text editing, remote 
job entry, time sharing, data base management and batch 
processing. Large systems as well as mln I -computers and 
terminals are tied together providing a "distributed capacity" 
available at many levels. Research Into the computer and 
Information sciences coupled with close cooperation between the 
N.I.H. medical investigators and the computer scientist have 
introduced computers directly into the research environment 
where they can perform most effectively In attacking the complex 
problems of medical research. 



14 



The medical res 
powerful and f 
today. The comp 
power that Is ea 
laboratory itsel 
enhance the comp 
and its admi 
appl icat ions are 
comprehensive t 
of the latest 
effectively mee 
1 aborator ies . 

1974 ACTIVITIES 



earch programs of N.I.H, require the most 
lexible of computer services and tools available 
uter network provided must have a distributive 
sily accessible when needed to scientists in the 
f. The goal is to mold, polish and, In general, 
uter into a complete tool for medical research 
nistrative support. New areas of computer 

sought out continuously in conjunction with a 
raining program to inform research investigators 

methods in the use of computers to most 
t the unique requirements of their individual 



In sp 

count 

annou 

NIH c 

proce 

addit 

for 

Incre 

mod ? f 

syste 

throu 

costs 



ite of a ge 
ry, the N 
ncement of 
omputer use 
ssed on b 
Ion, the Nl 
all work p 
ased workl 
icat ions t 
n performa 
shout the y 



nera 

IH 

the 

rs . 

oth 

ght 

roce 

oad, 

o t 

nee, 

ear 



1 upwar 

Compute 

mo s t si 

Rates 

the IBM 

Serv ice 

ssed be 

large 

he ope 

comb i 

in spit 



ds spi ral 

r Center 

gn i f leant 

we re re 

System 3 

discount 

tween the 

r comput 

rating s 

ned to 

e of cont 



ing 

be 

rat 

duce 

70 a 

rat 

hou 

er 

yste 
ma in 
Inua 



of cost 
gan th 
e reduc 
d 22,8 
nd the 
e was I 
rs of 6 
systems 
m resu 
tain t 
1 1 y Inc 



s throug 
e year 
tion eve 
% for 
DECsyste 
ncreased 
p.m. a 
and 
1 1 ing in 
he 1 owe 
reas ing 



hout the 

with the 

r offered 

all work 

m-10. In 

to 25?; 

nd 8 a.m. 

Internal 

improved 

r rates 

operat Ing 



As the effects of the manpower shortage continued to become even 
more acute throughout NIH, many areas turned to "automation" as 
a means of compensating for decreased manpower without 
curtailing programs. Existing computer programs were modified 
or extended to accommodate new applications and entirely new 
programs were designed and implemented specifically to automate 
procedures that had previously been done by hand. As a result, 
the demand for computer services from the Center continued to 
increase dramatically throughout the year. Total workload 
increased 25% to 205,000 jobs/sessions processed per month. 
Interactive terminal systems provided service to 3000 sessions 
dally and the number of on-line disk datasets increased to 
80,000 wh i 1 e the printers produced over 150 million lines of 
printed output per month. NIH is undoubtedly the most 
"automated" Agency of the Federal Government. 

Two new processing services, "discount" and "quick" were 
introduced this year. These services were designed to encourage 
the shifting of workload from the peak load period during the 
daylight hours to overnight service. Users electing to use the 
discount service have their jobs automatically held until after 



W 1 




in 



15 



b p.m. when the job is run at a 25% rate reduction. This has a 
double effect in that it also improves turnaround time for all 
daylight work and reduces the user's cost for computing 
services. Quick service, on the other hand, provides a 
facility to insure fast turnaround for users who choose to work 
at night. Throug!, the quick service, jobs submitted during 
evening hours are run ahead of the large overnight production 
runs, thereby eliminating the long waits and making the user's 
time much more productive. Quick service also receives the 
night-time discount. 

Because of the increasing national concern for personal privacy 
and the security of information stored and used in computers, 
the Computer Center designed and implemented a number of 
security improvements for the NIH Computer Utility. Most 
significant of these was the development of an automatic data 
encoding (scrambling) facility which is usable In all languages 
and from all systems supported by the Center. This facility 
permits a user to easily encode sensitive data In such a way 
that even the Computer Center could not decipher it. In 
addition, "keyword" protection became mandatory for both batch 
processing work and Interactive terminal sessions while access 
to registered initials and account numbers was restricted. 
Additional facilities to further Insure the confidentiality of 
sensitive data and the physical security of the Computer Center 
itself were designed and implementation was begun. 

Many new or improved software services were introduced this 
year. The Integrated Plotting Package provides the user with a 
mechanism to generate intermediate text which will be processed, 
possibly after storage on an external file, by a variety of 
different plotting devices. 

The Extended Printing Facility which provides a convenient means 
of printing mathematical expressions containing superscripts and 
subscripts as well as greek letters was Improved to provide 
additional function and convenience for the user. 

This year saw many improvements for TSO users, especially in the 
area of performance. After a slow start, internal systems 
software and hardv/are modifications brought TSO response up to 
an acceptable level. A new function gave users the ability to 
monitor CPU time used during a TSO session. With this facility 
users had more control over their terminal environment and 
"runaway" TSO programs became a thing of the past. 

Many additional internal system changes were made that were 
transparent to the user, except that the changes increased the 
efficiency and reliability of the system and therefore either 
improved turnaround time or kept it from increasing as the 



16 



workload grew. The disk accounting system was modified to 
improve internal performance and provide more effective dataset 
recovery facilities. As the size of the tape library increased 
to over 27,000 reels, an automatic tape inventory and 
registration was implemented. In addition to insuring more 
accurate handling of tapes and reducing the manual burden for 
machine operators, this facility consolidated the "Tape Listing" 
and "Dataset Listing" into one convenient report for users. 



The 

and 

illu 

faci 

pack 

HASP 

j;ove 

The 

cont 

Mult 

Spoo 



usefulness a 
improvement 
strated by 
1 i t ies throu 
ages such as 
, OCR, COM 
rnments, aca 
superior! ty 
rol 1 ing mul 
iple Access 
1 System. 



nd pop 
s des 
numero 
ghout 

SHARE 
etc. 
demi c 
of the 
tlple 
Spool , 



ular i ty o 

igned by 

us reques 

the world 

D SPOOL, 

have been 

inst i tut i 

Shared S 

CPUs wa 

wh I ch is 



f many 

the 
ts for 

Over 
V/YLBUR, 

di str i 
ons and 
pool pa 
s illu 

the i r 



of the so 

NIH Comput 

copies rece 

150 copie 

DATASET Ml 

buted to fe 

commerc i al 

ckage over 

strated whe 

version of 



f tware 
er Ce 
ived f 
s of 
GRATIO 
deral 

organ 
other 
n IBM 
the HI 



systems 
nter was 
rom other 

sof tware 
H, SPOUT, 
and state 
i zat ions . 

ways of 
announced 
H Shared 



The DECsystem-10 was expanded to meet the demands of the 
workload which increased throughout the year. April 1, 1974 saw 
the addition of a second K I -10 CPU as a slave processor. The 
dual master-slave Kl processors have provided the increased 
capacity needed to maintain excellent time-sharing services as 
well as CPU redundancy assuring continued service in case of 
failure of one processor. 

The rapidly accelerating use of this system for time-sharing, 
laboratory-oriented programs, graphics problems required a 
continuous enhancement of both the software and hardware of the 
DECsystem-10. Plans were developed to provide additional 
on-line disk storage capacity and improved magnetic tape drives 
for this system next year. 

Selection of the NIH Computer Center as one of two test sites 
for advanced monitor software paid dividends in terms of 
increased system reliability and early availability of new 
features, e.g., virtual memory. 

The telephone line capacity of the DECsystem-10 was increased to 
41 lines thus reducing the frequency of busy signals experienced 
by users. In addition, this year saw the introduction of 
support for 2741 terminal users by single-digit dialing on the 
NIH dataswitch. 





DRG 





V 

I 






, o 




73 


11 


00 


li 


I 


V 


l 



A very stable version of the SAIL programming 
Introduced and generated very few problems, 
compiler with excellent optimization was added 



language was 

A new Fortran 

to decrease 



17 



running time for compute-bound programs. The double-precision 
hardware features of the KI -10 processor further helped decrease 
execution times. 

Dataset controls were added to improve the computer's handling 
of dial-In telephone lines. With the dataset controls, the 
computer detects when a telephone connection has been broken and 
suspends or detaches the session. The line is then 
re- in It ial Ized and freed for the next caller. 



Omnigraph, the graphics system on 
extended and Improved both to achle 
of the entire computer system ' 
facilities. The Ornnigraph system 
executable code of large Omnlgrap 
shared among many users. This has 
much as 150K core at a time, I 
added to facilitate the use of vert 
the DEC3U0 display. Support 
Fortran-10, was also implemented. 



the DECsystem-10, has been 
ve more efficient utilization 
and to provide more flexible 
was modified to allow the 
h programs such as MLAB to be 
resulted In a saving of as 
n addition, new routines were 
leal text and raster mode on 
for the new PEC Fortran, 



TXTCOM 

DECsys 

normal 

letter 

files 

even 

proced 

comma n 

operat 

transp 

370. 



, an 

tem-1 

ly av 

Ing 

betwe 

eas le 

ures, 

d fl 

ional 

ortat 



additional ml 
users. Th 
a I lable, glan 
across the 
en the DECsys 
r by the d 

which are 

les and the 

procedure wa 

ion of tapes 



crof iche 
Is packag 
t letterl 
top of t 
tem-10 an 
evelopmen 

used wl 

EBCDIC 

s impleme 

between 



package, wa 
e provides 
ng of file 
he fiche. 
d the IBM37 
t of seve 
th corresp 

program, 
nted to a I 
the DECsyst 



s made available to 
ASCII characters not 
titles and Index 
The transfer of data 
System was made 
ral 370 catalogued 
onding DECsystem-10 
In addition, a new 
d in the physical 
em-10 and the System 



Changes in both the System 370 and the DECsystem-10 
significant revisions to Computer Center technical doc 
to update and describe new standards and facili 
Computer Center Users Guide was updated while new edit 
issued for the NIH TSO Command Reference Manual and 
Reference Manual . Documentation revised during 
included: the CPS Basic Primer . RHB Routines , the p_E 
Timesharing Guide and DECsvstem-10 Pisnlav Systems Ma 
addition, the MLAB Manual was revised, and thre 
manuals were published. 



requi red 
umentat ion 
ties. The 
ions were 
the V/YLBUR 
the year 
Csvstem-10 
nual . In 
e new RMAG 



The Technical Information Office was kept busy distributing 
these new manuals as well as those provided by vendors. 
Altogether, 35,6U6 pieces of documentation were distributed to 
users of the NIH Computer Center during the year. Most 
distributions v/ere done through the Automatic Documentation 
Service which served the needs of 2,606 customers whose 



18 



Individual 
off ice. 



documentation profiles are kept on-line by the 



The PAL unit, the interface between our users and the Computer 
Center, continued to provide aid and assistance to the U500 
registered users of the Center. Individual assistance to users, 
on specific problems, was given over the counter, by telephone 
(In numbers too numerous to count) and by written responses to 
2000 Program Trouble Reports (PTRs). A new PTR facility was 
developed called the "Remote PTR". This facility allows a user 
to submit a .Programmer Trouble Report by using the TSO 
interactive terminal system. This aid was developed to help In 
problem determination for remotely located users who need help 
but do not have convenient access to the PAL Unit facilities, 
and whose problem cannot be solved through telephone 
conversation. 3etween calls the PAL Unit wrote over 100 pages 
of technical Information to users thru the "Diagnostics, Bugs, & 
Hints" section of INTERFACE, developed a new version of PALTAPE, 
contributed to numerous system reconfigurations and applied over 
U58 major fixes to the vendor supplied software to Improve the 
reliability and efficiency of the Computer Utility. These 
changes were made with minimal effect on the user community. 

The training activities of the Computer Center were In great 
demand In 197^. Forty-three different courses and seminars were 
given covering general purpose programming languages, operating 
systems, terminal systems, and special facilities and 
programming aids, etc. Over 2000 requests to train people to 
use both the System 370 and the DECsystem-10 were received this 
year. Although 82% of all requests for training were 
accommodated, it was, unfortunately, necessary to reject 36U 
applicants due to lack of staff. 

The requests for the elementary training courses were 
particularly strong as more and more MIH researchers, 
administrators and clerical employees discovered the usefulness 
of the computer in their daily work. It was necessary to teach 
eight complete sessions of the two week "Introduction to WYLBUR 
for Administrative and Secretarial Personnel" course this spring 
and summer in order to satisfy the requests made during the 
spring of 197U. Even so, the number of requests received for 
this course is still far greater than we can satisfy. 

INTERFACE, the Computer Center's vehicle of communication with 
the users, was published 8 times during the year, an increase of 
one from the previous year. 307 pages of documentation on all 
phases of computing were distributed In these issues. 

To give complete coverage to all facets of computing a 
Diagnostics, Bugs, S Hints section for the DECsystem-10 was 






19 



added to INTERFACE this year. This, along with the regular 
Diagnostics, Bugs, & Hints section, provides the users with the 
detailed technical information necessary to process work using 
hoth systems. IT.3 Compleat Computor and the Programming Methods 
sections appeared regularly covering timely topics. The third 
Annual Index through 1974 was the last issue of INTERFACE to be 
published in calendar year 1974. 



Since over 955 of all work processed 
is received via the teleprocessing n 
facilities of the system were improve 
from Model 2703 teleprocessing units 
Model 3705 teleprocessing unit was co 
permitted the addition of more lines 
the announcement of new teleproce 
v;ith the displaced units. Autospeed 
and teletype terminals to use the sa 
varying speeds up to 300 baud. The 
provide additional lines for WYLBUR a 
provide 1200 baud service. Over 850 
use with the '! I H Computer Utillt 
accessible to the system was Increas 
the work load. The expansion of 
number of daily interactive sessions 
the number of simultaneous users were 
reached 239 simultaneous sessions and 



by the NIH Computer Center 
etwork, the communication 
d considerably. Conversion 

to the newer more powerful 
mpleted. These new units 
but more importantly led to 
sslng services not possible 
came first, allowing 2741" s 
me communication port at 
data switch was expanded to 
nd TSO users and also to 
terminals are available for 
y and the number of lines 
ed to over 300 to handle 

lines was timely since the 

passed 3000. New highs for 

established when WYLBUR 

TSO hit 38. 



The major ha 
370/165 and 
pov/er was 
felt as turn 
by the Cente 
necess I tated 
al so an in 
and three 15 
system. Th 
met by conve 
The 3330 uni 
older 2314 
faster. The 
In early 1 
datasets was 
the completl 
space shoul 
continues to 
current acti 



rdware change of the 
a 360/65 by a 370/16 
instal led beh Ind s 
around time returned 
r and its users. Th 

not only an Increas 
crease in periphera 
00 1 I nes per minute 
e need for addltlona 
rting the Model 2311* 
ts have from two to 

units and transfe 

3330 conversion sta 
975. The transfer 

accomplished with n 
on of the disk conve 
d be over. Rata 

Insure that disk s 
ve projects. 



year was the replacement of a 
8-MP. This increase in computer 
chedule, but its impact was soon 

to the limits normally expected 
e continual increase in workload 
e In computational power but 
Is as twenty-two new tape drives 
printers were added to the 
1 on-line disk storage space v/as 

disk units to Model 3330 units, 
four times the capacity of the 
r data two and one-half times 
rted in July and was completed 
of over sixty thousand on-line 
o Interruption in service. With 
rslon, the shortage of on-line 

migration of inactive data sets 
pace is always available for 



Directly addressable memory on the 370/145 was doubled to two 
million bytes. The additional memory will enable more thorough 
testing of the large software systems to be done Independently 
of the main CPU's in the system. 



20 



As the use of microfiche as a computer output medium Increased 
to over 5.7 million images per month, a second COM unit was 
added to the system. The ease of use of the system, the 
reduction of bulk and an Interest In saving paper all contribute 
to the constantly growing popularity of microfiche. 



Year end saw the last major hardware 
availability and support of high speed CRT 
users of the NIH Computer Utility. Opera 
a second, the CRT's will provide users wit 
four times faster than previously availabl 
functional capability, the new CRT's 
(more efficient use of lines), and better 
capabilities. Using an attached hardcopy 
will be able to receive more printed out 
The CRT is usable with all systems support 
both the System 370 and the PECsyste 
little difficulty using the CRT with 
designing new programs specifically ori 
input/output device. 



announcement, the 
display terminals for 
ting at 120 characters 
h transmission speeds 
e. In addition to new 
offer shorter sessions 
data entry and editing 
printer remote users 
put at their location, 
ed by the Center on 
m-10. Users will have 
existing programs or 
ented to the CRT as an 



As the year came to a close, a Request for Proposals (RFP) for a 
major equipment upgrade to the MIH Computer Utility to provide 
additional capacity to meet the projected workload over the next 
three years was written and forwarded to GSA for appropriate 
action. 

1976 Plans 

In order to provide effective computational support to meet the 
constantly changing and diverse requirements of the MIH 
biomedical research activities, the Computer Center maintains a 
continual program of expansion and development. In addition to 
a significant increase in computational capacity to support 
existing programs, the Computer Center plans to implement a 
number of new computational facilities and services In support 
of new research and administrative programs during the coming 
year. 

To accommodate the increasing demand for service In a responsive 
manner, the processing power of both the IBM system 370 and the 
DECsystem-10 will be Increased significantly. 

Procurement actions, begun last year, should result in the 
exchange of a presently installed IBM 370/165 with an IBM 
370/168-MP central processing unit. This will represent an 
increase of approximately 28% In raw processing power as well as 
provide the capability for operation under the newer Virtual 
Operating System. This change will also Include a corresponding 
increase in peripheral devices. Additional disk drives will 



!L-J 



21 



provide more on-line storage capacity for data and programs; new 
communication facilities will allow Interactive access to the 
system using high speed (120 characters per second) CRT 
terminals; additional fixed-head-storage devices will be 
Installed to Improve system performance and efficiency; and high 
speed tape drives will allow faster tape processing. 



During the same period, the D 
more significant Increase in 
the present processors In th ! 
and more sophisticated KL-10 
processor power as well as t 
multiprocessor operations; a 
will provide for automatic on 
System 370; new disk drlv 
on-1 ine data storage capa 
communication facilities wil 
remote timesharing users; and 
drives will Improve rellablll 
dependable facility for trans 
System 370. 



ECsystem-10 wll 1 
computational c 
s system will be 

units providing 
he abi 1 I ty for 
direct communlca 
-1 ine data trans 
es will provide 
city; new 12 
1 provide more e 

replacement of 
ty significantly 
fering large vol 



exper le 
apaci ty . 

replace 

a 200% 
dl rect 
tlons 11 
fer to a 

double 
00 bau 
f feet Ive 
the exl 

and wll 
umes of 



nee an even 
Both of 
d by faster 
Increase In 
ly coupled 
nk (PDP-11) 
nd from the 
the present 
d d lal-up 
access for 
sting tape 
1 provide a 
data to the 



The present graphics display equipment (AGT 30 & DEC 3U0) will 
be replaced by a more modern surface display unlt(s) to 
facilitate molecular structure research and biomedical image 
process ing. 

A standard Interface will be designed and built to permit the 
interconnection of laboratory computers to the central 
DECsystem-10 without requiring "special" softv/are to accommodate 
the differences between various manufacturers' equ Ipment . 



A new higher resolution Incremental 
installed this year to replace the pre 
addition to providing finer plotting 
twice as fast as present equipmen 
reliable. This should result In redu 
plotter users as well as Improved 
productivity of the operator. Proc 
new higher speed Interactive hardc 
Interactive terminals, terminal plo 
scramblers, and batch RJE terminals 
Issued this year. 



digital plot 
sent obsolete 
increments th 
t and const 
ced turnarou 
accuracy a 
urement actio 
opy terminal 
tter, commun 
for computer 



ter will be 
plotter. In 
e new unit Is 
derably more 
nd time for 
nd Increased 
ns to provide 
s, portable 
Icat ion 1 Ine 
users will be 



To accommodate the planned hardware conversion, major 
modifications to the physical plant will be initiated but will 
not be completed for several years. Although a long range 
architectural plan has been completed for a total renovation of 
the second floor of building 12 to provide sufficient 
environmental support facilities (power, air conditioning, 



22 



water) to house both major computer systems, only phase 1 will 
be completed during this year. This phase will provide only 
temporary facilities to house a small number of disk drives. A 
roof-top "penthouse" will be partially completed to provide 
additional chilled water and electrical generators required for 
the immediate hardware expansion planned for this year. The 
administrative processes necessary for scheduling and 
Implementation of the overall renovation plan will be Initiated 
this year. 

Flew software facilities and services planned for this year will 
have an even greater Impact on the effective use of the computer 
In support of the f!lH mission. 



A completely new version o 
development for the past two 
year. The new WYLBUR will p 
designed specifically to meet 
research and administrative p 
facility will allow appllcati 
document preparation feat 
preparation of research manus 
documents and reports. Mu 
evaluator, more flexible file 
new facilities will make NEW 
computational services avalla 



f WYLBUR, which has been under 

years, will become operational this 

rovlde a multitude of new functions 

the unique requirements of the MIH 

rograms. Its new macro processing 

ons not previously possible and the 

ures will permit more effective 

crlpts as well as administrative 

ltlple active files, an expression 

searching features, and many other 

WYLBUR one of the most usable 

ble anywhere. 



A 






A newly designed MILTEN, a communication line handler, will 
provide software support for high speed interactive CRT terminal 
access to the system for the first time. In addition to 
providing forms entry, block text editing, multiple type fonts, 
and character sets, and communications across virtual address 
spaces HEW MILTEN can accommodate thousands of simultaneous 
terminal users and at the same time simplify operator 
Interaction. 



. 



The most complex software conversl 
the Computer Center, conversion 
3.1 to 0S/VS2, Release 3, JES2, wi 
and is scheduled to be completed 1 
new "Virtual" operating system wll 
developed/processed without the de 
segmenting or overlaying progra 
and reliability will facilitate a 
fewer interruptions due to soft 
translation will permit more efflc 
resources as well as more effectlv 
the basis of application requireme 



on effort ever undertaken by 
from OS/MVT, Release 21,6 HASP 
11 be started during this year 
8 to 2** months later. This 
1 permit larger programs to be 
lay and overhead introduced by 
ms. Improved system Integrity 
more dependable service with 
ware failure. Dynamic address 
lent use of critical system 
e manipulation of user data on 
nts. 



It is anticipated that the Computer Center will offer the 
service of a data base management system, IMS (Information 



23 



Management Sy 
capabi 1 I ty wi 
transact ion-o 
Independent, 
developed an 
technical 1 1 ie 
message swft 
checkpoint/re 
fntegrity an 
elaborate c 
protection a 
modification 
only on a res 



stem) for the first time t 
11 prov'de fllH with the abll I 
rlented applications using 
data flies. Conversational 
d maintained Independent of 
s, Input/output traffic, and 
ching. IMS also provides au 
start facilities to provid 
d minimum "out-of-serv Ice 
ontrol mechanisms provide 
gainst unauthorized access 

of the data base. This sy 
trlcted basis during fiscal y 



his year. This new 
ty to develop multiple 
large centralized, but 

applications may be 
terminal /communlcat Ion 
terminal and program 
tomatlc journal Ing and 
e maximum data base 
11 time. Extremely 
the maximum possible 

to the system or 
stem will be available 
ear 1976. 



During the coming year a new version of 
will be installed on the PECsystem-1 
for users as well as improved internal 
reliability. This new software ope 
provide a facility for interprocess 
result In more effective scheduling and 
system. A more flexible software inter 
dynamic switching among tasks and 
support will permit both the servic 
simultaneous users and the development 
programs. 



the timesharing monitor 
to provide new function 

system performance and 
rating environment will 
communications which will 

control of the entire 
rupt facility will permit 
expanded virtual memory 
ing of a larger number of 

of larger applications 



Because of the 
software for 
be necessary 
documentat ion 
documents are 
users* manual 
will be publ is 
Time Sharing 
will be comp 
addition, the 
updated to ref 
OMNI GRAPH syst 
COM, OCR, CPS, 
Language wi 1 1 
virtual operat 
final ized. 



plans for major changes in both 
both the System 370 and the DECsyste 
to completely rewrite almost al 
published by the Computer Center. F 

planned for HEW WYLBUR/MI LTEN and 
describing the use of the MIH5200 

hed this year, A completely new 
Guide for the DECsystem-10 has been 

leted and available to users th I 
DECsystem-10 Display Systems man 

lect the incorporation of new displa 

em. Technical documentation for TSO, 

HASP (SHARED SPOOL), etc., as well a 

be extensively re-written to re 

ing environment, and an IMS Users Gu 



hardware and 
m-10, It will 
1 technical 
I ve major new 
an extensive 

CRT terminal 
comprehens I ve 

outl lned and 
s year. In 
ual will be 
ys Into the 

SPOUT, CICS, 
s Job Control 
fleet the new 
Ide will be 



All on-going activities including support activities, problem 
consulting, documentation distribution, and training will 
continue at an increased pace. The task of fine tuning the MIH 
Computer Utility to keep It responsive to the changing needs of 
the FIIH, and the investigation of new computational techniques 
must continue so that the Utility can best support the NIH 
mission. 



24 



July 1, 1974 thru June 30, 1975 
PUBLIC HEALTH SERVICE - NATIONAL INSTITUTES OF HEALTH 
DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY 



Summary of Branch Activities 
2. COMPUTER SYSTEMS LABORATORY 



1 . DCRT 

3. Alan M. Demmerle 
Chief 



INTRODUCTION 

The primary mission of the Computer Systems Laboratory (CSL) is to identify 
problem areas in biomedical research and clinical care in which the computer 
offers a potential for improved research productivity or improved health care. 
The concentration of work is on applications where real-time data collection, 
analysis, display, and experiment control are required, where economic con- 
siderations favor a small computer or where equipment proximity is important. 

The staff of CSL has, in addition to expertise in both the engineering and 
programming aspects of laboratory computing and automation, extensive experi- 
ence in working on problems in the biomedical area. Many of the laboratory's 
projects require a coordinated effort between engineers and computer scien- 
tists from CSL and researchers from other Divisions and Institutes. 

I. COMPUTER SUPPORT FOR AUTOMATION OF LABORATORY EXPERIMENTATION 

CSL is engaged in a number of projects supporting research in the physical 
sciences. The primary goal of this support is automation of the collection, 
processing and display of laboratory data. Achievement of this goal has, 
generally, involved the design, and implementation of a number of computer 
systems of varying sizes. The larger systems, usually, serve a number of 
users simultaneously and require several years of effort to attain full 
operational status. An example of such a system is the NIAMDD System which 
serves several NIAMDD Laboratories, permitting a number of experiments 
to be processed simultaneously. Smaller laboratory systems are usually 
dedicated to a single user at a time, and can usually be implemented in less 
time. The NMR System in NIAMDD, which is used for Fourier Transform Spectros- 
copy calculation, is typical of this class of system, as is the NIAID System 
which is used with experimentation concerning the structure of immunologically 
important proteins. 

During the past year, the CSL engineering staff has been involved in various 
phases of the implementation of 10 systems aimed at automating laboratory 
experiments. The capabilities of the NIAMDD System , mentioned abcve, have 
been expanded to include processing of data from an EPR Spectrometer and 
McPherson Spectrophotometer. A system for the Laboratory of Vision Research 
(NEI) which was started the previous year has been made operational during 
this past year. Analog voltage data relating to the photo transduction 
process in the retina are collected and processed and analyzed data are 
displayed. Further work has proceeded on automation of a Flourescence 



,- 



I .... 






25 



Activated Cell Separator for NCI. This system was also started in the 
preceding fiscal year. A computer for this system has now been procured and 
the utility programs written to allow it to use the DCRT PDP-10 interactively 
for data storage and complex mathematical analysis. Interfacing to the cell 
sorting instrument has begun. A second system for NEX was started. This 
system is to be used for two different studies. The first is a study aimed 
at understanding the normal and pathophysiological mechanism for the control 
and production of eye movements. Normal volunteers as well as patients with 
all forms of disturbance of eye movement will be studied with mechanized 
visual stimulation equipment. Eye movements over a range of 0-45 degrees 
will be analyzed in detail. The second use involves analysis of data 
concerning pupil movement. 

The Hybrid Computer , purchased about 10 years ago as a general utility for 
the NIH research community, is now being used primarily on NHLI research 
projects. This system and its supporting staff occupy 5 modules of Building 
10. The demand for this space has become so acute that the system will be 
replaced with newer and more compact equipment, thereby making available 3 
of the 5 modules for other purposes. Elements of the new system have been 
ordered and will be made operational before the old system is dismantled 
and removed during the coming fiscal year. The new system is to provide a 
comparable facility for general purpose data acquisition, A/D conversion , 
plotting and display . 

II. CLINICAL CARE & RESEARCH 

CSL has, for the last several years, become increasingly involved in the 
support of several clinical care and research functions at the NIH. This 
has occurred because of an increased understanding and awareness by clinicians 
of the potential of computers and automation, and also because of advances in 
medical instrumentation and techniques which have led to the generation of 
voluminous amounts of data that must be analyzed and examined prior to use 
in patient diagnosis and treatment. 

The role of the computer in the clinical environment is still evolving. 
Currently, it performs functions that cannot be accomplished by manual means, 
provides the physician with a valuable tool in decision making and promotes 
direct patient care activities by relieving highly trained medical personnel 
of routine clerical functions. The technical requirements in this environment 
include the acquisition, storage, analysis and display of clinical data . For 
the most part, these functions are performed on-line and in real-time. All 
require extensive cooperation among engineers, computer scientists, programmers 
and medical personnel. 

THE NHLI INTENSIVE CARE UNIT 

This project provides for the continuous monitoring of patients in the heart 
surgery recovery area in order to provide the earliest possible detection of 
abnormal or dangerous conditions. For the past two years, the ICU System has 
collected and analyzed ECG, temperature, fluid loss, arterial pressure and 
venous pressure data from a single patient. During the past year this 
capability has been extended so that these same functions can be provided 

26 



simultaneously for four patients. This extension has required the opti- 
mization of the processing of the ECG and pressure wave forms. Much of the 
analysis of these signals is now done external to the computer using special 
purpose hardware developed here over the past several years. Further develop- 
ment of these techniques using the new microprocessor technology is now 
underway. These preprocessors will be used on a number of projects. An ECG 
preprocessor implemented with a microcomputer , for instance, will be used in 
the ICU System and also in conjunction with an NHLI project that requires the 
analysis of PVC's obtained from ambulatory patient electrocardiograms. 

NUCLEAR MEDICINE DEPARTMENT 

CSL has continued to contribute engineering expertise to a joint project with 
LAS, DCRT and the Clinical Center's Nuclear Medicine Department. We have 
worked toward more fully developing the potential of a computer system which 
has been operational for several years and an additional system which was 
acquired this year. The accomplishments of this project are described in 
the LAS report. 

PHONOCARDIOGRAM RESEARCH 

For the past three years, CSL has collaborated with the Surgical Branch of 
NHLI in the development of methods by which characteristics of the phonocardio- 
gram can be used as diagnostic indices of prosthetic heart valve performance. 
We are searching for a reliable, easy to apply, non-invasive indicator. For 
more than one year now, phonocardiograms have been routinely taken on about 
six patients per week and analyzed on the hybrid computer. The analysis 
involves beat-to-beat correlation of heart sounds , a determination of the 
ratio of the amplitude of the opening sound to that of the closing sound and 
sound spectrographs analysis. Current indications are that the correlation 
technique offers no significant improvement, as a diagnostic indicator, over 
the opening to closing sound ratios, particularly for the SE1000 series 
values. Attention is now being directed to the 1200 series values, for which 
much less data is currently available. Partly as a result of this project, 
it became clear that a computerized retrieval system for the patient data 
collected in the Surgery Branch of NHLI was needed. The data base includes 
demographic data, laboratory tests, surgical notes, autopsy report data, 
catheterization data and phonocardiogram data on all patients. The develop- 
ment of this information retrieval system began this fiscal year. 

CATHETERIZATION LABORATORY SYSTEM 



An extensive dual goal project was started this year with the Catheterization 
Laboratory of NHLI. The first goal envisions on-line computer support in the 
acquisition and processing of data acquired during catheterization procedures. 
Electrocardiogram data, several blood pressures, dye concentration measure- 
ments, thermal dilution cardiac output signals, phonocardiograms, HIS bundle 
electrograms, and possibly other physiologic parameters are to be processed. 
CSL, after exploring several alternative methods of implementation recommended 
that an existing commercial system be procured and modified to meet specific 
NHLI requirements. That purchase, however, was not made this year. 

The second goal of this project is to organize the medical data associated 
with the NIH patients who have been catheterized, into a computer-based data 

27 



management system that can readily provide answers to complex research oriented 
queries. Very considerable emphasis is attached to the problem of developing 
techniques that will promote simple flexible data retrieval capable of being 
initiated and operated by the scientific user. As such techniques are perfected, 
it is planned to integrate them into other projects using similar data bases. 
An example of this projected transfer is provided by an on-going project with 
the Microbiology Service of the Clinical Center's Clinical Pathology Department. 
That Service is, among other things, (1) actively studying methods of organism 
identification, (2) developing resistance patterns of organisms to antibiotics, 
and (3) attempting to trace the existence and source of hospital infections. 
This effort has been greatly facilitated by a retrieval system, utilizing GNR 
data and antibiotic sensitivity data , that has been implemented by CSL during 
the past year. Although operational, however, the complexity of system use 
is such that CSL rather than the Microbiology Service remains responsible for 
operation. 

III. OTHER COMPUTER SUPPORT PROJECTS 

Two projects were started this year which are neither exclusively for labora- 
tory nor clinical support. The NIEHS in the Research Triangle, North Carolina 
has, during the past few years, developed an increased need for computer 
support beyond that available to them from a keyboard terminal connected to 
a computer utility. Their four basic requirements are: 1) a high speed data 
entry facility to a remote computer utility, 2) a high speed printing and 
graphic output facility from a remote computer utility, 3) a capability for 
elementary processing of data produced by laboratory instruments such as 
spectrometers which produce data in a form and on a medium suitable for 
computer processing, and, 4) the collection, processing and retrieval of 
data relating to their animal colony. Analysis of these requirements led to 
the purchase, this year, of computer equipment capable of satisfying their 
first three requirements. Work has not begun on the fourth requirement. Also 
started this year is a computer system for the NIH Library that is designed 
to automate the collection and maintenance of daily transaction information 
(charging, discharging, reserving and reviewing library materials). The 
system is based on a computer to be located in the library along with optical 
scanning devices, a CRT terminal and other specialized input devices. Every 
day or so, the data collected on the library computer will be transferred to 
the DCRT central facility where master files will be maintained. This system 
is to start out as a near duplicate of one developed at the University of 
South Carolina and is to be further developed here in accord with NIH specific 
requirements. 

IV. GENERAL RESEARCH 

While the bulk of the work in CSL is connected with laboratory automation and 
clinical care, there is considerable effort devoted to other areas of computer 
research related to biomedical applications. Currently, there are two major 
areas of general research, the use of computer pattern recognition methods in 
biomedical problems, and the development of a medical telecommunications system. 

PATTERN RECOGNITION STUDIES 

Work in applying pattern recognition techniques to predict structure-activity 



28 



relationships was continued. An on-line system which attempts to predict 
the pharmacological activity of drugs was developed. This system, using 
pattern recognition and substructural analysis methodology assigns pharmacol- 
ogical activity in two ways. First, the methodology attempts to find overall 
similarity in molecules by determining how "similar" a compound is to known 
drugs by using the Euclidean distance criteria. Then the compound is assigned 
the activity of the "most similar" compound. The second procedure predeter- 
mines those substructural units that are most indicative of a pharmacological 
class using the learning machine. Then if a compound possesses these common 
substructural units, it is predicted to possess this activity. In addition, 
the structures of the known drugs used in assigning the activity can be dis- 
played to check the pharmacological assignment. Thus, this empirical approach 
allows past biological data to guide current testing. 

MEDICAL TELECOMMUNICATIONS SYSTEMS 



For several years, CSL has been engaged in the development of a technology 
by which computer services can be made available to the medical community 
using only a conventional touch tone telephone as a computer terminal . The 
plan has been to make such services readily available so that the power of 
the computer can be applied in assisting physicians in such areas as diagnosis, 
treatment and therapy planning. A prototype system was completed more than 
one year ago which permits use of the push buttons on the telephone as a means 
of providing input to the computer, while the computer responds in voice over 
the telephone. Six medical application programs have been developed which 
are indicative of the types of applications which might be used. The medical 
school of the University of Wisconsin has been demonstrating this system in 
their hospital. Improvements to the system during the past year have been 
directed toward making the speech generation more economical. It is expected 
that a voice generator, tied to a microcomputer, will permit the use of this 
technology with only a modest hardware addition to any commercial time-share 
facility. Thus, the current need for an entire dedicated computer (SEL-810B) 
will be el iminated. 



'll 



V. CONSULTATION 

In addition to the work described above, CSL consults with researchers in 
need of computer expertise. This consultation can be simply providing advice 
on a specific problem or can result in the design of special purpose hardware 
or in the writing of special software. A typical example of this type of 
supportive work occurred with a data collection problem in NCI. Help was 
sought in determining the optimum method of replacing an old unreliable noisy 
punch paper tape system. CSL examined alternatives, specified a programmable 
calculator with cassette tape for the collection of long runs (24 hours) of diet 
intake of animal colonies, and will soon interface the new system to the 
instrumentation involved. Five other projects of comparable size vere under- 
taken this year, each one consuming 3-6 man-months of effort. 



29 



CSL Summary of 

LEVEL OF EFFORT AND EXPENDITURE 

BY PROJECT 

Project Name Project DCRT Man-Power DCRT Capital Central Facility 
Leader (M-Y/Year) Invested ($~X K) Charges ($ X K) 

Including 
Maintenance 







FY-74 


FY-75 


FY-74 


FY-75 


FY-75 


Bldg. 2 516 


Schultz 


2.0 


1.5 


2.0 


8.0 


2.0 


NMR 


Schultz 


2.0 


1.5 


24.8 


12.0 




NIAID 


PI ex i co 


3.0 


1.5 


9.0 


5.0 




NEI 


Schultz 


1.5 


1.5 


1.0 


3.0 




NEI 


Plexico 




0.5 








NCI 


Schultz 


1.0 


1.5 




2.0 




ICU 


Syed 


7.0 


5.0 


80.6 


90.0 


11.0 


Nuclear Med. 


Schultz 


0.5 


0.5 


40.0 


3.0 


1.0 


Phonocardio- 


Schultz 


0.5 


1.0 


0.5 




20.0 


gram 














Medical Tele- 


Plexico 


1.0 


1.5 


14.5 


17.0 




communications 














Pattern 
Recognition 


Chu 


3.0 


1.0 






50.0 


NIEHS 


Plexico 




0.5 








NIH Library 


Plexico 




0.5 




1.0 




Hybrid 
Replacement 


Plexico 




2.0 




10.0 


1.1 


Cath Lab. 


Syed 




2.0 






5.0 


Special 
Consultation 






3.0 








Support 






3.0 








Microbiology 






1.0 






5.5 



30 



July 1, 1974 through June 30, 1975 
PUBLIC HEALTH SERVICE - NATIONAL INSTITUTES OF HEALTH 
DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY 



Summary of Branch Activities 

2. PHYSICAL SCIENCES LABORATORY 



1 . DCRT 

3. Dr. G. H. Weiss 



I. OBJECTIVES 



The Physical Sciences Laboratory is devoted to the study of problems in 
physics and chemistry that relate to the biological sciences. Several 
disciplines are represented in the membership of the laboratory. These 
include applied mathematics, theoretical chemistry, and theoretical physics. 
Whenever possible the theoretical studies are performed in conjunction with 
experimental work, either in collaboration with workers in outside units, 
or by members of the Physical Sciences Laboratory working in other labora- 
tories at NIH. In addition to performing research of its own choosing, 
members of the Physical Sciences Laboratory provide consultation to other 
researchers at NIH on different topics in the disciplines represented in 
the Laboratory. These services are enumerated in the project reports. 

II. SUMMARY OF LABORATORY PROGRAMS 

1. The Physical Sciences Laboratory together with the Fogarty Center held 
a symposium celebrating the fiftieth anniversary of the ultracentrifuge. 
Speakers from all over the world participated and proceedings of the meeting 
will appear, hopefully within a year. We have continued our own research on 
numerical solutions of the Lamm equation. These solutions have enabled us 

to obtain new insight into the Johnston-Ogston effect in interacting species. 
We have also begun a study of the wall effect in cell separation by the 
ultracentrifuge. 

2. Our studies in the forces important in biological phenomena have con- 
tinued, and in collaboration with Professor R. P. Rand of Brock University 
we have succeeded in measuring the repulsive forces between membranes cf 
the phospholipid lecithin. This experimental arrangement allows us to 
further study the effects of sugars on the model membrane. A theory for the 
anomalous swelling pressure of the cornea has been derived. This new theory 
is in agreement with experimental results which show that the pressure can 
decrease with increasing temperature. All previous theories came to the 
contrary conclusion. The suggested theory can be further tested experiment- 
ally. Further work on the van der Waals forces has included the development 
of methods for converting absorption spectra into intermolecular forces. 



I 



1 




i 





31 



3. Considerable effort has been devoted to a project on laser light 
scattering in biological systems. We are currently constructing an in- 
elastic light scattering spectrometer for use at NIH to be located in Build- 
ing 4. Most of the work on this apparatus has been concluded and we hope to 
begin actual experiments shortly. We have continued work on cellular 
motility and chemotaxis. In particular, we are engaging in joint experi- 
mental and theoretical studies of the cellular mechanisms of the MIF assay 
and in particular the use of fluctuation spectroscopy to determine mobility 
parameters. 

4. Our work on nuclear magnetic resonance spectroscopy has focused mainly 
on the rapid scan technique. This allows a considerable improvement in 
signal to noise ratio. We have continued our studies of helix-coil trans- 
formation of polypeptides in solution, concentrating on the effects of 
finite chain lengths. The usual theories of this phenomenon are based on 
the approximation of infinite chain length. We have shown that the effects 
of finite chain length are important for peptide numbers up to 1,000. 

5. A collaborative study with Dr. William Caveness on the long range effects 
of head injuries is presently being concluded. Our studies of the mortal- 
ity rate and other details of death on German veterans injured in World War 

I has shown that severe head injuries lead to increased mortality in later 
life and increased deaths due to cerebrovascular causes over a control 
population. We have also collaborated with Dr. Eugene Fischmann of Freed- 
men's Hospital on the possible improvement of electrocardiographic techniques 
through the use of increased numbers of leads. We have so far identified 
the most appropriate sets of leads for new techniques of data processing of 
this information. 

6. Our work on the use of adaptive sampling in clinical trials has consisted 
in the application of the likelihood methodology for treatment-control com- 
parisons. We have shown that the likelihood selection and likelihood 
stopping techniques offer a considerable improvement over sequential proce- 
dures already in the literature. Another study concluded is the effects 

of covariant information on the performance of different adaptive sampling 
rules. The inclusion of covariant information is found to be mandatory for 
adaptive sampling. 



32 



Project No. Z01 CT 00014-08 PSL 

1. Physical Sciences Laboratory 

2. Not Applicable 

3. Bethesda 



PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30,1975 



Project Title: Theory of Biochemical Separation Technique 

Previous Serial Number: 5.1 

Principal Investigator: George H. Weiss, Ph.D. 

Other Investigators: None 



Cooperating Units: 



Man Years: 



David Yphantis, Ph.D., University of Connecticut, 
David Rodbard, M.D., Reproductive Research Branch, 
NICHD, Thomas Pretlow, M.D., University of Alabama 
Medical School, Marc Lewis, Ph.D., Laboratory for Vision 
Research, NEI. 



Total: 0.2 
Professional: 0.2 
Others: 0.0 

Project Description: 

Objectives: 

To determine the physico-chemical effects influencing different 
biochemical separation systems such as ultracentrifugation, chromatography, 
and electrophoresis. To determine the quantitative significance of these 
effects. To devise numerical techniques for processing data from chemical 
separation procedures to determine properties such as molecular weight and 
diffusion coefficients. 

Progress in FY 1975: A symposium celebrating the fiftieth anniversary of 
the ultracentrifuge was held jointly with the Fogarty Center. Proceedings 
of the meeting jointly edited by G. Weiss and Marc Lewis are to be published 
as a special issue of Biophysical Chemistry within a year. We have continued 
our study of the resolving power of one and two dimensional separation 
systems, finding that almost any criterion gives the same result for optimiz- 
ing parameters provided that it takes into account the phenomenon of over- 
resolution. Results of the investigation are applied to determining optimal 
gel parameters in pore gradient electrophoresis. We have completed a numer- 
ical and analytical study of the Johnston-Ogston effect in ultracentrifuga- 
tion, finding that results previously obtained for special systems have 






33 



much wider application. We have begun a study of the wall effects in the 
density gradient centrifugation of cells, in collaboration with Dr. Thomas 
Pretlow of the University of Alabama, with the object of relating the cell 
loss to the initial configuration and other parameters of the experiment. 
We have developed a technique for extrapolating the concentration profiles 
in equilibrium centrifugation experiments to infinite time using an Aitken 
transformation. The procedure requires relatively noise-free data but has 
the potential of reducing experimental times by factors of at least two under 
almost all experimental conditions. 

Keyword Descriptors: Ultracentrifuge, electrophoresis, resolution in 
chromotography, wall effect. 

Honors and Awards: none 

Publications: 

Weiss, G. H., Rodbard, D.: Resolution of species showing micro- 
heterogeneity by zone electrophoresis and chromatographic systems. Separa- 
tion Science 9, 117-124, 1974. 

Weiss, G. H., Catsimpoolas, N., Rodbard, D.: Transient state iso- 
electric focussing: Theory. Archives of Biophysics & Biochemistry. 163, 106- 
112, 1974. 

Correia, J. J., Johnson, M. [_., Weiss, G. H., Yphantis, D. A.: 
Numerical study of the Johnston-Ogston effect in two component systems. 
Biophysical Chemistry (to appear). 



34 



Serial No. Z01 CT 00015-04 PSL 



1. Physical Sciences Laboratory 

2. Not Applicable 

3. Bethesda 



PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 

Project Title: Theory of the Helix-Coil Transformation of Polypeptides in 
Solution 

Previous Serial Number: 5.2 

Principal Investigator: James A. Ferretti , Ph.D. 

Other Investigators: None 

Cooperating Units: Robert L. Jernigan, Ph.D., Laboratory of Theoretical 
Biology, NCI 

Man Years: 

Total: 0.4 
Professional : 0.4 
Other: 0.0 

Project Description: 

The purpose of this project is to understand at the molecular level 
the nature and underlying mechanism of the helix-random coil transition in 
polypeptides. Relaxation rates for the transition have been obtained using 
ultrasonic attenuation and dielectric relaxation experiments. In terms of 
the theoretical model we have developed, it is possible to relate these: 
measured relaxation rates to the molecular rate constants and equilibrium 
conformational statistics. The results are based upon a general description 
of the time rate of change of the conformational probabilities in the form of 
a set of coupled differential equations. We find that the effects of finite 
chain length are important and that these effects can persist to greater than 
1 ,000 peptide units. 

Keyword Descriptors: Helix-coil transformation, mean relaxation rate, 
conformational statistics, molecular rate constants. 

Honors and Awards: None 

Publications: 

R. L. Jernigan and J. A. Ferretti: Mean Configurational Relaxation 
Rates in Finite Length Polypeptides. J. Chem. Phys ., 62, 2519-2527, 1975. 



73 



hr 1 



35 



Project No. ZO] CT 00016-02 PSL 

1 . Physical Sciences Laboratory 

2. Not Applicable 

3. Bethesda 

PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 

Project Title: Rapid Scan Nuclear Magnetic Resonance Spectroscopy 

Previous Serial Number: 

Principal Investigator: James A. Ferretti , Ph.D. 

Other Investigators: None 

Cooperating Units: E. D. Becker, Ph.D., Laboratory of Chemical Physics, 
NIAMDD, Richard R. Ernst, Ph.D. Laboratorium fur 
Physikialische Chemie, Eidgenossische Technische 
Hochschule, Zurich, Switzerland, Raj K. Gupta, Institute 
for Cancer Research, Philadelphia, Pa., Thomas Clem, 
Biomedical Engineering Branch, DRS. 

Man Years: 

Total: 0.6 
Professional: 0.6 
Other: 0.0 

Project Description: 

The technique of rapidly scanning the magnetic field or the radio 
frequency to obtain NMR spectra has received further attention. The basic 
method consists of rapidly scanning a response, digitizing the analog data 
and storing the results in a Raytheon 704 computer. As long as the spin 
system can be considered as a linear and time-independent one, the response 
signals develop independently and without interference. The computer is then 
used to cross correlate the response signals either with a suitable reference 
response or with an appropriate analytical function. The result is an un- 
distorted spectrum with considerably improved sensitivity. The principal 
effort during this fiscal year has been to demonstrate the advantages of the 
method and also to determine its limitations. We have demonstrated the ease 
with which a portion of the spectrum of a protein in water can be ?canned 
without recording the HD0 or FLO peaks. This is a distinct advantage of the 
rapid scan method, since the pulse technique is severely 'limited due to the 
dynamic range problem. We have also developed a means using rapid scan to 
determine spin-lattice relaxation times. The approach, which is in some 
ways analogous to the saturation recovery method in pulse NMR is fairly 
general and good for both short and long times. Together with Professor 
Richard Ernst, I have investigated the effects of nonlinearity using rapid 



36 



scan on coupled spin systems. We find both experimentally and theoretically 
that for certain scan rates there are phase and intensity anomalies which 
appear when large flip angles are used to drive the spin system into a non- 
linear region. 

Keyword Descriptors: Rapid scan, cross correlation, Nonlinear response 

Honors and Awards: None 

Publications: 

Gupta, Raj K., Ferretti , James A., and Becker, Edwin D.: Spin- 
Lattice Relaxation Measurements Using Rapid Scan FT NMR. J. Magnetic 
Resonance, 16, 505-507, 1974. 




7 

I 


JaMBL,— 




o 




73 




1 CO 


5 


1 


rti 


- 



37 



Project No. Z01 CT 00017-03 PSL 

1. Physical Sciences Laboratory 

2. Not Applicable 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: Cellular Motility and Chemotaxis 

Previous Serial Number: 5.4 

Principal Investigator: Ralph Nossal , Ph.D. 

Other Investigators: George H. Weiss, Ph.D. 

Cooperating Units: Leonard D. Kohn, M.D., Yao T. Chang, M.D., Laboratory of 
Biochemical Pharmacology, NIAMDD. 

Man Years: 

Total: 0.8 
Professional: 0.6 
Other: 0.2 

Project Description: 

Primary among the objectives of this project is the elucidation of 
cellular mechanisms involved in chemoreception and cellular response, parti- 
cularly regarding cell motility. Theories are constructed to related macro- 
scopic mobility coefficients to microscopic response parameters and experi- 
ments are performed with both bacterial (E. Coli) and mammalian cells 
(leukocytes). New assay systems, involving laser light scattering and time- 
lapse cinemicrography are employed, and procedures are devised to isolate 
materials from cell surfaces for assay on reconstituted lipid bilayers. 

One aspect of these studies relates to leukocyte migration as an 
assay for cellular immune sensitivity (MIF assay). In collaboration with Dr. 
L. D. Kohn of LBP/NIAMDD, we have modified migration inhibition assays and 
applied them to study autoimmunity in patients suffering from exophthalmic 
Graves' disease. A mathematical theory for the capillary MIF assay has been 
developed, with a view towards optimizing assay design. 

The cellular mechanisms of the MIF assay are being investigated by 
cinemicrographic techniques which rely upon novel occupation number schemes 
for determining mobility parameters (in collaboration with Y. T. Chanq, LPB/ 
NIAMDD). 



38 



Cellular chemo taxis is implicated in inflammation and wound healing, 
and in the recognition of bacteria by leukocytes. It also may be related 
to tissue organization in multicellular organisms. 

Keyword Descriptors: Chemotaxis, migration inhibition, cellular immunity, 
cell locomotion. 



Honors and Awards: 
Publications: 



None 



Nossal, R., and Weiss, G. H.: A generalized Pearson random walk 
allowing for bias. J. Stat. Phys . 10, 245-253, 1974. 

Nossal, R. and Weiss, G. H.: A descriptive theory of cell migration 
on surfaces. J. Theor. Biol . 47, 103-113, 1974. 



39 



Project No. Z01 CT 00018-03 PSL 

1. Physical Sciences Laboratory 

2. Not Applicable 

3. Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 



Project Title: Measurement of van der Waals Forces 

Principal Investigators: V. A. Parsegian, Ph.D., G. H. Weiss, Ph. D. and 

James E. Kiefer 

Other Investigators: None 

Cooperating Units: Arnold Shi h , Ph.D., National Bureau of Standards, and 

Malcolm Shrader, Ph.D., Naval Weapons Research Laboratory. 

Man Years: 

Total: 0.8 
Professional: 0.6 
Other: 0.2 

Project Description: 

To continue to develop the theory and measurement of van der Waals 
electrodynamic forces to be useful in the study of biological organization. 

Formulations of van der Waals forces have been extended to apply 
to the attraction of atoms or molecules with solid walls and to the 
attraction between curved parallel surfaces. We have continued to progress 
in developing methods for converting absorption spectra (from Oak Ridge 
National Laboratory) into intermolecular forces. 

Measurements of forces attracting atoms or molecules in a beam to 

a planar surface have been carried out (at the National Bureau of Standards). 

Comparison with theoretical expressions developed in this lab are much better 
than theories previously available. 

Wetting by water of clean surfaces seems to be compatible with our 
present understanding of van der Waals forces. We have collaborated success- 
fully with Dr. Malcolm Schrader in making measurements of water adhesion. 
These measurements, contrary to earlier findings and earlier theories, 
suggest that conducting surfaces are a uniquely good surface for the ad- 
hesion of polar materials. 



I 



40 



There are several parallels between the adhesion of cells to 
material substrates and that of liquids to solid bodies. The ability to 
analyze precise wetting experiments will strengthen our ability to look at 
cellular adhesion. 



The measurement between beam particles and substrate are not 
directly biological. They are crucial to rigorous tests of the theoretical 
physical methods that we are using in a biological context where their accur- 
acy cannot be verified yery well. 

Keyword Descriptors: van der Waals forces, theory; van der Waals, measure- 
ment; molecular beams, wetting of surfaces. 

Publications: 

Parsegian, V. A.: Formula for the electrodynamic interaction of 
point particles with a substrate. Molec. Ph.ys . 27, 1503-1511, 1974. 

Parsegian, V. A. arid Weiss, G. H.: Electrodynamic interactions 
between curved parallel surfaces. J. Chem. Phys . 60, 5080-5085, 1974. 

Shin, A. and Parsegian, V. A.: Van der Waals forces between heavy 
alkali atoms and gold surfaces: Comparison of measured and predicted values. 
Physical Review A (to appear). 



k- 



_ 





.-- 






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s 


73 


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41 



Project No. Z01 CT 00019-07 PSL 

1. Physical Sciences Laboratory 

2. Not Applicable 

3. Bethesda 

PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 

Project Title: Physical Force Interactions Between Cell Membranes and 
Cell Membrane Analogues 

Principal Investigator: V. A. Parsegian, Ph.D. 

Other Investigators: None 

Cooperating Units: D. Gingell, Ph.D., Middlesex Hospital Medical School, 
London, R. P. Rand, Ph. D., and D. M. LeNeveu, Ph.D., 
Brock University, St. Catherine's, Ontario. 

Man Years: 

Total: 0.4 
Professional: 0.4 
Other: 0.0 

Project Description: 

To measure, compute, and learn to modify forces between cell 
membranes. 

We have succeeded in measuring the repulsion forces between membranes 
of the phospholipid lecithin. This has been possible by exerting an osmotic 
stress on a stack of membranes while doing x-ray diffraction to measure their 
spacing. Repulsion forces are mechanically large between these membranes 
and exceed two atmospheres even at 20 Angstrom separation. With the success 
of this method we are now introducing selected lipids bearing charge or 
sugars into the model membranes to measure systemic changes in membrane 
repulsion forces. 

We have found that small sugar solutes in the medium between model 
membranes apparently modify the van der Waals attraction forces which create 
the lamellar array. This effect of solvent has been predicted by the general 
theory of forces but not been seen before. 

Dr. D. Gingell has done two experiments that are a direct outgrowth 
of his work here in the DCRT. First, he has found red cell aggregation 
following precisely that predicted by modulating electric charge on the 
membrane surface. (His data were processed here at the DCRT during his visit 
last summer.) Second, he has succeeded in designing a substrate to which 



42 



cells may adhere which is at the same time an electrode to which attractive 
or repulsive potentials may be applied. He has demonstrated stable attrac- 
tion of cell-to-substrate with an apparent gap between them. Modulation of 
the applied potential and observation of resultant cellular sticking or non- 
sticking will allow us to make quantitative estimates of cellular attraction 
forces. 



We expect that the above measurements coupled with force computa- 
tions will continue to give us a coherent physical understanding of cellular 
association in tissues. There is good evidence that aberrations in the 
electrostatic repulsion between cells are what create a failure to form 
good tissues. 

Repulsion between membranes also affects cell fusion and vesicle 
fusion. Accurate measurements will be helpful in determining fusion 
mechanisms. 

Keyword Descriptors: Cell membrane interaction, measurement, computation, 
electrostatic forces, electrodynamic forces. 

Honors and Awards: None 

Publications: 

Parsegian, V. A. : Possible modulation of reactions on the cell 
surface by changes in electrostatic potential that accompany cell contact. 
Ann. N. Y. Acad. Sci . 238, 362-371, 1975. 

Parsegian, V. A.: A physical approach to the study of cell 

membranes. T welve Lectures to be published in the book based on the 

Simon Fraser University Summer School on Membranes, ed. K. Colbow, Alta 
Lake, B.C. Canada. 



v- 




43 



Project No. Z01 CT 0020-07 PSL 

1. Physical Sciences Laboratory 

2. Not Applicable 

3. Bethesda 

PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 

Project Title: Influence of Electric Forces on the Organization of Proteins 
and Model Systems 

Principal Investigators: V. A. Parsegian, Ph.D., Stephen L. Brenner, Ph.D., 

and R. J. Nossal , Ph.D. 

Other Investigators: None 

Cooperating Units: None 

Man Years: 

Total: 1.5 
Professional : 1.5 
Other: 0.0 

Project Description: 

To learn how interactions between electrically charged bodies, 
particularly proteins, govern their mutual arrangement and perturb their 
surroundings. 

We have developed an efficient way to formulate the electrostatic 
forces between charged particles in salt solution. This method has been 
applied to rod-like particles such as the Tobacco Mosaic virus and to 
spherical bodies. 

We have derived a suggestion for the "anomalous" swelling pressure 
of the cornea. This pressure is seen to go down with increasing temperature 
while all previous theories predicted the reverse. Our suggestion includes 
direct measurements to test its validity. 

The transparency of the cornea is highly sensitive to the amount of 
water it holds. Apparently a major force for its swelling to opacity is the 
electrostatic repulsion between its protein components. By learning to probe 
and possibly to modify the pressure for swelling we may have a better under- 
standing for preventing unwanted swelling. 

We have also applied the theory of attractive (electrodynamic) and 
repulsive (electrostatic) forces to the formation of ordered arrays of 
Tobacco Mosaic virus particles. Different causes suggest different relations 
between interval separation and medium salt concentration. 

44 



Keyword Descriptors: Electrostatic forces, corneal swelling, Tobacco Mosaic 
virus. 

Honors and Awards: None 

Publications: 

Brenner, S. L. and Parsegian, V. A.: A physical method for 
deriving the electrostatic interaction between rod-like polyions at all 
mutual angles. Biophys. J . 14, 327-334, 1974. 

Brenner, S. L. and Parsegian, V. A.: Suggested explanation for the 
anomalous temperature dependence of the corneal swelling pressure. Exptl . 
Eye Research (to appear). 



45 



Project No. Z01 CT 00021-04 PSL 

1. Physical Sciences Laboratory 

2. Not Applicable 

3. Bethesda 

PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 

Project Title: Correlation Function Spectroscopy/Laser Light Scattering 

Previous Serial Number: 5.6 

Principal Investigator: Ralph Nossal , Ph.D. 

Other Investigators: Stephen L. Brenner, Ph.D. 

Cooperating Units: L. Kohn, M. D. Laboratory of Biochemical Pharmacology, 
MIAMDD, B. Berne, Columbia University, S.H. Chen, 
Massachusetts Institute of Technology 

Man Years: 

Total: 0.6 
Professional: 0.6 
Other: 0.0 

Project Description: 

A principal objective of this project is to develop laser inelastic 
light scattering techniques for performing measurements on biological cells 
and macromolecules. Theoretical analyses are performed in conjunction with 
various experimental studies: major emphasis is related towards problems of 
biological transport and cellular motility. 

Previously, experimental work was performed in laboratories located 
at the Massachusetts Institute of Technology and Columbia University. How- 
ever, we currently are constructing an inelastic light scattering spectro- 
meter for use at NIH, to be located in facilities being made available to us 
by the Laboratory of Biophysical Chemistry, NIAMDD. The next phases of 
instrument development will involve design and construction of apparatus for 
detecting electrophoretic mobilities and also, instrumentation for performing 
fluorescence intensity fluctuation spectroscopy. 

Laser inelastic light scattering techniques enable rapid and 
precise measurements of various physical parameters pertaining to biological 
molecules and cells. In principle, any process giving rise to refractive 
index fluctuations can be monitored; for example, concentration fluctuations 
can be used to determine diffusion coefficients of macromolecules, rate 
constants of bimolecular reactions, or swimming speed distributions of motile 
microorganisms. 

46 



Numerous applications structures larger than the wavelength of 
light can be envisioned. However, in this case new theories to relate 
observed spectra to underlying dielectric constant fluctuations must be 
provided. Thus, in the past year we have elucidated the effects of cell 
substructures on measurements of mobility coefficients, and also have provided 
a rubric for interpreting diffusion coefficient data for large anisotropic 
particles. 

Keyword Descriptors: Lasers, light scattering, macromolecules, diffusion 
coefficients, motility, correlation functions. 

Publications: 



Boon, J. P., Nossal, R., and Chen, S.H.: Light scattering spectrum 
due to wiggling motions of bacteria. Biophys. J . 14: 847-864, 1974. 

Berne, B., and Nossal, R.: Inelastic light scattering by large 
structured particles. Biophys. J. 14: 865-880, 1974. 



V^ 



o 

TO 
TO 



I* I 



47 



Z01 CT 00022-08 PSL 



Project No. 

1. Physical Sciences Laboratory 

2. Not Applicable 

3. Bethesda 



i 



PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 

Project Title: Consulting Services 

Previous Serial Number: 5.8 

Principal Investigator: George H. Weiss, Ph.D. 

Other Investigators: Mildred L. McNeel 

Cooperating Units: William F. Caveness, M.D., Laboratory of Experimental 

Neurology, NINDS, Eugene J. Fischmann, M.D., Freedmen's 
Hospital, Jay Herson, Ph.D., Howard University, Steven 
Weinstein, Ph.D., Howard University, Charles W. Boone, 
M.D., Viral Biology Branch, NCI, Steven Yeandle, Ph.D., 
Naval Medical Center. 

Man Years: 

Total: 1.6 

Professional ; 1.0 

Other: 0.6 

Project Description: 

Members of the Physical Sciences Laboratory render assistance to 
other, primarily experimental scientists, in the areas of mathematics, 
statistics, theoretical physics and chemistry. 

Progress in FY 1975: We have nearly completed a study of the effects of 
head injury on mortality in German veterans of World War I. The mortality 
rate and causes of death were correlated with severity of injury for varying 
numbers of head injured and uninjured controls from the same military units. 
The data indicate increasing mortality with increasing severity of injuries 
of different kinds, with an increase in the fraction of deaths due to cerebro- 
vascular causes in the head injured. This work will shortly be written up 
and submitted for publication. 

Considerable effort was made in assisting investigators at Freed- 
men's Hospital to determine the effectiveness of potential mapping in improv- 
ing the performance of standard electrocardiography. For this purpose it was 
necessary to determine the best diagnostic variables from multilead data. So 
far we. have considered only the QRS complex, and compared the time variation 



48 



of electrode potentials from different leads and at different times. Some 
tentative identifications of the most informative leads have been made using 
pattern recognition techniques. We have also examined the problem by means 
of discriminant analysis but this has proved to be less useful. Some tech- 
niques from signal processing appear to have some promise in this type of 
problem. More data is awaited to complete this study. 



With Dr. C. W. Boone we have begun to develop some models to 
interpret experiments related to contact inhibition. 

We have also developed mathematical theory to test different 
hypotheses about secondary reactions to visual stimuli in the eye, which 
have been studied experimentally by Dr. Steven Yeandle. We have found that 
several hypotheses are indistinguishable when the fraction of primary events 
that give rise to secondary responses are small. 

Keyword Descriptors: Head injuries, mortality rates, cerebrovascular 
accidents, potential mapping in electrocardiography, pattern recognition. 

Honors and Awards: None 




o 

73 
CD 



Publications: 

Weiss, G. H. and Yeandle, S. 
visual sense cells after weak stimuli. 



Distribution of response times in 
J. Theoret. Biol, (to appear). 



- 



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Si 

I 

-1; 

ft 

a 

i "' 
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1 


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73 









49 



Project No. 7m r.T 00023-08 psl 

1. Physical Sciences Laboratory 

2. Not Applicable 

3. Bethesda 

PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 

Project Title: Miscellaneous Studies 

Previous Serial Number: 5.9 

Principal Investigators: George H. Weiss, Ph.D. 

Other Investigators: James E. Kiefer 

Cooperating Units: David G. Hoel , Ph.D., Biometry Branch, NIEHS, Menachem 
Dishon, Ph.D., Weizmann Institute of Science, Rehovot, 
Israel, Richard Simon, Division of Cancer Treatment, NCI, 
Dennis Blumenfeld, Ph.D., University of London, Donald 
R. McNeil, Ph.D., Princeton University, Robert J. Rubin, 
Ph.D., National Bureau of Standards. 



Man Years: 

Total: 0.8 
Professional : 0.4 
Others: 0.4 

Project Description: 

We have continued work on adaptive sampling in clinical trials, 
with the object of reducing either the expected number of patients in a 
clinical trial, the expected number of patients administered the poorer 
treatment during the course of a clinical trial, or the number of failures 
during the trial. Specifically, further applications of likelihood techni- 
ques for the stopping rules of sequential trials, as well as for adaptive 
sampling were made to the problem of choosing the better of a treatment 
compared to a control, where the new treatment can be as good as, or better 
than, the control. The likelihood sequential design was found to be the 
best of competing trial designs. Another topic that was investigated was 
the design of a clinical trial in which the maximum number of failures during 
the trial is fixed. Here we have showed that for many values of the 
probability of success, alternating allocation of patients to treatments is 
preferred to adaptive allocation, as suggested by Fushimi. Another topic 
investigated was the effect of minimizing the expected number of failures 
during the course of a clinical trial rather than the expected number of 
patients given the poorer treatment. Here it was found that this design 
criterion tended to favor alternating allocation as opposed to adaptive 
allocation in trial design. Finally we have investigated the effects 



50 



of covariates on clinical trial design, and found that they have a crucial 
importance when a trial is designed, and may altogether vitiate the use of 
adaptive allocation. 

The extension of a singular perturbation technique developed for 
studying chromatographic systems, has been made to the solution of certain 
Fokker-Planck equations especially relevant to noise in lasers. 

Together with Dr. R. J. Rubin we have developed the theory of 
ordered spans of random walks with relation to the configurations of polymer 
chains. Recent interest in such problems has been stimulated by the work of 
Stockmayer and Sole on the asymmetry of random walk models for polymer chains 
even when the step probabilities are isotropic. The ordered spans give 
another measure of this asymmetry which can persist to \/ery large chain sizes. 

We have continued a study of acoustic pollution from traffic by 
enumerating the effects of non-exponential ly distributed headway spacings. 
These are shown to be of considerable importance in decreasing noise variance, 
which has been shown to be a critical factor in environmental impact. 

Together with Professor D. R. McNeil we have developed a technique 
for estimating parameters in birth and death processes in large populations. 
These processes occur frequently in ecological and epidemiological models, 
and the technique that we have developed is expected to have wide applica- 
tion. 

Keyword Descriptors: Clinical trials, adaptive sampling, sequential analysis, 
likelihood stopping, random walks, ordered spans, Fokker-Planck equations, 
singular perturbation, birth and death processes, estimation techniques. 

Honors and Awards: None 

Publications: 

Hoel , D. G., Sobel , M., Weiss, G. H.: Comparison of methods for 
choosing the best binomial population with delayed observations. J. Stat . 
Comp. and Simul . (to appear). 

Hoel, D. G., Sobel, M., Weiss, G. H.: A survey of adaptive sampling 
for clinical trials, in Advances in Biometry (to appear). 

Kiefer, J. E., Weiss, G. H.: Truncated version of a play-the- 
winner rule for choosing the better of two binomial populations. J . Am . 
Stat. Assoc . 69, 807-809, 1974. 

Simon, R., Weiss, G. H. : A class of adaptive sampling schemes 
for selecting the better of two binomial populations. J. Stat. Comp. and 
Simul . (to appear) . 

Hoel, D. G., Weiss, G. H.: A clinical trial design with a fixed 
maximum number of failures. Commun. in Stat, (to appear). 



.J 



V^ 



«l I 



51 



Hoel , D. G., Simon, R., Weiss, G. H.: Reexamination of the problem 
of choosing the better of two treatments in the context of clinical trials. 
Proc. Nat. Acad. Sci . (to appear) . 

Weiss, G. H., Dishon, M. : Application of a singular perturbation 
expansion to the solution of certain Fokker-Planck equations. J. Statist. 
Phys . (to appear) . 

Blumenfeld, D. E., Weiss, G. H.: Some radial and direction depend- 
ent models for densities of homes and workplaces. Transp. Res . 8, 149-155, 
1974. 

Blumenfeld, D. E., Shrager, R. I., Weiss, G. H.: Spatial distribu- 
tions of homes for journeys to work by different modes of transport. Transp. 
Res . 9, 19-23- 1975. 

Blumenfeld, D. E., Weiss, G. H.: Attenuation effects in the propaga- 
tion of traffic noise. Iransp. Res , (to appear). 

Blumenfeld, D. E., Weiss, G. H.: Effects of headway distributions 
on second order properties of traffic noise. J. Sound and Vib. (to appear). 



52 



July 1, 1974 through June 30, 1975 

NATIONAL INSTITUTES OF HEALTH 
DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY 

Summary of Branch Activities 1. DCRT 

2. LABORATORY OF APPLIED STUDIES 3. Eugene K. Harris 

Chief 

During the past year, the Laboratory of Applied Studies (LAS) has 
strengthened those collaborative ties within NIH and extramurally which 
enable application of the mathematical and computing science methods 
developed by LAS staff. 

For example, expertise in the numerical solution of partial differential 
equations under unusual boundary conditions was applied to the measurement 
of wall shear stress in model arteries as part of a cooperative study with 
NHLI and DRS (BEIB) scientists engaged in research on the development of 
atherosclerotic lesions at arterial branch points (Project No. 3.4 ). 
Similarly, continuing close collaboration among LAS, Nuclear Medicine and 
I/D clinical staff, particularly in NHLI, have produced several new applica- 
tions of computer-based radionuclide scintigraphy with benefits to patient 
care and evaluation (Project No. 3.2 ). Two of these techniques, allowing 
high- resolution but non- invasive studies of dynamic changes in ventricular 
volume and myocardial contractility throughout the average cardiac cycle, 
have become important adjuncts to cardiac catheterization in patients with 
coronary artery disease and valvular diseases. 

Another example is represented by the special skills in computer graphics 

which laboratory staff have applied to various projects in cooperation with 

NlH investigators. A noteworthy product of this work is the integrated 

plotting package, not initially developed at NIH but substantially improved $ 

here and modified for running on the NIH central computing system. One 

feature of this series of programs provides contour mapping of bivariate 

frequency distributions, particularly useful for epidemiologic investigations 

(e.g., Reference 13 ). 



o 

73 



Finally, in other areas, such as the evaluation of computerized systems for 
interpretation of electrocardiograms (Project No. 3.1 ); the development of 
realistic models of transport of substrate through the microcirculation 
(Project No. 3,4); or the statistical analysis of serial blood chemistry 
studies in normal volunteers and patients (Project No. 3.6 ), the Laboratory 
has strengthened its collaboration with individuals and organizations outside 
the NIH actively working in these areas. For example, LAS staff members are 
currently serving as advisors to governmental agencies in this country and 
abroad on problems concerning the selection of ECG analysis programs and the 
data processing of time series of biochemical profiles in normal subjects. 



Hi I 



53 



As in past years, LAS staff participated in NIH educational programs. 4 
Dr. J. E. Fletcher, Head of the Applied Mathematics Section, is the current 
chairman of the FAES Department of Mathematics where he teaches many of the 
advanced applied mathematics courses. The course taught in FY 75 was Methods 
of Mathematical Physics I and II. Mr. J. D. Ashbrook conducts a regular 
course in computer graphics as part of the DCRT in hours training course 
program. 

In July 1974 the Biomathematics and Statistics Section was detached from LAS 
to provide the leadership required for a new laboratory within DCRT (LSMM) . 
Dr. James E. Mosimann, formerly head of this section, was designated chief 
of the new laboratory. 

LAS reports published or "in press" during FY 75: 

1. Agress, H. , Jr., Levenson, S.M., Gelfand, M.J., Green, M.V. , Bailey, J.J., 
and Johnston, G.S. : Application of computer-generated functional (para- 
metric) maps in radionuclide renography. Proceedings of the Fifth 
Symposium on Sharing Computer Programs and Technology in Nuclear 
Medicine^ U.S. Atomic Energy Commission Technical Information Center , 
Oakridge , Tennessee, 1975 (in press). 

2. Ashbrook, J.D., Spector, A. A. , Santos, E.C., and Fletcher, J.E.: Long 
chain fatty acid binding to human plasma albumin. Journal of Biological 
Chemistry , Vol. 250, No. 6, pp. 2333-2338, March 1975. 

3. Ashbrook, J.D. , and Sande, G. : A User's Guide to the Integrated Plotting | 
Package . U.S. DHEW, PHS, NIH, DCRT, LAS., Wash., D.C. , U.S. Govt. Print. 
Off., 1975, 120 pp. 

4. Bailey, J.J., Itscoitz, S.B., Hirshfeld, J.W. , Jr., Grauer, L.E., and 
Horton, M.R. : A method for evaluating computer programs for electro- 
cardiographic interpretation. I. Application to the experimental IBM 
program of 1971. Circulation 50: 73, 1974.* 

5. Bailey, J.J. , Itscoitz, S.B. , Grauer, L.E., Hirshfeld, J.W., Jr., and 
Horton, M.R. : A method for evaluating computer programs for electro- 
cardiographic interpretation. II. Application to version D of the 
PHS program and the Mayo Clinic program of 1968. Circul ation 50: 80, 
1974.* 

6. Bailey, J.J. , Horton, M.R. , and Itscoitz, S.B. : A method for evaluating 
computer programs for electrocardiographic interpretation. III. Repro- 
ducibility and the sources of program errors. Circulation 50: 88, 1974.* 

7. Fletcher, J.E.: A Model Describing the Unsteady Transport of Substrate 
to Tissue from the Microcirculation. SIAM J. Applied Math. , Vol. 29, 
No. 2, September 1975 (in press). 

8. Fletcher, J.E.: Distributed Parameter Modeling of the Microcirculation. 
Systems Analysis of Biomedical Transport, edited by D.D. Reneau , 
Marcel Dekker, Inc., New York (in press). 

54 



9. Green, M.V. , Agress, J., Jr., Brody, W.R. , Pearlman, A.S., Itscoitz, S.B., 
and Johnston, G.S.: A comparison of high temporal resolution left 
ventricular volume curves before and after initial replacement. 
Proceedings of the Fifth Symposium on Sharing Computer Programs and 
Technology in Nuclear Medicine . U.S. Atomic Energy Commission Technical 
Information Center, Oak Ridge, Tennessee, 1975 (in press) . 

10. Green, M.V. , Ostrow, H.G., Douglas, M.A. , Myers, R.W. , Bailey, J.J., and 
Johnston, G.S. : Scintigraphic cineangiography of the heart. Medinfo 



1974, North Holland Publishing Company, Amsterdam, August 1974, pp. 
830. 



827- 



11. Green, M.V. , Ostrow, H.G., Douglas, M.A. , Myers, R.W. , Scott, R.N. , 
Bailey, J.J., and Johnston, G.S.: High temporal resolution ECG-gated 
scintigraphic angiocardiography. J. Nucl. Med . 16: 95, 1975 

12. Harris, E.K. : Effects of intra- and interindivi dual variation on the 
appropriate use of normal ranges. Clin. Chem. 20: 1535, December 1974. 

13. Hoffman, H.J., Stark, C.R. , Lundin, F.E., Jr., and Ashbrook, J.D.: 
Analysis of birthweight, gestational age, and fetal viability, U.S. 
births, 1968. Obstetrical and Gynecological Survey , Vol. 29, No. 9, 
pp. 651-681, September 1974. 

14. Horton, M.R. , and Bailey, J.J.: Computer assisted electrocardiographic 
interpretation: I. Evaluation of computer processing. In Jenkin, M.A. 
(ed) : Clinical Medicine and the Computer - Proceedings of the Fourth 
Annual Conference of the Society for Computer Medicine . Minneapolis , 
Minnesota, Society for Computer Medicine, Section 2.6, pp. 1-5, 1974. 

15. Lutz, R.J., Cannon, J.N., Fletcher, J.E., and Fry, D.L.: The Measurement 
of Wall Shear Stress in Model Arteries by an Electrochemical Technique. 
Proceedings of ACEMB , October 1974. 

16. Pottala, E.W. and Mortimer, J. A.: A hybrid compartmental model for 
the alligator purkinje cell. 1: Preferred somatopetal conduction of 
dendritic spikes and soma-axon interaction. J. Neurosci. Res. 1975 
(in press) . 

17. Rinzel, J., and Rail, W. : Transient response in a dendritic neuron model 
for current injected at one branch. Biophys. J. 34, 1974. 

18. Rinzel, J.: Voltage transients in neuronal dendritic trees. Federation 
Proc. 34: 1350-1356, 1975. 



" 



o 

I 











19. Rinzel, J: Spatial stability of traveling wave solutions of a nerve 
conduction equation. Biophys . J . , 1975 (in press) . 

20. Simpson, R.B. , Ashbrook, J.D., Santos, E.C., and Spector, A. A. : Partition 
of fatty acids. Journal of Lipid Research , Vol. 15, pp. 415-422, July 
1974*. 

*Reported in FY 74 as "in press". 



55 



Serial No. Z01 CT 00002-05 LAS 

1. Laboratory of Applied Studies 

2. Medical Applications Section 

3. Bethesda 

PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 

Project Title: Evaluation of Computer Systems for ECG Analysis 

Previous Serial Number: 3.2 

Principal Investigator: J. J. Bailey 

Other Investigators: M. R. Horton, S. B. Itscoitz 

Cooperating Units: Cardiology Branch, NHLI; ECG Laboratory, CC 

Man Years : 

Total: 1.3 
Professional: 1.2 
Others: 0.1 

Project Description: 

Objective: 

To assess on a sound statistical and clinical basis, the 
usefulness of computer systems for ECG analysis. 

Progress during FY 75: 

This work begun in FY 70 has involved the study of various methods 
for ECG analysis, including the use of orthogonal transforms 
(Fourier, Hambly) , use of vector loops, and use of computer 
programs to interpret resting ECGs. In FY 74 a clinical evalua- 
tion of three such programs was completed (publications 1-3) . 

In FY 75 an updated (improved) version of the IBM program was 
implemented and is now in daily use for routine ECGs from the 
Clinical Center. A 360 version of AVA 3.4 (Pipberger) program 
which uses Frank lead data was implemented and has been distributed 
to users in Europe and elsewhere in the U. S. Reproducibility of 
the AVA 3.4 program was tested by the previously reported method 
(publ. 3 § 4) and the results submitted for publication. A 
reliable method for acquiring ECG data on clinically documented 
cases from the Royal Glasgow Infirmary, Scotland has been achieved. 



56 



Proposed Course: 

NHLI now has the capacity to provide good clinical documentation 
of cases through the use of cardiac catheter studies, echocardi- 
ography, radionuclide angio- cardiography, and myocardial scinti- 
graphy. These cases will make excellent material with which the 
heuristic algorithms for the ECG diagnosis of chamber enlargement/ 
overload in the IBM program can be tested and likewise also the 
multivariate statistical algorithms of the AVA 3.4 program. It is 
also proposed to compare the IBM program against the McFee lead 
program developed by the Royal Glasgow Infirmary using their 
clinically documented cases. 

Keywords : 

ECG analysis, heart disease, computer programs, clinical applica- 
tions, clinical evaluations. 

Publications : 

1. Bailey, J.J., Itscoitz, S.B., Hirshfeld, J. W. , Jr., 
Grauer, L.E., Horton, M.R. : A method for evaluating computer 
programs for electrocardiographic interpretation. I. Applica- 
tion to the experimental IBM program of 1971. Circulation 50 : 

73, 1974.* 

2. Bailey, J.J., Itscoitz, S.B., Grauer, L.E., Hirshfeld, J.W. ,Jr. 
Horton, M.R. : A method for evaluating computer programs for 
electrocardiographic interpretation. II. Application to 
version D of the PHS program and the Mayo Clinic program of 
1968. Circulation 50: 80, 1974.* 

3. Bailey, J.J., Horton, M.R. , Itscoitz, S.B.: A method for 
evaluating computer programs for electrocardiographic interpre- 
tation. III. Reproducibility and the sources of program 
errors. Circulation 50: 88, 1974.* 

4. Horton, M.R. , and Bailey, J.J.: Computer assisted electro- 
cardiographic interpretation: I. Evaluation of computer 
processing. In Jenkin, M.A. (ed) : C linical Medicine and 
the Computer - Proceedings of the Fourth Annual Conference of 
the Soci ety for Computer Medicine" Minneapolis, Minnesota., 
Society tor Computer Medicine, Section 2.6, pp. 1-5, 1974. 



. _ 



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*Reported in FY 74 as "in press". 



57 



Serial No. Z01 CT 00003-04 LAS 

1. Laboratory of Applied Studies 

2. Medical Applications Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: Computer Systems for Nuclear Medicine 

Previous Serial Number: 3.2 

Principal Investigators: J. J. Bailey, M. V. Green (NM/CC) 

Other Investigators: H. Agress, Jr., M. A. Douglas, 
H. G. Ostrow, S. L. Bacharach, 
S. M. Levenson, B. R. Line, G. S. Johnston, 
W. R. Brody, D. R. Redwood, S. B. Itscoitz 

Cooperating Units: Nuclear Medicine Department, Clinical Center, NIH 
Cardiology Branch, NHLI 
Pulmonary Branch, NHLI 
Surgical Neurology Branch, NINDS 
Computer System! Laboratory, DCRT 

Man Years : 

Total: 2.7 
Profess icnal : 2.6 
Others : 0.1 

Project Description: 

Objectives: 

To provide computer-based mathematical analysis in support of 
diagnostic activities in the Nuclear Medicine Department (NM) 
of the Clinical Center. 

Progress during FY 75: 

Since FY 72 LAS with support from CSL and in collaboration with 
the NM has accomplished the specification, selection, and acquisi- 
tion of a minicomputer system which was mated to two gamma 
scintillation cameras in NM. Subsequently LAS programmers have 
developed and implemented extensive software (on both the NM 
minicomputer system and the PDP-10 facility in DCRT) which has 
found wide-ranging applications, including time function manipu- 
lation, curve fitting, and functional mapping for dynamic studies; 
orthogonal transforms for image restoration by deconvolution and 
for non- restorative image enhancements; and interpolation, expan- 
sion, and contraction of image arrays. 

58 



The most important clinical application developed in FY 74 and 
FY 75 is the computer-based ECG-gated technique of radionuclide 
angiocardiography (publications 1,2, and 4). Because of its 
non- invasive, non-surgical nature (cf. cardiac catheterization) 
requiring no anesthesia and less radiation dose than a single 
chest Xray, this study can be repeated frequently or can be 
performed on patients too sick to undergo cardiac catheterization. 
Thus, this technique shows considerable promise as an addition to 
the diagnostic armamentarium of clinical cardiology. 

Another important computer-based technique begun in FY 75 is ECG- 
gated myocardial scintigraphy during rest and stress using radio- 
nuclide labeled macroaggregated human serum albumin or albumin 
microspheres. This technique promises to help determine the 
pathophysiologic effect of anatomic lesions revealed by coronary 
angiography and thereby add considerably to the evaluation of 
patients who might be candidates for coronary artery surgery. 

A third computer-based method involving functional (parametric) 
maps in radionuclide renography was begun in FY 73. In FY 74 and 
FY 75 this method was applied to 130 patients and was found to 
enhance the detection of functional abnormalities in more than 
one-third of the cases (publication 3) . 

The computer-based method for ventilation and perfusion scanning 
of the lungs was begun in FY 73. At that time it proved useful 
in following the changes in pulmonary dynamics in patients who 
underwent surgical repair of valvular heart disease. In FY 74 
and FY 75 this method is being refined by the incorporation of 
volume gating. 

During FY 75 the use of computer-based statistical studies of 
"flooded" gamma camera fields revealed non -uniformities in the 
camera response which, heretofore, had been unsuspected. The 
photomultipliers of the camera were re-tuned and this method is 
now being used weekly as a quality control measure for the gamma 
camera data. 

In FY 75 computer-based methods for determining regional blood 
flow are being used to study the course of experimental cerebral 
infarction in monkeys. 

Proposed Course: 

The method for radionuclide angiocardiography will be validated 
using patient data from cardiac catheter laboratory and also 
experimental data in baboons with a surgically emplaced flowmeter 
about the ascending aorta. This method will also be used to 
detect regional abnormalities in left ventricular wall motion in 
patients with coronary heart disease. The method for myocardial 
scintigraphy will be used to assess coronary artery disease in 



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59 



NHLI patients. The functional mapping of radionuclide renography 
will be added to the nuclear medicine armamentarium as a standard 
procedure. The method for ventilation/perfusion scanning of the 
lung will be used to study NHLI patients with a variety of pul- 
monary abnormalities and also patients from the D.C. Veterans 
Administration Hospital who have interstitial pulmonary fibrosis. 
Work on image enhancement through use of orthogonal transforms and 
other techniques and methods of pattern recognition in nuclear 
medicine will be extended. 



Keywords 



radionuclide, radioisotope, nuclear medicine, scanning, scinti- 
photography, non- invasive techniques, computer analysis, coronary 
heart disease, myocardial infarct, left ventricular wall motion, 
ejection fraction, renography, renal function, functional mapping, 
pulmonary function, ventilation/perfusion, pulmonary disease, 
stroke, cerebral blood flow, iodohippuran-I 131, xenon-133, 
xenon-127, technecium-99m. 



Publications : 



1. Green, M.V. , Ostrow, H.G. , Douglas, M.A. , Myers, R.W. , 

Bailey, J.J., and Johnston, G.S.: Scintigraphic cineangiography 
of the heart. Medinfo 1974, North Holland Publishing Company, 
Amsterdam, August 1974, pp. 827-830. 

2. Green, M.V. , Ostrow, H.G. , Douglas, M.A. , Myers, R.W. , 
Scott, R.N., Bailey, J.J., and Johnston, G.S. : High temporal 
resolution ECG-gated scintigraphic angiocardiography. 

J. Nucl. Med. 16: 95,1975. 

3. Agress, H. , Jr., Levenson, S.M. , Gelfand, M.J., Green, M.V. , 
Bailey, J.J., and Johnston, G.S.: Application of computer- 
generated functional (parametric) maps in radionuclide 
renog raphy . Proceedings of the Fifth Symposium on Sharing 
Computer Programs and Technology in Nuclear Medicine . 

U.S. Atomic Energy Commission Technical Information Center, 
Oak Ridge, Tennessee, 1975 (in press). 

4. Green, M.V. , Agress, J., Jr., Brody, W.R. , Pearlman, A.S., 
Itscoitz, S.B., and Johnston, G.S. : A comparison of high 
temporal resolution left ventricular volume curves before and 
after initial replacement. Proceedings of the Fifth Symposium 
on Sharing Computer Programs and Technology in Nuclear Medicine . 
U.S. Atomic "Energy Commission Technical Information Center, 

Oak Ridge, Tennessee, 1975 (in press). 



I 



60 



Serial No. Z01 CT 00004-04 LAS 

1. Laboratory of Applied Studies 

2. Medical Applications Section 

3. Bethesda 

PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 

Project Title: Investigations of Physiologic Signals and 
Simulation Models by Distributed Hybrid 
Computing 






Previous Serial Number 



3.6 



Principal Investigators: Erik Pottala 
Other Investigators: 



Cooperating Units: 



J. J. Bailey, J. B. Eisenberg, G. Wright, 
D. Humphrey, J. Mortimer 

National Institute of Occupational 
Safety and Health; Emory University, 
Atlanta, Georgia; University of Minnesota, 
Minneapolis, Minnesota 






Man Years : 

Total: 1.9 
Professional : 
Others: 0.1 

Project Description: 

Obj ectives : 



(1) To develop physiologic simulation models using 
distributed hybrid computing implemented on the 
LAS laboratory mini-computer with special pur- 
pose microprocessors: 

(a) in neurophysiology to simulate neural 
networks and central nervous subsystems 
(e.g. cerebellum), 

(b) in cardiovascular physiology to develop 
a global model of circulatory dynamics 
which can be easily modified to simulate 
pathophysiologic states (e.g. valvular 
disease) . 



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61 



(2) To develop the LAS mini -computer system as 

a research tool for handling physiologic data. 

Progress during FY 75: 

Neural network simulation employing physiologically 
realistic hardware neural models, which incorporate 
a distributed input system (analogous to a dendritic 
net) with simulated action potentials, has been 
pursued since FY 72. In FY 74 a neural hardware 
model interfaced with the mini-computer system was 
used to study a small neural net and show how an 
action potential can modify the shape and duration 
of post-synaptic potentials and their spatio-temporal 
interactions. This work with small neural nets and 
their reciprocal inhibition-excitation behavior has 
been extended to the study of the cerebellum (publ. 1) 

Development of the LAS mini-computer system has 
continued. It has been interfaced with the Marquette 
tape drive (for routine ECGs from the Clinical 
Center); with the Honeywell 7600 analog tape trans- 
port; with a general purpose switch-filter network; 
with a real time spectral analyzer and ensemble 
averager; and with the neural control panel for the 
model work described above. 

This system is capable of processing various analog 
(physiologic) signals. For example, in FY 74 and 
75, electromyographic signals collected at the 
National Institute of Occupational Safety and Health 
from stressed subjects were analyzed by this system 
using the spectrum analyzer. The optimum ranges of 
power spectra for this study were determined by this 
analysis and the results are now being used to study 
muscle fatigue. Another example involves ECG data 
collected at the Royal Glasgow Infirmary (see 3.2). 
These data contain varying levels of 50 Hz. noise. 
With the aid of the LAS mini- computer system, the 
character of this noise was studied and an analog 
notch filter was designed. The effect of this filter 
on the data and ultimately upon the diagnostic state- 
ments of an ECG analysis program were greatly facili- 
tated by means of the mini-computer system. The 
optimal parameters (attenuation and window size) of 
the filter could then be selected, in terms of a 
trade-off between noise suppression and artifact 
generation. 

A general advantage of this system which has been 
demonstrated before in other studies (ECG and pres- 
sure from monkey preparations) is that an investigator 

62 



can automatically pre-process (edit, filter, and 
digitize) dynamic physiologic data so that optimal 
use of a large scale digital computer can be obtained, 

Proposed Course: 

The neurophysiological simulation work will be 
extended to larger nets of cerebellar cells and 
to other central nervous subsystems (e.g. walking 
reflexes) . It is also proposed to build a global 
model of the cardiovascular system based on power 
conversion and distribution; data (e.g. time course 
of intraventricular pressure and volume) has already 
been collected, which can be used for testing sub- 
sections of the model. In the coming year the LAS 
mini-computer system will be upgraded with the 
addition of 16K core, a 1600 BPI magnetic tape drive, 
a MAP 100 array processor, a disk pack, and a grey- 
level CRT. It is anticipated that these improvements 
will allow speedy investigation of image processing 
schemes for nuclear medicine data (see 3.6). 

Keywords : 

neurophysiology, hybrid computer, simulation, 
cerebellum, cardiovascular models, signal analysis, 
electrocardiography, electromyography, image 
processing. 

Publications : 

1. Pottala, E.W., and Mortimer, J. A.: A hybrid 
compartmental model for the alligator purkinje 
cell. 1: Preferred somatopetal conduction of 
dendritic spikes and soma-axon interaction. 
J. Neurosci. Res , (in press) 1975. 



Hi I 






63 



Serial No. Z01 CT 00005-05 LAS . 

1. Laboratory of Applied Studies I 

2. Applied Mathematics Section 

3. Bethesda 

PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 

Project Title: Mathematical Modeling of Biological Processes 

Previous Serial Number: 3.5 

Principal Investigators: J. Fletcher, J. Rinzel (transferred 

to NIAMD 2/1/75) 

Co-Investigators: R. Lutz, BEIB, DRS; W. Rail, MRB, NIAMD 

Man Years: Professional 1.8 

Project Descriptions: 

Background and Objectives: 

The primary responsibility of the Applied Mathematics 
Section is to provide DCRT and the NIH with high 
level mathematical competence for biomathematical 
modeling and data analysis. This competence includes 
both theoretical and applied techniques, as well 
as numerical computation methods. Each individual 
in the section has a primary specialty in computer 
science or mathematics, and in addition, each is a 
capable programmer. 

Project Tasks during FY 75: 

1) A Simulation Model for Substrate Supply in the 
Microcirculation: 

During FY 75, a new mathematical formulation of 
substrate kinetics in capillary blood was discovered. 
This formulation resulted in some simplification of 
the model equations and permits the direct use of 
the substrate dissociation curve rather than its 
mathematical inverse which was used previously. In 
this form, the model suggested that substrate transfer 
to tissue was directly related to the slope of the 
dissociation curve rather than its coordinate position 
CP50 point) and subsequent modeling studies confirmed 
this conjecture. A number of simulations were com- 
pleted relating the effects of substrate kinetics 



64 



2) 



to tissue supply, and the role of 2-3 DPG in 
modifying the oxygen-hemoglobin dissociation curve 
in humans was examined. The simulation results were 
presented at a recent international meeting, and a 
publication will appear in the proceedings. 

Dynamic Behavior of Mass Transfer in Pulsating 
Laminar Tube Flow: 



During FY 74, the collaboration of the Applied 
Mathematics Section was requested in a project 
directed toward the development and validation of 
an experimental technique for the measurement of 
mass transfer in tubes with pulsating flow. The 
ultimate objective was a technique for measuring 
shear stress in arteries' and its possible relation- 
ship in the formation of sclerotic lesions at 
bifurcations. A brief literature survey revealed 
that the commonly used approximations were inappro- 
priate for the full model equations, while most 
standard numerical methods were invalidated by the 
mathematical singularity induced by the leading edge 
of the imbedded electrode. During FY 75, a new 
formulation was developed which removed this singular- 
ity, thus posing the problem in a form more adaptable 
to numerical solution. A new numerical solution 
technique has been developed and is being tested for 
its validity. Some preliminary results have been 
presented at conferences and an application has been 
published. Further work in this area will center on 
validation of both experimental and theoretical results 
and the development of a valid error analysis. 

3) Mathematical Description of Cellular Neuroelectric 
Signal Transmission: 

The objectives of this study are to obtain biophysi- 
cal understanding through mathematical modeling of 
integration in a model dendritic neuron and of 
impulse conduction along a model nerve axon. During 
FY 75, a simplified version of the FitzHugh-Nagumo 
nerve conduction model was used to study the phenomena 
of active axonal conduction. Though it too yields 
a nonlinear partial differential equation, its 
traveling wave solutions can be obtained explicitly. 
This permits a complete parametric description of its 
solutions, which model a simplified ideal nerve 
impulse, and periodic trains of pulses. The results 
suggest that, for steady repetitive firing, the 
propagation speed of a periodic train depends on 
firing frequency. Additional numerical calculations 



\W 



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■x> 



65 



are planned to further explore this dispersive 
aspect of nerve conduction. 

As do other nerve conduction models, this simplified 
one has a multiplicity of traveling wave solutions. 
Such multiplicity is not found in experimental 
observations and has led several investigators to 
conjecture on the stability properties of these 
various waves. For the simple model, stability has 
been analyzed explicitly to verify the conjectures 
and to suggest which waves are likely to be observed. 
Two different stability notions are formulated: 
temporal stability, for perturbations generated at 
a single instant of time; and spatial stability, 
which may be continually applied in time, but spatially 
restricted to a fixed location. This is appropriate 
for many nerve signaling problems. Stability results 
for this simple model motivate their attempted exten- 
sion to a general class of nerve conduction equations. 
Critical stability transition properties for these 
models have been analytically and parametrically 
examined. For periodic wave trains, maximum frequency 
was found to distinguish the transition from spatial 
stability to instability. A manuscript describing 
these results has been submitted. 



Keywords : 



applied mathematics, biomathematical modeling, 
numerical computation, simulation model, microcircu- 
lation, pulsating flow. 



Publications : 



Fletcher, J.E.: A model describing the unsteady 
transport of substrate to tissue from the 
microcirculation. SI AM. J. Applied Math. , Vol. 29, 
No. 2, September 1975. 

Lutz, R.J., Cannon, J.N., Fletcher, J.E., and 
Fry, D.L.: The measurement of wall shear stress 
in model arteries by an electrochemical technique. 
Proceedings of ACEMB , October 1974. 

Fletcher, J.E.: Distributed parameter modeling 
of the microcirculation. Systems Analysis of 
Biomedical Transport , edited by D.D. Reneau, 
Marcel De'kker, Inc., New York (in press). 



I 



66 



4. Rinzel, J.: Voltage transients in neuronal 

dendritic trees. Federati on Proc. 34, 1350-1356, 
1975. — 



5. Rinzel, J., and Rail, W. : Transient response 

in a dendritic neuron model for current injected 
at one branch. Eiophys.J. 14 . 759-790, 1974. 

6. Rinzel, J.: Spatial stability of traveling wave 
solutions of a nerve conduction equation. 
Biophys. J. (in press) . 



! ^l 



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V 


* 

_ 



67 



Serial No. Z01 CT 00006-05 LAS 

1. Laboratory of Applied Studies 

2. Applied Mathematics Section 

3. Bethesda 

PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 

Project Title: General Mathematical and Computational 
Collaborative Efforts 

Previous Serial Number: 3.5 

Principal Investigators: J. Ashbrook, E. Hill, J. Fletcher 

Co- Investigators : A. Spector, Univ. of Iowa 

R. Shrager, DCRT; R. Feldmann, DCRT; 

H. Hoffman, Biometry Branch, NICHD; 

W. Sperry, CCB, DCRT 

Man Years: Professional - 2.2 

Project Description: 

1) Modeling of Macromolecule- ligand Binding: 

A study of the binding of physiologically important 
long- chain fatty acids to human plasma albumin has 
been completed and published. Further work in this 
area will concern displacement of albumin bound 
ligands by drugs or other competing compounds. 

2) Low Weight for Age Study: 

Computer software was completed for the generation 
of contour plots of collected data. The NICHD has 
employed this software for the construction of contour 
levels for bivariate distributions of birth weight 
and gestational age by race, sex and metropolitan 
status. Details of resulting studies are described 
in the reports of the Institutes concerned. Additional 
studies utilizing this software are currently being 
conducted by the Biometry and Epidemiology Branches, 
NICHD. 

3) Computer Generated Graphics and Display Systems: 

Several new post-processors have been added to the 
Integrated Plotting Package (IPP) . This new software 
allows an IPP program to generate plots on any terminal 
in the Tektronix 4010 family of graphic displays, or 

68 



on a CalComp plotter attached to a remote job 
entry (RJE) workstation in addition to the previously- 
supported plotting devices. Supporting software 
was rewritten in American National Standard (ANS) 
FORTRAN to preserve machine independence. The 
software has been distributed to other computer 
centers, and a user's guide is now in press. 
Additional research is being conducted in collabor- 
ation with CCB, DCRT in the general area of computer 
generated graphics and textual data representation. 

4) Simulation of Body Fluid Balances: 



This project involves the imp 
active digital computer model 
scientists study the interact 
major body systems in health 
called MACPEE is being analyz 
DCRT's PDP-10 and IBM System 
is a model of heart, circulat 
ments, kidneys, and various h 
can be used to approximate mo 
disease, body fluid disturban 
acting disorders such as neph 
failure, Addison's disease, e 



lementation of inter- 
s designed to help 
ing physiology of 
and disease. A model 
ed and implemented on 
370 computers. MACPEE 
ion, body fluid compart- 
ormones . This model 
st problems of renal 
ce or complex inter- 
rotic syndrome, heart 
tc. 



r- 



5) Image Processing of Nuclear Medicine Data: 

Algorithms are being developed to extract features, 
find edges, perform texture analysis, and find 
profiles of digitized radioisotope distribution 
patterns. These attributes will be used to classify 
images as either normal or abnormal using an adaptive 
supervisor. Discriminant analysis, classical pattern 
recognition techniques, and other optimization tech- 
niques are being used in developing such routines. 

6) Energy Minimization of Protein Structures: 

This project involves the integration of energy 
minimization techniques into the body of DCRT's 
molecular structure manipulation system. This 
involves determining the best methods for doing 
energy minimization and data structure manipulation 
with respect to protein structures. A group of 
computer programs that allow one to study the con- 
formations of biological macromolecules is being 
analyzed and implemented on the PDP-10 computer 
system. The conformation is altered to minimize 
an empirical energy function by moving all atoms by 
the method of steepest descents. These techniques 



69 



are needed to refine coordinates obtained by X-Ray 
Crystallography and thus improve the techniques of 
stereochemistry. 



Keywords : 



mathematics, modeling, macromolecule- ligand binding, 
graphical displays, graphics, simulation, image 
processing, energy minimization, protein structures. 



Publications : 



Simpson, R.B., Ashbrook, J.D., Santos, E.C., and 
Spector, A. A. : Partition of fatty acids. Journal of 
Lipid Research , 'Vol. 15, pp. '415-422, July 19747* 

Hoffman, H.J., Stark, C.R., Lundin, F.E., Jr., 
and Ashbrook, J.D.: Analysis of birth weight, 
gestational age, and fetal viability, U.S. 
births, 1968. Obstetrical and Gynecological 
Survey , Vol. 29, No. 9, pp. 651-681, September 
1974. 

Ashbrook, J.D., Spector, A. A. , Santos, E.C., and 
Fletcher, J.E.: Long chain fatty acid binding 
to human plasma albumin. Journal of Biological 
Chemistry , Vol. 2 50, No. 6, pp. 2333-2338, 
March 19 75 . 

Ashbrook, J.D., and Sande , G.: A User's Guide 
to the Integrated Plotting Package . U.S. DHEW, 
PHS, NIH, DCRT, LAS. Wash., D.C., U.S. Govt. 
Print. Off., 1975, 120 pp. 



Reported in FY 74 as "in press" 



70 



Serial No. Z01 CT 00007-08 LAS 

1. Laboratory of Applied Studies 

2. Office of the Chief 

3. Bethesda 

PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 

Project Title: Statistical Research in Clinical Pathology 

Previous Serial Number: 3.4 



Principal Investigators: 
Co- Investigators : 



Eugene K. Harris, assisted by 
G. Shakarji, DMB, DCRT 



M. Healy, Clinical Research Centre, Medical 

Research Council, England 

S. Brown, Clinical Chemistry, Clinical 

Research Centre, England 

D. S. Young, Clinical Chemistry Service, 

Clinical Center, NIH 

May Years: Professional 0.5 

Project Description: 

Background: 

The studies of variation in normal blood chemistries 
which form the background of this project have been 
amply discussed in earlier annual reports. 

Progress during FY 74, 75: 

This report covers two years because the principal 
investigator continued research in this area during 
assignment to the Clinical Research Centre near 
London in FY 74. During the past two years attention 
has focussed on the development of statistical theory 
to evaluate 1) the use of population-based normal 
ranges in assessing individual laboratory tests, and 
2) use of previous measurements on the same individual 
to forecast and test a current measurement. These 
issues have particular significance for the inter- 
pretation of results from periodic health examinations 
of presumably normal individuals or from more inten- 
sive serial studies of patients in clinical trials. 
Two papers have resulted so far: one referenced 
below and a second just completed and submitted for 
publication (April, 1975). In addition, an extensive 
unpublished report was prepared on the use of 



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71 



statistical methods in analyzing serial measurements 
on patients under intensive care following surgery, 
myocardial infarction, or other traumatic experience. 
Aims are rapid detection of eventual outcome. 

To support this work, computing packages have been 
developed for the storage, updating, retrieval and 
statistical analysis of cumulative clinical data on 
individuals. A general description and full docu- 
mentation of these programs is now in preparation. 
The storage, updating and retrieval programs have 
been in routine operation for the past 2 years in the 
Hypertension-Endocrine Laboratory of NHLI under Dr. 
F. C. Bartter, and now contain information on upwards 
of 100 patients. The full set of programs, including 
analysis routines, are expected to be used very 
shortly in the analysis of a serial study of normal 
volunteers designed in cooperation with the Clinical 
Chemistry Service of the Clinical Research Centre, 
Harrow (London), England and completed during FY 75. 
Data will be transmitted to NIH for analysis and a 
joint report prepared. 

Plans for FY 76: 

During the coming year, documentation of the computing 
programs mentioned above will be completed and in- 
cluded in a technical report for general distribution. 
Immediate application will be to the data from England 
cited above. Later, it is expected to apply these 
programs and supplemental theory to new data from 
normal subjects including baseline measurement series 
followed by single samples at periodic intervals. 
Cooperative efforts are also expected with the 
Clinical Chemistry Service of the Clinical Center in 
the application of various statistical monitoring and 
forecasting methods to the quality evaluation of new 
high- volume, multichannel autoanalyzer machines, 
possibly including a study of normal volunteers. 
Thus, FY 76 will see an emphasis on the application 
of theory developed during the preceding two years. 

Keywords : 

normal variations, inter- intra-individual variation, 
baseline reference values, normal ranges, clinical 
chemistry. 



72 



Publications 



Harris, E.K.: Effects of intra- and 
interindividual variation on the appropriate 
use of normal ranges. Clin. Chem. , 20 , 1535 
(December, 1974). 




73 



July 1, 1971* through June 30, 1975 

PHS-NIH 

Division of Computer Research and Technology 

Summary of Branch Activities DCRT 

Data Management Branch J. Emmett Ward 

Branch Chief 



I . SUMMARY 

Providing practical solutions to complex research and 
administrative computer data processing problems is still the 
raison d'etre of the Data Management Branch (PMB). 

Reasonable progress has been made in providing a useful 
Clinical Information Utility. This effort supports the 
Clinical Center's Office of Clinical and Management Systems by 
providing clinical investigators with diversified methods for 
reviewing and extracting clinical data from three available 
sources: Clinical Pathology Laboratory, Discharge Diagnosis and 
Census. The linkage, retrieval and security functions of this 
system are discussed under the Clinical Support Section's 
summary. 

The impact at NIH of a new approach to systems development 
known as Data Base Management Systems (DBMS) has not been 
established at this time. IBM's Information Management System 
(IMS) is one of many such DBMS's currently marketed by software 
vendors. In a joint effort, the NCI and DMB have begun an 
evaluation of this system. A data base developed by Stanford 
Research Institute for an ongoing NCI study of potentially 
hazardous compounds was transferred to NIH during the year. 
DMB personnel adapted this data base to run under the IMS 
Interactive Query Facility and NCI is now testing the 
flexibility of this software to meet its needs. In an attempt 
to examine the full IMS utility, DMB Is In the process of 
developing a Divisional Information System for Cancer Cause and 
Prevention . 

A critical review of DMB applications software facilities 
resulted in a complete upgrade of the Recursive Macro Actuated 
Generator (RMAG) to Its latest version RMAG21. This new 
facility handles all varieties of record formats, eliminates 
the need for intermediate reading of edit format data sets, 
provides automatic blocking and deblocking and enables parsing 
of input data In extremely flexible form. The overall Impact 
of this effort is easier programming, shorter execution times 
and reduced costs. A complete rewrite and integration of all 

74 



of the existing generator programs using RMAG21 is currently in 
process and should be available for final testing by mid-fall 
1975. 



The IBM STATPAK software, a package of UO on-line 

statistical routines, was recoded to FORTRAN IV from BASIC and 

implemented under the Time Sharing Option. Current usage of 
this package exceeds 175/week. 

During the past year, development of a data management and 
statistics package (DMSP) was undertaken. This package will be 
used to solve a variety of problems including editing, 
consistency checking, updating , selection, transformation, 
recoding, and elementary statistics. It is desirable to 
consolidate the solutions to these problems into a single 
package in order to make the computer easier to use. 



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ava i 1 abl 
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■X) 

73 



\ system has been completed to provide massive storage and 
retrieval of chemistry data for the Endocrinology Branch, MHLI. 
Complete demographic and the associated chemistry data on 75 
patients have been stored on tape using this system. This data 
base will provide patient chemistry Information for the MHLI 
staff. It wi 1 1 also provide data for statistical evaluations. 
Statistical analysis, to date, has included evaluations of time 
of blood as well as blood pressure data, and trend analysis to 
evaluate short-term effects on blood pressure of patients using 
certain drugs. 

In collaboration with the N.I Af'PP Field Studies Section in 
Phoenix, Arizona, we are examining insulin responses in a 
relatively well-known Indian population. In another project 
Branch personnel are Involved in orienting the research 
investigators in the NIAf'P Field Studies Section in Phoenix, 
Arizona with statistical packages In PCRT, especially with the 
capabilities of the Statistical <\nalysis System. This 
orientation will provide them with tools to analyze large 
volumes of data representing relationships of insulin level to 



75 



oral glucose load In subjects with a wide spectrum of glucose 
tolerance among the Pima Indians (a group having an extremely 
high prevalence of diabetes). We have developed special 
procedures to in ure the proper evaluation and execution of 
computer runs and to reduce computer run time on the projects. 

In an effort to assist patients who have had laryngectomies 
the Veterans Administration is examining Individual self 
concepts using O-technique. A self assessment of definable 
personality traits is provided by each patient. Then 
evaluations of these data are performed. Evaluations have 
included correlations between "actual self-concept" and ideal 
self-concept; "actual self-concept" and "other" self-concept; 
evaluation of self-acceptance, independence/ and r;ood emotional 
control; and evaluation of self-rejection, dependence, poor 
emotional control, and withdrawal. 

PMB has been working with the Laboratory of Statistical and 
Mathematical Methodology to evaluate and to detail test all 
options of the Statistical Analysis System (SAS) in order to 
determine the algorithmic validity of all features. Data 
Management Branch Staff was Hriefed on SAS capabilities and the 
use of this package is proving to be very valuable in editing 
and analyzing data. 

In collaboration with Pr. Eugene Harris of the Laboratory 
of Applied Studies analysis software has been developed to 
assist him in evaluating in tra- indl v i dual variations in serum 
blood constituents. Major portions of this package are 
complete. It has the capability to compute and plot tests for 
normality, test multivariate normality for selected 
combinations of tests, estimate average I ntra- indi v idual 
variance, calculate pairwise correlations, calculate selected 
multivariate normal regions, and estimate purely physiologic 
variance. 

A set of programs was modified and fully tested, on our 
system, to perform spectral analysis of digitized input data. 
These programs were written at Johns Hopkins University Applied 
Physics Laboratory. The programs compute three main functions: 
the power of spectral density data to decompose into different 
frequency components; autocorrelation to examine data 
periodicity; and stationarity and normality to determine the 
suitability of the data to be represented by spectral aralysis 
a 1 on e . 

The applications programming summary Is as follows: 

Documentation and Systems Support Section 

1. In processing Case Reports new procedures to more closely 
control the editing and balancing of data using computer 
runs and AUTOTAB were introduced this year and personnel in 

76 



the OP/ORA Offlre were trained to use them effectively. 
For Fiscal Year 1973 approximately 50% of the 137 output 
reports were produced using generated programs. At the 
present time the OP/ORA Office is considering only 
producing about 25 general summary tables for this fiscal 
year and supplying detailed information by use of Query and 
AUTOTAR to those requesting such reports. 



Continued our support for esoteric CICS programs in the 
ARMS Personnel System. Turned interactive retrieval 
programs over to SAB Staff. 



Interfaced 
faci 1 i tate 



the Opportunity Skills System 
update and reduce manual effort. 



wi th ARMS to 



__ _ 



Set up a system to verify Central Account Numbers 
via OFM CAN tables. 



for PRS 



To support various DRS Branch activities/ we are. currently 
designing and developing systems for maintaining and 
controlling the 1) Glassware Billing System, 2) the Small 
Animal Billing System and 3) the Planning System. 



Peveloped an NEI Information System for 
programs including contracts via the PPG 
manually entered data of additional interest, 
provides update, edit, report and query facilities. 



al 1 extramural 

IMPAC System and 

System 



Established an on-line consultant file for the NMLI, which 
provides update, edit and query canab i 1 i t i*>s to facilitate 
the selection of team members for such things as site 
visits. 

Currently developing an inventory system for the N!'LI to 

control approximately 25,000 "cell line" vials stored in 

six freezers at various locations within the Laboratory of 
Biochemical Genetics. 



^r 



9, 

10, 



Produced a Pata File of Soviet Cytologists and 
for MIFHS. 



Geneti cists 



Currently producing Machine Readahle and Searchable indices 
of the PHS-1U9 series: "Survey of Compounds which have been 
tested for Carcinogenic Activity" for NCI. 



V 

1*1 I 



11. Developed some fifty-one report programs which provide 
inventory and natural history data on primates (C^BUS 
monkeys) used in the NINPS Herpes Study. 



77 



12. Currently designing a system to evaluate the Siperstein 
method of diagnosing dlahetes. Current plan is to apply 
Siperstein's basement membrane theory to a known Pima 
Indian population and Caucasian normal control group. Drs. 
Siperstein and Williamson will provide input to the system 
in support of this M I AMD Field Studies Section evaluation. 

13. Currently developing a system intended to correlate the 
incidence/ morbidity and mortality of kidney and urinary 
tract disease with research need. The population being 
studied is the three armed services from January, 1971 
through December/ 1973. 



Ik. Developed a Print Format Generator (PFG) for 
production of report programs from data layout 
formats. 

15. Case Data Preparation for NSF, OD/ORA. 

it). KWIC Indices for the MIH Central Library, DRS/L. 

17. NICHP Grant System. 

18. Baltimore Cancer Research Center (BCRC) Study, NCI. 

19. Lupus Study, MIAMD. 



easy 
sheet 



20. This section also supports Tablemaker and is responsible 
for reviewing all DMR documentation before it is released 

to NIH users. 

Applied Systems Programming Sections 

1. In support of the Type II Intervention Study for the Lipid 
Metabolism Branch, NHI.I, continued our monitoring of all 
data base activities and provided several new reporting 
faci 1 i t ies . 

2. Currently providing an interface between data base 
functions and the statistical segment for the 
Carcinogenesis Bioassay Data System. 

3. Currently participating in a retrospective study of Cardiac 
Valve Replacements for the Clinical Surgery Branch, NHLI. 
The study involves the collection and analysis of various 
pre-and post-operative data on the more than one thousand 
patients v/ho have had heart valves replaced at the NHLI. 



78 



U. Developed a completely new interactive system for the 
Emergency Virus Isolation Facility/ NCI. . All medical 
information on employees of the facility is now entered and 
retrieved in-house; this provides the facility with 
excellent security and privacy for all employee data. 

5. Developed a computerized distribution list for the Grant 
and Contract Guide Distribution Center of DRG. The system 
creates/ maintains/ and selectively produces labels to be 
used in the distribution of the Grant and Contract Guide 
and/or any of its various supplements. Other NIH mailing 
list requirements have also been satisfied using this 
system. 

6. Produced the 15 Federal Survey Tables depicting DHEW 
funding to institutions of higher education for Office of j § 
Resources Analysis, O.D. ! ^ 

7. Provided an indexed information system for the Research 
Analysis and Evaluation Branch/ Division of Research 
Grants. The RAF branch has found that by indexing several 
different files, 1) Inventory of Clinical Trials; 2) 
Application for Grants; 3) NIH Grants Abstracts and k) NIH 
Contracts Abstracts, with PMB's Indexing programs and by 
searching the index files with DMB's Index query program, 
they can very quickly satisfy questions relating to these 

data. Prior to the development of this technique data ' D 
volume precluded quick access and retrieval. i 2° 

I 

8. Developed an NIH Central Registry of Biological Agents and 
Materials for the Environmental Services Branch, Division 
of Research Services. DHB is currently augmenting this ESB 
system to include carcinogenic chemicals in use at NIH. '» 

t 

fa 

9. Developed a pharmacy computer file system for the Clinical 
Center Pharmacy. The file contains drug product data on 
all drugs available through the Pharmacy. 

10. Established a computerized data processing system for the 
Laboratory of Parasitic Diseases, MIAir. The system 
maintains all pertinent data on monkeys infected with 
malaria and rnosquitos infected by feeding fron the malaria 
infected monkeys. The study is Intended to trace the life 
cycle of malaria. 

! 

11. Currently developing computerized grants information files 
for the Program Analysis and Evaluation Branch, Division of 
Cancer Grants, MCI . 

12. Provided a Water Supply Systems Inventory facility for the 
Water Supply Branch, Environmental Protection Agency. This 
data processing system helps the EPA monitor the thousands 



79 



15 



of water supply systems in the U.S. To date, there are 
approximately U6,000 water utilities on the master file. 
This accounts for approximately 138,000 water sources. The 
data source i. a questionnaire distributed to each system. 
System data includes such things as treatment processes, 
capacities, sources, etc. 

Implemented a system to produce the Journal of the National 
Cancer Institute (.IHCI) for the Division of Cancer Cause 
and Prevention, NCI. The computerized system aids the 
Office of the Editor in Chief, Jf'C I in handling of data 
endemic to approximately 900 manuscripts per year submitted 
for Dubllcation in JNCI. 



1U. Provided programming support for the data collection and 
reporting segment of the Cigarette Condensate Study for the 
Etiology Branch, MCI. 

15. Continued development of the complete inventory anH 
retrieval system in support of the Institute of Laboratory 
Animal Resources C.I LARS ) . This system is SDonson°d by the 
MCI . 

16. Developed an International Activities and Personnel 
Monitoring System for Fo<>:arty International Center. 

Scientific Applications Section 

1. In support of the Laboratory of Socio and Environmental 
Studies, NIMH, developed a generalized data management and 
statistical analysis system for psychological and 
physiological measures. Programs for handling heart rate 
and galvanic skin response are available, as is the ability 
to retrieve data from those measures using behavioral 
characteristics (or time) as the retrieval criteria. A 
statistical program nroduces summary statistics for single 
physiological measures and regression statistics for pairs 
of measures. During this fiscal year a program for 
identifying and flagging faulty data, programs which 
identify missing data and prevent erroneous data intervals 
from entering the statistical segment of the system, were 
developed. Future efforts include f i ne-tun inp: the user 
documentation and writing a routine for correcting of 
behavioral data. 

2. Added nine new protocols to the Surgery Branch, MCI data 
files. ^ Current plans call for retention of the operation 
data files and dropping the core and protocol Hata from the 
active system. 



80 



_ 



3. Currently developing a clinical patient followup file for 
the Surgery Branch. Using the DMB generators, programs 
were generated and modified for creating update 
transactiors and for the update and edit functions. 
Retrieval programs and a print program which provides the 
physician with a summary of his patient's treatment history 
will be available soon. Plans for the future include 
changing the site and histology codes and the associated 
error checking routines when the new international cancer 
surgery coding scheme is available. 

k. Continued support of the current awareness search for 
Clinical Biological Activities (CBAC). This service is 
still offered free of charge to all researchers at NIH and 
is run biweekly as tapes are received from Chemical 
Abstracts Service in Columbus, Ohio. Current plans are to 
drop retrospective searches in favor of timesharing 
systems. Programming effort to duplicate what is already 
offered by timesharing organizations precludes duplicate 
development. Use of timesharing services would also 
provide NIH reseachers access to CA Condensates, which 
reflects the entire 80 sections of CA, as well as easier, 
quicker access to CBAC. 

Completed first full year of support for current awareness 

search of Biosciences Information System ( B I OS IS). Twice a 

month tapes are received from the Biological Abstracts I 

Service and information is disseminated to the NIH | zt 

community through the same vehicle as CBAC. 

Mr. Gillespie of the NIH Library has been the primary 

contact for NIH researchers wishing to search this data 

base; he submits their profiles to DUB for Current :, 

Awareness searching. K 

if 

5. Continued support of the Survival System, which was 
originally developed to support the End Results in Cancer 
studies of NCI and now serves other NIH Institutes. 

i. I 
During the year several new requests for copies of the jjj I 
system by organizations outside the NIH were satisfied. 

The next submission of data wi 1 1 involve changes in format 
and data code values making it necessary to modify the 
Survival System to reflect these changes. 

G. Initiated work on the survival or life table analysis for 
the Cutting Oil Study. This system supports the efforts of 
the National Institute of Occupational Safety and Health. 
It is a study relating job type to mortality and morbidity 
of cutting oil workers. A data base has been established, 
and preliminary frequency tables have been produced. 

81 



7. Revised the programs which evaluate the dally 
scintillation counter output of radioimmunoassays for 
MICHP. Periodic revisions are necessary to keep pace with 
changing theory and methodology. In addition the plot 
portion of the system was replaced by a new printer plot 
canah ? 1 i ty . 

8. Developed a cataloging system for sera and the multiple 
tests run on them for the Surgery Branch, NCI. Retrieval 
is possible by cancer site, histology, patient number and 
name. Time for collecting a representative batch of sera 
for desired lah tests has been cut from 1^ hours to one 
hour . 

9. Continued support of the Mass Spectral Retrieval System, in 
collaboration with Pr. Fales, Laboratory of Chemistry, 
NHL I . 

During FY 75, a new data file, which Increased the number 
of spectra from 12,000 to 28,000 was put up despite severe 
interface problems between the system's two computers. A 
17-tape file of spectra sorted hy peak was also put up. 
The fiche generation program was updated and successful ly 
run, a new option was added to the search, and a number of 
problems were uncovered and removed. A new data file which 
will raise the number of spectra to 35,00C is being worked 
on currently. When purified, subsets of the new file will 
be made available as the complete file is too large for 
present hardware. Maintenance documentation of the system 
is being completed. 

10. Developed a program, which provides plots and quality 
control statistics for laboratory experiments having to do 
with radioimmunoassays, for the Reproduction Research 
Branch, NICHD. 

After a period of use in the lab, more tests will be added 
to the program. 

11. In collaboration with Pr. Rodbard, Reproduction Research 
Branch, MICHP, modified a npc^arp of programs which do oeak 
detection and non-linear curve-f i t t i n* analysis on 
chromatographic data. Several ootions for clu^pinr; and 
smoothing of data points have been added and a plot 
capability included in the package. 

Future plans for this pzckarp Include the development of a 
preprocessor for deriving initial values from computer 
examination of data, a histogram to aid in making manual 
decisions on initial values, and addition of other 
equations, e.g., log-normal, to the curve-H tter oro^.ran 
which now is used in the Oaussian mode. 



82 



12. Began development for the analysis phase of the 
Carcinogenesis Bioassay Pata System. This involves data 
from ongoing bioassay experiments in mice. The immediate 
aim is to detect previously unidentified carcinogens. 
During the next fiscal year a statistical description 
program giving counts of animals with specific pathologies, 
and a program generating regular survival curves, 
Kaplan-Meier curves, and the Breslow statistic will be 
incorporated Into a terminal -dri ven analysis system, which 
will build (in the conversational mode) parameter cards and 
JCL for batch runs. 

13. Redesigned the format of the drug file for the Division of 
Cancer Treatment. This data set, which contains cost 
information on clinical trials and preclinical screening of 
drugs, required new variables and new codes for existing 
variables. A data edit and update program was generated 
and a report summarizing the input data was proviHed. Also 
to be completed are four other summary reports. Future 
plans include addition of data retrieval via a CRT. 

1I+. Provided programs for performing analytic calculations on 
scintillation counter data and plotting the manipulated 
data for the Laboratory of Chemistry, NIAMD. Future plans 
include adding new input formats whenever new instruments 
are purchased, and adding more efficient correction 
equations as new types of experiments are undertaken. 

15. Developed programs to provide summary statistics on Mi rex 
pesticide residue potency and exposure time for the 
Department of Agriculture. It was also necessary to create 
a reformatted tape with generated fields. Statistical 
analysis of this data (e.g., regressions) is taking place 
at the Department of Agriculture and the EPA. 

16. Provided Wy 1 bur-ori ented data collection and search 
procedure for Dr. Freese, NIMPS, to allow him to access by 
computer a collection of about 10,000 paper and journal 
c i tat ions . 

17. Assisted Dr. Reichert, Laboratory of Meurochemi stry, MIMPS, 
in developing a data file to best utilize DCRT computer 
facilities for data analysis of sound-induced epilepsy. 
Laboratory of Statistical and Mathematical Methodology, 
DCRT, is providing statistical advice. 

18. Completed development of a Jata base of journal abstracts 
from the literature of gastroenterology. Reformat and 
print programs were written. The CRAC system was utilized 
for searching the text. This is a pilot project to 
determine the usefulness of computerizing this data base. 
A number of searches were run on the data base in order to 



83 



explore the completeness of the file and the utility of the 
search. This experience indicates that automatic searching 
would not be cost effective at this time / and that a manual 
search is adequate. Running the Concordance program on the 
data base to produce a KVJI C index for manual searching is 
the direction currently being explored. 

19. Provided analysis and statistical programming support for 
the Type II Coronary Intervention Study. 

20. Converted five PL/ I programs from F-level compiler to 
Opt imiz-Opt imiz ing compiler for ■'Lf's Toxline Tata Rase. 
One program was incomplete anH required that an additional 
nodule be written. 



Clinical Support Section 



T^r INFORMATION SYST r M 

During the past year the Clinical Support Section, in 

collaboration with Pr. Sharna, NIM'PP, has developed new 

modules for a planning and forecasting system, and 

conceptually/ has improved t^e structure and utility of 
tbp system. The new modules are defined as follows: 

. PERSONNEL f'odule - This module permits the operator 
to retrieve user-selected information in the field of 
personnel for decision-making purposes. The selections are. 
made using the output selection sub-module wh i ch permits the 
user to display all or specific parameters from the unit 
record. 

PROJECT Module - The PROJECT Module displays 
selected information fror^ three major sources: allotment 
allowance registry, object classification data, and program 
and monetary data. 

TRACKING - In the planning area, a module was 
developed that permits the collection, processing, 
recording, and displaying o^ program information for 
administrative and management purposes. The TRA0KI M f'odule 
was developed using the following assumption: the planning 
phase gops through many stages, and managers would like 
to recall, manipulate, an^ display various changes, 
additions and modifications made to programs in the 
p 1 ann ing phase . 



84 



Functional descri nt ions 

systen are: 



of the older nodules of this 



. PROJECTION - This nodule displays contract and 
grant information in o. very special way: using a base 
year and a selection strategy, the module will project over a 
six-year period monetary requirements for the defined time 
period and area specified. 

. RETRIFVAL - Thp RETRIEVAL Mo^uIp displays contract 
and grant information in a matrix format. The hasic 
information displayed may he characterized as a profile 
of grants and contracts in a selected arpa. 

.SUPPORT Modules - These nodules are simply support 
programs designed for system maintonance purposes. 



Since this system was designed to 
and interactively, some work was 
display of operational information, 
uniquely defined commands with 
parampters for defining rptrievals. 



he operated on-line 

done to improve the 

Each nodule has 

positioning selection 

Thesp commands and 



selection parameters form sub-modules within each major 
module, and are. used to extract subsets o* a riven data 
hasp for display. 

\ HELP r ommand was dpvplope^ that permits the user 
to display information on how to operate a user-selected 
module or specific command v.ithin the selected module. This 
dpv^ 1 opmen tal work was done using BMP M otions not only for 
assisting thp user, but to document the p->odule. 

THE CLINICAL CENTER PROJECT 

The improvement of the availability of clinical data to 
the NIH research community has been our primary concern this 
past year. This task was done through the expansion of data 
coverage and the completion, of our initial concept of a 
Clinical Information Utility (CIU). 

Presently, there are. three clinical data sources: 
clinical pathology laboratory data, discharge diagnosis and 
census data. Although only two of these data sources are 
accessed using the CIU System, clinical pathology laboratory 
and discharge diagnosis data, techniques have been defined 
which permit the retrieval of census data within the CIU 
structure . 

The Clinical Information Utility System is a special 

data base management system that accesses clinical data by 

patient hospital numhers, data coded elements or a logical 

expression of data coded elements. The accnss by patient 

hospital numhers is simply a direct procedure that permits 
the retrieval of all or subsots of patient data. 

85 



iV^ 



o 

73 
73 

I 

5 . 



The most powerful accessing technique of clinical data 
is performed by defining a patient set using Boolean 
logic. This procedure allows the user to define a set of 
patients using data coded elements from clinical pathology 
laboratory data, discharge diagnosis or both. The data coded 
elements are laboratory test codes and ICPA codes. 

The Boolean logic accessing technique is made possible 
by simply inverting the files on the data coded elements, 
i.e., the keys in the inverted files are the data coded 
element. The unit record, uniquely defined, contains all 
patients that have had a given test or all patients that were 
discharged and assigned a specific ICPA code. 

The Boolean logic module uses RMAC, a data support 
system developed in the Data Management Branch. All of 
the Boolean operators can be used for defining a selection 
st rategy . 

The Privacy Bill requires all systems accessing Federal 
Pata Bases to maintain a log-file. In this log-file, the 
systems must record the following information: 

a) Who accessed the data? 

b) When was the data accessed? 

c) Why was the data accessed? 

d) What data was retrieved? 

This feature was defined and implemented this past year 
for rpcording the above information. The Privacy 
questions arp answered by simply running an inquiry using 
IRS to retrieve the requested information from the log-file. 

Administratively, C I U is operated by the 
Clinical Center Staff, OP AMS . Access to the data base is 
approved byOCAI'S. This office will request answers to 
the questions previously stated on Privacy for recording 
into the log-file. Other information such as accounting 
and type o* retrieval will he requested for the completion of 
access privileges. 

The search parameters that are used for retrieval 
purposes are as follows: 

a) patient hospital nunher 

h) data coded elements 

c) date or date range 

H) test value or value range. 

In general t^e types of retrievals that may He define^ are : 
a) All data on specific tests for a list o* natients; b) Ml 
data^on for a list of patients; c) all discharge diagnoses on 
a list patients; and d) any coronation of search 
pa rameters . 

86 



Software Support Section 

As discussed in the Branch summary/ RMAG21 has been 
developed this year and all of the DMB generators are being 
redesigned and implemented using this flexible software. 



87 



July 1, 1974 through June 30, 1975 

NATIONAL INSTITUTES OF HEALTH 
DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY 

Summary of Branch Activities 1. DCRT 

2. LABORATORY OF STATISTICAL AND MATHEMATICAL 3. James E. Mosimann 
METHODOLOGY Chief 



1. INTRODUCTION 

In its initial year of activity, the Laboratory of Statistical and Mathe- 
matical Methodology (LSM) developed its role of service in statistics, 
mathematics, and computer science for the NIH community. First priority was 
given to the establishment of computational and consultative services 
available to any member of NIH. New program packages of statistical and 
mathematical routines were implemented, and an active program of consultation 
was initiated. The description of computational and consultative services is 
outlined in sections 2 and 3, respectively. Some consultative services 
resulted in close collaboration of LSM staff with the investigator, and joint 
publication of results occurred. 

LSM's own research activity is indicated in section 4. This activity is 
essential, since a program of consultation and service like that of LSM 
requires highly skilled professionals in statistics, mathematics and computer 
science . 



2. COMPUTATIONAL SERVICES OF LSM 

An important part of LSM's activity is the implementation and maintenance of 
statistical and mathematical program packages for the NIH user community. 
These packages offer a variety of programs to the user. 

In addition to those previously available, four packages have been newly 
installed on the IBM 370. These are: SAS, the Statistical Analysis System 
from North Carolina State; TMSL, the International Mathematical and 
Statistical Library; PSTAT, the Princeton Statistical Package; and BMDP, the 
new UCLA Biomed series of programs. Along with the old BMD series, which will 
still be offered, and the NIH program collection known as MSTAT1, a broad 
statistical and mathematical capability is now available to 370 users. 

Each package has its own characteristics and advantages. Some attractive 
features of SAS are the ease of use, convenient analysis of subsets of a data- 
set, and simplicity in editing, modifying and transforming data. SAS and 
WYLBUR are particularly compatible since SAS statements are column-independent. 
SAS is usable by anyone willing to learn a few procedure statements. The TMSL 
library comprises about 400 mathematical and statistical routines. Unlike SAS, 



88 



the user writes his own main routine to call these. A strong point of this 
library is its use of up-to-date numerical algorithms. PSTAT, the Princeton 
statistical package, offers programs that will perform multivariate analyses 
on large databases involving many variables. 

The use of LSM-supported statistical and mathematical packages at NIH is 
considerable. Routines of the BMD package had an average of over 600 user- 
accesses per month during the past year (low, 430; high, 890). The new BMDP 
series was implemented at the end of the fiscal year, and counts of its use 
are not yet available. SAS, a new package, has shown steady growth in use. 
Accesses for the last four months have climbed as follows: 220, 320, 480, 530. 
This system now has close to 200 users. As an example of a package used for 
specialized but essential purposes, PSTAT had an average of 10 accesses per 
month. Since TMSL is a subroutine library, counts are not available. The old 
math/stat library MSTAT1 had 900 accesses per month in the first half of the 
year. Unfortunately, comparable counts are. not available for the second half 
of the year. 

Important packages in the mathematical modeling area are MODELAIDE (S/370) and 
MLAB (PDP-10). Both packages receive wide use at NIH and elsewhere. Their 
authors are currently with LSM. Both the authors of MODELAIDE and MLAB are 
active in consultation and collaboration with NIH users . Both systems have 
been exported internationally and domestically to a variety of institutions. 
Most recently, the SUMEX computer project at the Stanford Medical School is 
providing MLAB to its users. 

In the past year, a new MLAB manual (the 5th edition) has been prepared and is 
available. MLAB is promoted with demonstrations and courses. This system 
provides an interactive mathematical modeling capability with extensive 
graphical capability. 

3. CONSULTATIVE SERVICES OF LSM 

The consultative services of LSM range in subject and scope from answering a 
question about the job control language needed for a particular program 
package, to the development of statistical methods and models for data analysis 
for a particular experiment. 

Specific consulting activity is defined as activity directly and consciously 
devoted to the needs of a specific user outside LSM. Hours devoted to direct 
consulting by LSM during the year are given below. Of course, other LSM 
activities underlie and support the direct consulting; for example, installa- 
tion and maintenance of statistical packages requires considerable time which 
does not appear as direct consulting. 

LSM averaged 550 hours per month of specific consulting out of 1600 total 
hours. All NIH institutes except NIGMS are represented in these hours. 
Eighty-five percent of LSM's specific consulting was directly to users out- 
side DCRT. The remainder was also directed to users outside DCRI , but through 
the intermediary of non-LSM, DCRT staff. 



^W 



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Of the total hours, 20 percent involved largely mathematical or statistical 
advice with little computer use; 40 percent involved mathematical and 
statistical advice alongside considerable computer use; 40 percent involved 
mostly computation with little or no mathematical or statistical advice. 

A major service of LSM consulting is responding to trouble-shooting questions 
rapidly and efficiently. Just over 50 percent of specific consulting 
activities involved sessions of one hour or less; and just over 80 percent, 
4 hours or less. Availability of staff for the rapid resolution of user 
problems is a prime concern of LSM. 

Of those jobs requiring more than four hours, many represent a sizeable effort 
on the part of LSM staff. The following list gives some indication of the 
variety of such projects. 

1. J. Bieri and R. Evarts, LNE, NIAMD. Evaluation of the Vitamin E activity 
of gamma- tocopherol relative to alpha- tocopherol. Consultation was done 
on the analysis of experimental data to assess the relative potency of 
gamma- tocopherol as well as on the statistical principles underlying 
parallel line bioassays. 

2. V. Bono, DE, NCI. Evaluation of chemotherapy drug assays. Computer 
models were developed and implemented for the analysis of cell DNA 
content, as revealed in histograms obtained from drug- treated tissue 
culture preparations. Therapeutic and non-therapeutic drug effects 
were contrasted. 

3. A. Cheever, LPD, NiALD. Study of the effects of schistomiasis using 
autopsy data. A large file was organized. Numerous tables were produced. 
Discriminant and other analyses were performed. To date, association of 
egg and worms burden by anatomical site with pathological conditions have 
been studied. 

4. B. Chock, LB, NHLI. Cascading enzyme systems. A system of cascading 
enzymes is simulated using MODELAIDE. 

5. J. Folk and R. Chung, LB, NIDR. Activation and inhibition of clotting 
factor XIII. Mechanisms of action are being modeled. 

6. M. Geier, LGCB, NIMH. Maintenance of data analysis software. Computer 
programs for evaluation and display of laboratory data were maintained, 
and user assistance provided as needed. 

7. V. Geoffrey, IR, NINDS. Study of dystonia. Analysis of time intervals 

comprising sequences of speech, dystonia, speech, Calcomp programs 

were written for graphic display of the sequences over time. A large 
FORTRAN program generated tables of data cross-classified and grouped. 
Various descriptive statistics were generated by use of packaged programs. 



90 



V. Geoffrey, IR, NINDS. Parkinsonian patients. Accelerometer observa- 
tions were made on speech sounds under two different treatments. The 
association of accelerometer variables with treatment was studied, 
assisted by Karen Pettigrew, NIMH. A package profile analysis, in 
conjunction with editing and other package programs was employed. 

R. Ginsberg, EFS, NIAMD. Investigation of the effect of phenobarbital on 
biliary lipid metabolism in man. Biliary parameters were measured before 
and after administering the drug. Statistical tests of significance were 
performed to determine whether differences existed between the means of 
the biliary parameters before and after administration of phenobarbital. 

R. Hamman, EFS, NIAMDD. Data on diabetes patients. Several days' study 
of BMDX76 (Survival Curve Program) to interpret options and output. 

R. Hamman, EFS, NIAMDD. Time-in-study without a positive glucose 
tolerance test: subjects from a population with high incidence of 
diabetes. Age/sex/weight were cross -classified and compared. A 
FORTRAN program was devised. 

R. Hendler, LB, NHLI. Oxidation of cytochromes. A paper has been 
completed using the non- linear fitting procedures of MLAB. 

R. Hendler, LB, NHLI. Mathematical modeling. A paper on oxidation of 
cytochromes is now in print. Models for an improved multi-channel 
technique for resolving absorption data into chemical species are being 
considered. Also, models for DNA damage and repair are under discussion. 

C. Hoover, DCBR, NIMH. Marital conflict in manic-depressive patients. 
The investigator is attempting to isolate factors in marital conflict 
which differentiate patients from their spouses or distinguish between 
diagnostic subclass if icat ions of manic-depressive illness. Thus far, 
discriminant analysis has been the principal statistical method employed. 
A program has been written to evaluate discriminant functions calculated 
by the BMD series discriminant analysis program. 

L. Keefer, CMT, NCI. Investigation of the hydrolysis of methyl 
(acetooxymethyl) nitrosamine (DMN-OAc) to the presumed carcinogenic 
metabolite of dimethylnitrosamine (DMN-OH) . In order to determine the 
uniform consumption rate of the starting material and a uniform 
disappearance rate of the total nitrosamines , regression analyses were 
performed . 

L. Kohn; R. Tate; L. Leive, LBP, NIAMD. Two counter scintillation. A 
mathematical solution for the optimum position of a discriminator between 
carbon and tritium channels was obtained. 



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17. L. Kvols, BC, NCI. Duration of remission and mortality data for Hodgkin's 
disease. Several analyses were made using the Breslow program. 



91 



18. C. Maloney, BOB, FDA. Pertussis potency tests. This project involves 
the development of statistical programs for use in the comprehensive 
examination of the potency and safety testing of pertussis vaccines by 
the Bureau of Biologies. Findings have led to innovations in testing 
procedures . 

19. C. Maloney, BOB, FDA. Bioassay. This project involves evaluation of 
different computational methods in an effort to refine the assessment of 
biologies products. A bioassay program with a number computes either 
probits or logits with options for individual and/or pooled slopes, with 
or without conversion of, and a test for parallelism in relative potency 
has been written. 

20. N. Matheson, EM, NLM. The impact of a one -year grants program on 
hospital library development. A master file was created, and programs 
to generate new variables were written. These were interfaced with the 
Statistical Analysis System (SAS) which was employed to calculate a 
large volume of descriptive statistics and tables. Ms. Matheson 's report 
concluded that the grants program had had a statistically significant 
effect on the development of hospital libraries. 

21. E. Mihalyi and D. Towne, LB, NHLI. Kinetics of Fibrinogen digestion. 
A fourth paper in a series on this topic has been completed. The 
analyses involved extensive use of MODELAIDE. 

22. R. Peabody, DIR, CC. Interview scheduling. LSM has assumed the 
responsibility of preparing and running the interview scheduling system 
for the NIH Associate Program of the Clinical Center. This system, 
which schedules the applicants for interviews, prints acceptance letters, 
interview, applicant, and master schedules, is run each spring. 

23". H. Pettigrew, B, NCI. Small-rodent carcinogen-bioassay experiments. The 
analyses employed survival curve methods. Modification of a previously 
existing Breslow program, and study of the literature on survival curves 
was performed. 

24. W. Reichert, LNC, NINDS. Study of sound exposure and audiogenic seizure 
on cerebral ATPase activity in mice. Comparisons of enzyme activity in 
sound-exposed and control mice of two strains were made using analysis 
of variance and t-tests. Data were first standardized by litter. 
Reichert has finished a paper on this work. 

25. D. Reiss, APB, NIMH. Multi-family group study. This study concerns 
disturbed adolescents and their families. There are four major types of 
data: "who-to-whom" speech data, cohesiveness questionnaire data, 
sociometry data, seating position data. Data for this study is 
voluminous. Although programs for each type of data are completed, 
maintenance and data processing does require considerable effort. 

Dr. Reiss is now with the Center for Family Research, George Washington 
University. 



92 



26. P. Savage, EFS, NLAMDD. Discriminant analysis of diabetes -related 
variables in patients with and without retinopathy. 

27. P. Savage, LFS, NIAMDD. Multivariate observations on diabetes patients. 
Queries on mathematical models were handled and multiple and partial 
correlation and regressions were performed. Relevant literature was 
reviewed. Interpretation of SAS options and outputs in regression and 
correlation programs was given. 

28. K. Smith, VR, DRS. Selection for body weight in mice. Statistical 
programs have been written for this study which are directed toward 
providing an objective evaluation of the effects upon genetic variation 
in inbred strains of mice. 

29. G. Spellman, CP, CC. Effect on clotting of varying amounts of red cell 
protein. Extensive editing and package programs were used in conjunction 
with mathematical modeling by Karen Pettigrew, NIMH. 

4 . RESEARCH ACTIVITIES OF LSM 

The LSM computational and consultative activities place highly qualified 
mathematicians, statisticians and computer scientists at the service of the 
biomedical community. LSM specialists must exhibit an up-to-date knowledge 
of their subject matter fields at the research level. Research activities 
within LSM in mathematics, statistics, or computer science (1) either spring 
directly from NIH problems which require new explorations in these fields or 
(2) contribute in a major way to the development of the staff member's 
excellence in the field for which he is responsible. 

The LSM research effort averaged 500 hours per month. About 50 percent of 
these hours are in support of direct consulting activities. Individual 
projects follow. 



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93 



Project No. Z01 CT 00008-01 LSM 

1. Lab. of Stat, and Math. 
Methodology 

2. Not Applicable 

3 . Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 



Project Title: Pattern Recognition 

Previous Serial Number: None 

Principal Investigator: Marvin B. Shapiro 

Other Investigators: David Symmes (NICHHD) 

Cooperating Units: None 

Man Years: 

Total: 0.5 

Professional: 0.5 

Others: 0.0 

Project Description: 

Objective: 

The development of a set of pattern recognition computer programs for 
use in biomedical research. 

Methods : 

A variety of pattern recognition techniques are being implemented for 
the PDP-10 computer. These techniques include the computer learning 
machine, the minimal spanning tree algorithm, non- linear mapping methods, 
feature selection, and nearest neighbor analysis. 

Major Findings: 

(1) Both learning machine and cluster analysis techniques were applied 
to an analysis of monkey vocalization patterns. Results clearly showed 
that the patterns for each individual monkey clustered together and that 
patterns for a given monkey can be recognized as different from those of 
other monkeys. 

(2) An algorithm was developed which considerably improved the 
efficiency of the nearest neighbor method, a widely used pattern 
classification technique. 



94 



(3) Learning machine and nearest neighbor classification techniques 
were applied to predicting the activity of cancer anti-tumor drugs 
based on substructural features. Using a training set of 138 drugs 
containing 421 different substructural features of three types - 
augmented atoms, ring structures, and paths between heteroatoms - a 
prediction rate of 80 - 90 percent was obtained on a test set of 24 
drugs of unknown activity. 

Significance to Biomedical Research: 

The recently developed field of pattern recognition offers important new 
approaches to organizing and analyzing biomedical data. Especially 
important is its ability to find unexpected relations among data. To 
display multidimensional data, to analyze features in data are other 
important benefits. 

Proposed Course: j §o 

The programs already developed plus a number of other important methods 
will be collected into a package designed for general use on the PDP-10 
computer. A manual describing the package will be written and distributed. 

Keywords : 

pattern recognition, cluster analysis, learning machine, nearest neighbor 
classification, feature extraction 

Honors or Awards: None 

Publications: 

Chu, K. C. , Feidmann, R. J., Shapiro, M. B. , Hazard, G. F., Geran, R. I.: 
Pattern Recognition and Structure-activity Relationship Studies. Computer- 
assisted Prediction of Antitumor Activity in Structurally Diverse Drugs in 
an Experimental Mouse Brain Tumor System. J. Med. Chem . , June, 1975. 

r«, 

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95 



-' 



Project No. Z01 CT 00009-01 LSM 

1. Lab. of Stat, and MathT" 
Methodology 

2. Not Applicable 

3 . Bethesda 



# 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 



I 



Project Title: Research Topics in Computer Science 
Previous Serial Number: None 
Principal Investigator: Gary D. Knott 
Other Investigators: None 
Cooperating Units: None 



Man Years : 




Total: 


0.7 


Professional: 


0.5 


Others : 


0.2 



Project Description: 

The object of this project is to develop theoretical bases for new computer 
methods which will expand and improve its use in biomedical computation. 
The methods used are the application of known and the development of new 
pertinent theorems from combinatoric and other related mathematics. 
Research work in storage and retrieval algorithms and their efficiency has 
been the primary topic of concern. A Ph. D. thesis on deletion in binary 
storage trees has resulted from this research and is cited in the publica- 
tions list below. This research will culminate in several further 
publications in the future. Other work concerns a numbering system for 
permutations of combinations cited below. 

Research on Operating Systems Interprocess Communications has been done, 
resulting in a two-part publication on a proposal for such a facility in 
Operating Systems Review (cited below) and in the presentation of this work 
at the recent workshop on interprocess communications sponsored bv SIGOPS 
and SIGCOMM of the ACM. 

Optimal item orderings in split hashing schemes and certain interesting 
algebraic characterizations of fixed permutation open addressing methods 
are currently being studied. 

These methods have and continue to improve the efficiency of computers in 
biomedicine and make new applications possible. 



96 



Keyword Descriptors: 

computer science, storage and retrieval, operating systems 

Honors and Awards. None 

Publications : 

Knott, Gary D.: "A Numbering System for Permutations of Combinations", 
CACM, to appear, 1975. 

Knott, Gary D.: Deletion in Binary Storage Trees, Ph. D. thesis, Stanford 
University, Computer Science Department, 1975. 

Knott, Gary D.: "A Proposal for Certain Process Management and Inter- 
process Communication Primitives, Part I", Op. Sys. Review , Vol. 8, No. 4, 
pp. 7-44, October 1974. 

Knott, Gary D. : "A Proposal for Certain Process Management and Inter- 
process Communication Primitives, Part II," Op. Sys. Review , Vol. 9, No. 1. 
pp. 19-41, January 1975. 



I 



97 



Project No. Z01 CT 00010-01 LSM 

1. Lab. o£ Stat, and Math. A 
Methodology % 

2. Not Applicable 

3 . Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: Nonlinear Equations 

Previous Serial Number: None 

Principal Investigator: Richard I. Shrager 

Other Investigators: Gary D. Knott (LSM, DCRT) 
Edward Hill (LAS, DCRT) 
John E. Fletcher (LAS, DCRT) 
J. Douglas Ashbrook (LAS, DCRT) 

Cooperating Units: DCRT, Laboratory of Applied Studies 

Man Years : 

Total: 1.0 

Prof es s ional : 1.0 

Others: 0.0 

Project Description: 

Ob j ective : 

To develop methods for solving nonlinear equations frequently encountered 
at NIH. 

Methods : 

A continuing effort is made to create methods or extend existing methods 
to solve problems in a host of NIH applications, and to make those 
methods available in convenient computer programs or routines, such as 
MODELAIDE and MLAB. 

Major Findings: 

a) Marquardt's method for nonlinear least squares was extended to 
handle linear constraints. 

b) A suitable error analysis was devised for constrained parameters. 

c) A method for solving nonlinear stiff differential equations was 
adapted to computer from a Ph. D. thesis of Kai-Wen Tu. 

d) Marquardt's method, see (a), is now being extended to norms other 
than least squares. Preliminary results are promising. 



98 



Significance to Biomedical Research: 

These methods are now being applied to problems in human metabolism, cell 
growth, chemical kinetics, and spectral analysis (UV, IR, CD, ORD, NMR, ESR) . 

Proposed Course: 

As the methods are proved in test and practice, they will be incorporated 
into easy-to-use systems like MLAB, and as a result, the systems themselves 
should evolve to do more useful work with both less human and less machine 
effort . 

Keyword Descriptors: 

nonlinear, parameter estimation, least squares, stiff differential equations, 
linear programming, quadratic programming, minimax approximation, error 
analysis 

Honors and Awards: None 

Publications : 

R. I. Shrager: Constraint analysis in model building. Proceedings of the 
Fifth (1974) Annual Pittsburgh Conference on Modeling and Simulation , 
Part 2 , 991-996, Instrument Soc. of America, 1975. 

D. E. Blumenfeld, R. I. Shrager, G. H. Weiss: Spatial distributions of 
homes for journeys to work by different modes of transportation. Transporta- 
tion Res ., 9_, 1, 19-23 (February 1975). 

R. W. Hendler, D> W. Towne, R. I. Shrager: Redox properties of b-type cyto- 
chromes in Eschericia Coli and rat liver mitochondria and techniques for 
their analysis. Biochimica et Biophysica Acta , 376, 42-62, 1975. 

I. G. Darvey, R. Shrager, L. D. Kohn: Integrated steady state rate 
equations and the determination of individual rate constants. J. Biol. 
Chem. , (in press) . 






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99 



Project No. Z01 CT 00011-01 LSM 

1. Lab. of Stat, and Math. M 
Methodology m 

2. Not Applicable 

3 . Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: Discrete Mathematics and Applications 

Previous Serial Number: None 

Principal Investigator: George Hutchinson 

Other Investigators: None 

Cooperating Units: None 

Man Years: 

Total : 0.5 

Professional: 0.5 

Others : 0.0 

Project Description: 

Ob j ectives : 

To make new mathematical methods, techniques and discoveries in discrete 
mathematics available and explore their application to biomathematics 
and computers. 

Major Findings: 

Advances were made in demonstration of recursive unsolvability of 
certain classes of problems concerning subspaces of a vector space. (In 
effect, no computer program can be written to solve this particular 
problem in a general way.) It was demonstrated that certain related 
classes of problems were solvable, and that the order relationships 
between arbitrarily many subspaces of a vector space can be reduced to 
their study between five subspaces. 

Significance to Biomedical Research and the Program of the Division: 

Contribution to mathematical research and constrains computer solutions 
to a wide class of applied biomathematical research. 



I 



100 



Proposed Course: 

An earlier study applying linear inequalities to chemical reaction 
systems will be revised for publication. Mathematical findings are now 
being edited and followup studies in preparation. Further development 
of chemical reaction system analysis will be considered, and new applica- 
tions explored. 

Keyword Descriptors: 

linear algebra, modular lattices, linear inequalities, chemical diagrams 

Honors and Awards: None 

Publications: 

Hutchinson, G.: On the representation of lattices by modules. Trans. 
Amer. Math. Soc. (In press) . 




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101 



I 



Project No. Z01 CT 00012-03 LSM 

1. Lab. of Stat, and Math. A 
Methodology \ 

2. Not Applicable 

3 . Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: Visual and Biological Shape 

Previous Serial Number: DCRT 1.1 

Principal Investigator: Harry Blum 

Other Investigators: Virgil Carlson (NIMH) 

Brian Murphy (NIMH § U. of Md.) 
Richard L. Webber (NIDR) 

Cooperating Units: NIMH, Laboratory of Psychology and Psychopathology 
NIDR, Clin. Invest, and Research Serv. Branch 

Man Years: 

Total: 0.6 

Professional: 0.6 

Others : 0.0 

Project Description: 

The overall objective of this project is to develop a formal descriptive 
language applicable to biological shapes and apply this language to the 
variety of problems arising in biology and medicine: taxonomy, neurobiology 
and organismic development. This would permit a better modeling, hence 
understanding of these processes and also allow for the automation of many 
shape processes now done by humans. 

The method employed stems primarily from a new geometry conceived by the 
principal investigator. It is applied to a variety of problems, both to 
clarify the biological processes taking place and to develop the mathematics 
in biologically relevant directions. These have included cells and tissues 
from light microscopy, skeletal descriptions in growing organisms, chromosome 
description, visual psychophysics and visual neurophysiology. 

A major accomplishment this year is the setting up of an experimental proce- 
dure for doing shape psychophysics on amorphous forms by humans. Other 
major accomplishments deal with theoretical developments to allow implementa- 
tion of such a geometry on a computer. These are: (1) the development of 
a method for getting proper description on a computer without sacrificing 
the smoothness of the forms, (2) the extension of the method to forms that 



102 



are specified by gray scale pictures and (3) the extension of the methods to 
the description of 3 -dimensional forms. 

Anticipated work next year includes the continued experiments on visual 
psychophysics of amorphous forms, continued descriptive work on skeletal 
forms, continued implementation of the theory to computer implementation, 
and finishing of the application to the theory of shape processing in the 
vertebrate visual system. 

Keyword Descriptors: 

biological shape, biomathematics , geometry, taxonomy, developmental biology, 
visual psychology, visual physiology, nervous system models 

Honors and Awards: None 

Publications: 

Blum, H.: A Geometry for Biology. In Gurel, 0. (Ed.)r Mathematical 
Analysis of Fundamental Biological Phenomena . Annals of the New York 
Academy of Sciences , Vol. 231, pp. 19-30,1974. 



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103 






Project No. Z01 CT 00013-01 LSM 

1. Lab. o£ Stat, and Math. 
Methodology 

2. Not Applicable 

3 . Bethesda 



PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 



Project Title: Multivariate Statistical Methods 

Previous Serial Number: None 

Principal Investigator: James E. Mosimann 

Other Investigators: Cecelia B. Clark (Project Stride) 

Cooperating Units: None 

Man Years: 



Total: 


0.2 


Professional : 


0.2 


Others : 


0.0 



Project Description: 

The overall objective of this project is the study of multivariate statis- 
tical methods for the analysis of data which take the form of ratios or 
proportions. Included is a study of properties of the multivariate log- 
normal distribution in the analysis of ratios. This distribution has broad 
applicability to biomedical data at NIH. 

Keyword Descriptors: 

size variable, shape vector, multivariate lognormal distribution, gamma 
distribution, Dirichlet distribution, constrained variables 

Honors and Awards: None 

Publications: 

Mosimann, J. E.: Statistical Problems of Size and Shape. I. Biological 
Applications and Basic Theorems. In Statistical Distributions in Scientific 
Work, Vol. 2, Model Building and Model Selection, G. P. Patil, S. Kotz, and 
J. K. Ord, eds. pp. 187-218, D. Reidel Publishing Company, Boston, 
Massachusetts, 1975. 

Mosimann, J. E.: Statistical Problems of Size and Shape. II. Characteriza- 
tions of the Lognormal, Gamma and Dirichlet Distributions. In Statistical 
Distributions in Scientific Work, Vol. 2, Model Building and Model Selection, 



104 



G. P. Patil, S. Kotz, and J. K. Ord, eds. pp. 219-240, D. Reidel Publishing 
Company, Boston, Massachusetts, 1975-. 



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CONTENTS 



Page 

Highlights iii 

Office of the Director 1 

Office of Grants Associates 5 

Office of Grants Inquiries 7 

Office of Research Manpower 9 

Administrative Branch 11 

Research Analysis and Evaluation Branch 13 

Referral Branch and Scientific Review Branch 15 

Statistics and Analysis Branch 23 






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HIGHLIGHTS 

The Division of Research Grants processed 30,167 applications for the 
FY 1975 councils. This represented a 19 percent increase over FY 1974 in 
applications processed and assigned and a 26 percent increase in competing 
applications reviewed. 

Training programs have become increasingly complex with three different 
types of programs in operation--the traditional research training program, 
the research manpower program, and more recently the NRSA program. New 
application forms and revision of old ones have been necessitated and new 
guidelines developed. 

There was a sharp increase in inquiries resulting from the NRSA program 
announced during the year. 

The centralization of research grant application kits in control offices 
in grantee institutions has been generally accepted. Problems remain with 
NIH components supporting special programs under the research grants mechanism. 



Eight conferences were held to review the status of research in popula- 
tion genetics, NMR resource facilities, nutrition intervention, bioinorganic 
chemistry, growth hormone and growth factors, behavioral toxicology, glyco- 
protein hormones, and epidemiology and biometry resources and needs. 

The Grants Associates Board reviewed 43 candidates; 11 were recommended 
for the Program. By the end of the fiscal year, 8 GA's will be on board and 
7 will have graduated. 

A new system was developed to track applications involving human subjects. 



f- 



Consolidation of various data-capture processes into a single system is 
presently under study. 

Several data items in the IMPAC system were converted to conform with the 
new DFM accounting numbers. 

An informational bulletin, "IMPAC Tech Notice" has been developed for 
issue as needed to keep users informed of current and proposed changes in the 
system. 

Total redesign of the CRISP system was initiated. 



! 



A chart book, "NIH Extramural Trends FY 1967-1974" was preparea for 
administrative use. A series of overhead slides on key extramural trends was 
developed and presented in August 1974. 



OFFICE OF THE DIRECTOR 



The Director attended several meetings during the year under review. He 
spoke at a workshop for new deans held by the Council of Graduate Schools of 
the United States in Gainesville, Florida, July 15-19, 1974; to the Association 
of Independent Research Institutes in Oklahoma City, Oklahoma, September 19-20, 
1974; and at a workshop on sponsored research and training at the University of 
Florida, Gainesville, Florida, October 20-21, 1974. 

The Director attended the meetings of the American Council on Education in 
San Diego, California, October 9-11, 1974; the Association of American Medical 
Colleges, Chicago, Illinois, November 11-14, 1974; the task force on biomedical 
sciences, Council of Graduate Schools, Phoenix, Arizona, December 4, 1974; the 
Western Association of Graduate Schools, Honolulu, Hawaii, March 3-6, 1975; and 
participated in a conference for science executives in Williamsburg, Virginia, 
December 8-13, 1974. 

The Director is a member of the Coordinating Committee for Program Manage- 



The Deputy Director participated in the annual meeting of the Association 
of American Medical Colleges in Chicago, November 13, 1974; in a seminar spon^ 
sored by the Faculty of the University of Arkansas in December 1974, and met with 
graduate and research committees of the University. He also participated in a 
workshop on proposal development, sources of support, and budgeting at North 
Carolina State University, Raleigh, North Carolina, February 5-6, 1975; and 
visited Michael Reese Hospital, Chicago, Illinois, March 19, to consult with 
grantees. 

The Deputy Director is Chairman of the Subgroup on Safeguarding Sensitive 
Statistical Data; the Coordinating Committee on Protection of Privacy; and the 
Manpower Utilization/Productivity Committee of ECEA. 

The Deputy Director is a member of the Committee on Dissemination of 
Research Results; the Federal Information Processing Standards Task Group 15; 
the Grants Associates Board; the ECEA; and the ECEA Subcommittee on Training. 
He also attends meetings of the Collaborative Program Directors. 

The Associate Director for Scientific Review acted as the moderator of the 
NIH Panel at the Federation of American Societies for Experimental Biology 
meeting in Atlantic City, April 14-18, 1975, and spoke at the Minority and 
Women's Opportunity and Resources Conference held at NIH on April 22-24, 1975. 
He also participated in a Conference for Federal Scientists and Science 
Executives sponsored by the Brookings Institute at Williamsburg, Virginia, 
March 9-14, 1975; and attended the Seminar for Executives on Legislative 
Operation held in Washington, D.C. , June 11-13, 1975. The Associate Director 
is a member of the NIH Executive Committee for Extramural Affairs; the ECEA 
Subcommittee on Research; NIH Minority Coordinating Committee; Committee on 
Human Rights; Committee for Development of Peer Review Regulations; Action 
Committee on Review of R & D Contract Proposals; and the NIH Grants Peer 
Review Study Team. He is co-Chairman of the Executive Secretaries ' Review 



it,, 



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Activities Committee and Acting Executive Secretary of the Advisory Committee 
to the Director, NIH, on DNA Combinants. In his role as Acting Executive 
Secretary of the DNA Combinant Committee, the Associate Director was responsible 
for the organization and selection of the membership of this committee. 

The Division's formal employee training program continued throughout the 
year to further the career needs of the staff. Eleven employees attended 
Federal City College under the Upward Mobility Program, and 27 signed up for 
the Staff Training Extramural Program (STEP). The Personnel Office received 
647 applications for training courses, of which 408 were approved. Of these, 
238 employees completed training programs. Ninety-two courses are still in 
progress. Fifty-six employees attended orientation sessions held throughout 
the Division during the year. 

The Opportunity Program (TOP) Committee held a half-day orientation for 
employees to help them with problems and complaints. The Committee also 
assisted in arranging meetings between the Division's female staff members and 
the Federal Women's Coordinator who held three sessions during a day-long visit 
to the Westwood Building. 

The Committee appointed a subcommittee to review the end results of 
training courses (especially those taken by minorities, women, and employees 
below GS 9)--whether or not the courses had a positive effect on employees' 
careers , and the reasons why they took courses if they did not apply for 
positions for which the training qualified them, or why they were not selected 
to fill such positions. 

TOP Committee placed a box in the DRG Reference Room where employees could 
place comments and suggestions that would increase communication between the 
Committee and the staff. 

New staff members are being approached informally by TOP Committee members 
to brief them on the Committee's role and to offer guidance or direction if 
needed. 

The Committee is actively involved in the review and updating of the 
brochure, "DRG is People," to be used as a hand-out for new staff members. 

The DRG-EEO Counselor participated in the NIH EEO Advisory Council 
functions and activities including bi-weekly council meetings, monthly 
Counselor Committee meetings, the annual 2-day NIH orientation for new EEO 
counselors, the Civil Service Commission 3-day on-site EEO Counselor Interagency 
Training Program, the NIH EEO Organizational Development Program, including 
Management by Objectives (2 planning sessions), and several of the NIH STEP 
Committee Continuing Education Program Modules. 

The Counselor met with TOP Committee on a continuing basis, and attended 
the DRG Director's Staff Meetings and those of his ad hoc EEO program group. 
The Counselor participated with members of TOP Committee in a periodic 1-day 
orientation of DRG personnel and office functions, and was a speaker in three 
1-day sessions of the DRG Employee Orientation Program, whereby 75 employees 
were informed of the EEO program. The Counselor also participated in several 



Special Management Workshops and Sessions conducted by the NIH Supervisory and 
Management Development Branch. 

The Counselor maintained a continuing open-door policy regarding opportu- 
nity for counseling on equal opportunity and discrimination procedures, and 
conducted several informal interviews and conferences with Division personnel 
regarding the new NIH Merit Promotion Plan, career ladder opportunities, 
training and participation in the Upward Mobility Program, and other training 
and education opportunities. 






a 

■X) 
73 



II 



OFFICE OF GRANTS ASSOCIATES 

The Grants Associates Program, unique to the Federal Government, is designed to 
train established biomedical and behavioral research scientists in health science 
administration. Since its inception in 1962, the Program has graduated 98 associates, 80 
of whom remain in the Federal Government (77 of these are in the PHS). Fourteen others 
are no longer in Federal employment (although many of these had been in the Public 
Health Service after graduation from the Program); two others are deceased and two 
have retired. 

Among the graduates are the Associate Director for Extramural Research and Training, 
and the Assistant to the Associate Director for Collaborative Research, Office of the 
Director, NIH, an NIH division director, an assistant NIH division director, institute 
associate directors of extramural programs, and several program directors and branch 
chiefs within the institutes. 

Graduates hold positions in all the PHS agencies with the exception of the CDC 
and FDA. Within NIH, former associates hold positions within all the institutes (except 
the newly-established Institute on Aging) and in DRR and DRG. Among the graduates, 
10 are women and 15 are members of minority groups. 



A new area of exploration, but related to the above, is the type of candidate who 
should enter the Program. Initially, the Program had been aimed at researchers with 
little, if any, administrative experience. The trend now is to allow into the Program 
scientists with varying degrees of administrative experience, not necessarily in 
Government. At present there is a mixture of both those with minimal and those with a 
fair degree of administrative experience. The rationale is that such a mixture would be 
advantageous to the GA's who learn a great deal from each other, and also that the person 
with a fair amount of experience in administration could transfer these skills to Federal 
administration, thus producing a stronger health scientist administrator. This kind of 
mixture resulted in an innovation being tried on one candidate, namely an abbreviated 



r*n 



A 3-day retreat was held this year to review the Program, its mission and the means 
toward its goals. Several recommendations resulted, some of which are being implemented; 
others are being processed or reconsidered. Among the recommendations is an emphasis | zo 

on more formalized training, particularly in management. The varied courses offered in 
this area are selected by the Grants Associates in consultation with their preceptors to 
insure that they are appropriate to their training needs. Subsequently these courses are 
evaluated in terms of relevance to other GA's generally or selectively. These courses 1 

have included congressional operations for managers, management principles, program Li™ 

planning and evaluation, committee dynamics, management by objectives and public 
policy, and management of scientific research. Another recommendation is a more refined :j, i 

mission statement followed by clearer selection criteria. This will assist the Board in its 
selective process of inviting to the Program the most qualified from among the increasing 
number of applicants. Another recommendation is the expansion of GA assignments to 
NIH-wide task forces and to other Federal agencies such as OM3 and NSF. 



i 



"'.i 



GA program. The abbreviated period would be decided upon during the first few weeks 
between the associate and his or her preceptor (as opposed to the Board's approving a 
request during the 12-month training period for an associate to terminate early). Although 
this option has been available during the history of the Program, it has not been exercised. 
Should this prove successful, then it could be used again selectively. 

The weekly seminars continue to be a blend of orientation to Public Health Service 
and examples of administration. This year they have included ethical issues: EEO, 
protection of human subjects, and concerns about conflict of interest. 

In FY 1973, 500 inquiries were received about the program, and 557 in FY 1974. 
Up to 300* are anticipated in FY 1975, based on the expected increase in inquiries after 
the FASEB meetings held in April. Sixty-six people, including 8 females and 1 3 minorities, 
were interviewed at FASEB. The meetings are also expected to produce an influx of 
applications. Over 250* are expected by the end of this fiscal year compared with 298 
received last fiscal year and 252 in FY 1973. Forty-three candidates will have reached 
Board review this fiscal year compared with 32 from over 250 applicants in each of 
FY 1973 and FY 1974. As of April 1975, 11 candidates were recommended to join the 
Program. By the end of this fiscal year, 4 of these will be on the Program, 3 others 
have firm EOD dates and 4 others have pending EOD dates. The Program has maintained 
from 8 to 10 associates at any given time. By the end of the fiscal year, the Program 
will have 8 associates on board and will have graduated 7. The 15 associates in the 
Program in fiscal year 1975 represent a variety of disciplines: one each in physical 
chemistry, genetics, experimental psychology, biochemistry, biophysics, microbiology 
and veterinary medicine, and molecular biophysics; and two each in physiology, organic 
chemistry, biology, and zoology. The range of disciplines does not affect the goal of 
the program to develop health scientist administrator generalists, but associates are 
encouraged to pursue their scientific interests on their own. 



The periodic recruitment advertisement in Science was not placed this year, hence 
these figures are not as high as in the past 2 years. 



OFFICE OF GRANTS INQUIRIES 



A sharp increase in routine mail and telephone requests for material 
resulted from the announcement of National Research Service Awards for indivi- 
dual and institutional postdoctoral fellows. 

Amendments to the Freedom of Information Act and the advent of the Privacy 
Act have required staff attendance at meetings for interpretation of the Acts 
prerequisite to applying policy. The Office established the DRG Freedom of 
Information Index as an integral part of the overall NIH Index. 



The centralization of grant application forms in control offices in 
grantee institutions has proved to be a speedier and less costly operation for 
the NIH than was the old method of mailing applications singly to investigators. 
Since the new system of bulk-mailing applications became effective in January 

1974, complaints have been minor and, in the past 6 months, centralization of 
applications has been generally accepted by the grantee institutions. The 
problems now are created internally by NIH institutes that have special programs 
requiring inserts with application forms. 

Restricted travel funds kept the Division exhibit in storage all year. 
The Grants Inquiries Officer accepted a local speaking engagement January 6, 

1975, before campus representatives of the Associated Colleges of the Midwest 
and the Great Lakes Colleges Association. 

A member of the staff was named by the Director as DRG's representative on 
the NIH Minority and Women's Resources Conference Committee. 

A sound-on-slide series, "How a Research Grant is Made," was updated to 
show women and minority group members on the study sections. 



V 






OFFICE OF RESEARCH MANPOWER 

During fiscal year 1974, the Office of Research Manpower (ORM) 
coordinated the reinstitution of training through the Research Manpower 
program. The National Research Service (NRS) Act of July 1974, however, 
rescinded these programs and all previous research training authority. 
Consequently, ORM has once again been involved in the many complexities 
associated with mounting new programs. For example, in cooperation with a 
committee of DRG and I/D representatives, the Office developed a new 
application form for the institutional NRS grant and expedited clearance of 
the form so that it would be available for the February 1975 application 
receipt date. 

ORM also: prepared new program announcements on the individual and 
institutional NRS awards, working closely with each I/D on specified research 
areas considered to be in need of additional trained personnel'; revised the 
individual fellowship application kit to reflect the NRS program, and obtained 
an extension on use of the application form and related materials until 
December 1975; and prepared the initial draft on the guidelines governing the 
NRS program. This document, which was issued in May 1975, reflects the 
official policy on the program. 

Since applicants under the NRS program are subject to certain payback 
provisions, each applicant under the Research Manpower program was contacted 
to determine if he or she still wanted to be considered. The Chief, ORM, is 
serving on the PHS Task Force to implement the payback provisions. These 
provisions have been of considerable concern, and have caused innumerable 
discussions with applicants, academia, and NIH personnel. 

Updated materials were also prepared for the Research Career Development 
Program : a) program announcement, b) extension on use of the application 
form, and c) a draft policy brochure for review by OERT. 

The major areas in which the Office is now involved are: 

1. developing a new continuation application form for the NRS 
institutional grant through a committee of DRG and institute representatives; 
and processing a request for extension of the old form for use under the 

old program; and, 

2. preparing for clearance of a new application form for the individual 
NRS award. This form was being developed this time last year, but because 

of the change from the Research Manpower to the NRS program, the drafting 
committee had to be reconvened to adapt the form to the new program. 

Routine operations of the Office included responding to numerous 
requests from within and outside NIH on status, statistics, and policy on 
the training programs. 



4 „ 

iii 



Several tasks remain to be completed, including: 

a. revision or extension before December 1975 of the RCDA application 



forms, both new and continuation; the individual fellowship continuation 
application form; and the fellowship supplementary forms, such as the 
activation notice and termination notice; 

b. revision of the Statement of Appointment Form to accommodate the NRS 
program, and 






. 



c. if the institutes consider it important enough, the Handbook for 
individual fellows will also need to be revised to accommodate the NRS 

program. 

Problems encountered during the year under review are to a large part 
situational. The training programs have been in a constant state of change 
over the last 2 years. As a result of the changes, NIH has an old training 
program, a Research Manpower program, and an NRS program, and, as indicated 
above, NIH is in a period when all of the training forms are expiring and 
need to be revised or extended. 



The individual NRS applications received under the May 1, 1974, receipt 
date were originally submitted under the Research Manpower program (F22) and 
had to be converted to NRS program. Although these applications were acted 
on at the November 1974 Council, no awards could be made until the final 
regulations governing the NRS program were published in the Federal Register . 
The regulations were published first as proposed rules on January 17, 1975, 
and then as final regulations on May 2, 1975. 



10 



ADMINISTRATIVE BRANCH 

The DRG Budget Office has assisted in administering about $12.1 million for DRG 
operations: $9.8 million from the NIH Management Fund and $2.3 million from the 
institutes for the support of 47 Study Section Scientific Evaluation Grants. The $2.3 
million was awarded among the study section cha.irmen; expenditures were monitored by 
a computer data base system which provides DRG management with up-to-date monthly 
costs analyses. For the first time, consultant costs were funded almost entirely from 
Scientific Evaluation Grants, saving time and effort in paying consultants. 

The Budget Office, in conjunction with the Personnel Office, has assisted the 
Department in updating its personnel data system. This required many changes to the 
data in the Department's terminal data collection system (TDCS). The personnel data 
system is now being used for the official employment reports to the Civil Service 
Commission. Future plans are to merge the system with the payroll data system for 
pay purposes. 

The Reference Room reorganized its card catalog system. All the books are now 
cataloged by subject, as well as title and author contributing to efficiency and savings in 
time. To correct a gap perceived in coverage of scientific areas, 84 new books and 43 
new journals have been acquired. Reference Room personnel continue to provide a 
service to all Westwood employees. 

The Travel Section continued providing information and assistance for DRG 
personnel and outside consultants traveling for the Government. During the past fiscal 
year, approximately 5,000 travel vouchers totaling over $2 million were processed and 
forwarded for payment for consultants who serve on the various study sections. Another 
$250,000 was spent to pay travel costs on approximately 800 vouchers for DRG travelers 
and other Government employees. 

The Special Services Section continued to provide typing and clerical assistance to 
DRG and other institute/division staff. Four typists with magnetic card typewriters and 
one CRT unit completed about 2800 letters, 10,000 mailing labels, and 600 Summary 
Statements. The Section also typed 540 pages of draft and final copy for renewal of 
Study Section Charters, and several other documents during the period under review. 

The Office Services Section compiled and handled an average of 9,000 grant 
application kits of all types and mailed 9,500 miscellaneous packages each mcnth . The 
Section also provided planning and assistance in accomplishing several major moves 
within the Division and acquired and maintained equipment, furniture and supplies, and 
provided duplication services for Division personnel. 

The DRG Mail Room received and processed approximately 30,000 grant applications 
of all types, and a large volume of supporting documents, letters and publications. 



*~ 



'4u, 
iiii . 



11 



RESEARCH ANALYSIS AND EVALUATION BRANCH 

The Research Analysis and Evaluation Branch continually provides support 
and answers to the Office of the Director, institutes, other Federal agencies, 
and interagency committees on a variety of questions and areas of the extra- 
mural activities of NIH. With the assistance of CRISP, IMP AC and the CSCS 
codes, the Branch has completed the following reports or assisted in their 
preparation: 

NIH budget analysis relating to competing and non-competing grants. 

Extramural funding in specified areas of hematology. 

Identification and analysis of extramural activities in basic, applied, 
clinical, development and control activities, research materials 
involved, and mechanisms of support of NIH extramural R&D. 

Inventory of clinical trials. 

NIH involvement in human fetal research, FY '72-74. 

Trends in priority scores assigned to traditional research projects. 

Summary and analysis of NIH support of research efforts on DNA hybrid 
molecules . 

Classification of NIH extramural research support primarily or 
partially concerned with nutrition. 

Extramural research activities in or related to social research and 
development. 

Estimate of NIH support of drug development. 

Research in chemistry and biochemistry supported by NIK contracts and 
grants. 

Research and research training programs which relate to maternal and 
child health. 

NIH and NIMH support of pediatric research FY '74. 

Follow-up studies on new principal investigators (first published in 
Science , July 20, 1973) . 

Grants and contracts for animal production and facilities. 

FY '74 Matrix of scientific areas of research by institutes that 
provided support. 

Many of the activities reported for prior fiscal years are updated 
periodically. Staff members are serving on the Federal Interagency Chemistry 



13 



Representatives, the NIH Library Committee, DRG Reference Room Advisory 
Committee, Training Opportunities Committee, and the Grants Associates Board. 
Nine of the twelve staff members undertook and completed work-related training 
during the year. 

The Branch serves as the contact resource for several ongoing projects and 
programs, and prepared NIH coordinated responses for several issues raised 
during the year that spanned several institutes. The Branch continues to code 
research projects and grants by the Central Scientific Classification System. 
The Central Scientific Classification Code is presently under revision by the 
staff. The Branch assumed responsibility for the schedule of NIH Conferences. 

At present the major thrust is on completing reports on the extramural 
programs in diabetes and toxicology, compiling data for the study and review 
of research and research training programs related to maternal and child health, 
updating periodical reports, improving the procedures for the broad scientific 
classification of NIH extramural research grants and contracts, and maintaining 
the files on the inventory of clinical trials. 



14 



REFERRAL BRANCH and SCIENTIFIC REVIEW BRANCH 
(Formerly Research Grants Review Branch) 

The number of applications assigned and processed by the Referral Branch 
and reviewed for scientific merit by the Scientific Review Branch in Fiscal Year 
1975 far exceeded the previous record year, FY 1974. Competing and non-competing 
applications reached 30,167, up almost 19 percent from the previous year's total 
of 25,448. Competing applications assigned to initial review groups for review 
of technical merit as well as to awarding units rose to 20,618, up 26 percent 
from the previous year. Almost 79 percent of the research applications were 
assigned to NIH. During the year, the Scientific Review Branch provided the 
initial review for scientific merit for more than 90 percent of the NIH competing 
applications. A table showing the distribution of applications processed in 
fiscal year 1975 is appended to this report. 

Early in the fiscal year, the Referral Branch and the Scientific Review 
Branch were established following a reorganization that abolished the Research 
Grants Review Branch and transferred its functions to the new branches. New 
responsibilities for referral and initial technical review of applications for 
fellowship and training programs were also assigned to the new branches. 

The Referral Branch (1) receives and reviews applications for PHS research 
and training support to determine referral to the appropriate PHS health agency 
and to the appropriate NIH initial review group; (2) develops criteria for 
determining appropriate assignment of applications within the NIH by program 
area and by competencies of review groups; (3) proposes uniform instructions to 
applicants for proper preparation of applications and (4) extracts and records 
preliminary data from such applications and serves as information center for 
applications pending review. 



A book, Invertebrate Immunity , to be published by Academic Press in June 
1975, resulted from the conference on this subject conducted by the Tropical 
Medicine and Parasitology Study Section in April 1974. 

"Computers in the Clinical Pathologic Laboratory: Chemistry and Image 
Processing" is the title of a paper written by Dr. Bernice S. Lipkin, a staff 









The Scientific Review Branch (1) recommends policies and procedures j 

governing technical review of applications; (2) administers the 52 study sections 
which provide scientific review of NIH research grant, fellowship, and research 
career development applications; (3) explains applications and interprets 
preliminary recommendations to the National Advisory Councils; (4) conducts the 
search for the most qualified and representative individuals to serve as members 
of initial review groups; (5) stimulates and coordinates the activities of NIH ' to 

study sections or committees in surveys of research fields to determine current 
status of research and need for further development; and (6) coordinates 
scientific review activities with appropriate representatives of components of 
the NIH. On April 25, 1975, four new study sections were established in the 'h 

Scientific Review Branch: Experimental Virology, Immunological Sciences, Molecular 1, 
Cytology, and Pathobiological Chemistry. 



15 



member of the Scientific Review Branch. The paper is in press for the June 
1975 issue of Annual Reviews of Biophysics and Bioengineering . 

Dr. Thomas M. Tarpley, Jr., Scientific Review Branch, has prepared for 
presentation and/or publication several scientific papers this year: 

(1) Wolf, R. 0., Moss, M. E., and Tarpley, T. M. : Serum Salivary 
Isoamylases in Sjogren's Syndrome. IADR/AADR, April 1975. 

The paper has been submitted to the Annals of Internal Medicine . 

(2) Cummings, Norman A. and Tarpley, T. M. , Jr.: Salivary Gland 
Antigen and Radio-labeled Anti Salivary Duct Antibody in 
Sjogren's Syndrome. For the annual scientific meeting of the 
American Rheumatism Association to be held in New Orleans, 
June 1975. 

(3) John E. Horton, D.M.D. , Thomas M. Tarpley, Jr., D.D.S. and 
Larry D. Wood, D.V.M. "The Healing of Surgical Defects in 
Alveolar Bone Produced with Ultrasonic Instrumentation, Chisel, 
and Rotary Bur." Accepted for publication in Oral Surg., Oral 
Med., Oral Path ., Vol. 39:4, April 1975, pp. 53b-546. 

(4) Dellon, A. Lee, M.D. , Tarpley, Thomas M. , Jr., D.D.S. , M.S., 
and Chreten, Paul B. , M.D. : Histologic Evaluation of Skin 
Grafts and Pedicle Flaps Placed Within the Oral Cavity in 
Humans. Submitted in April 1975 for presentation at the 
American Society of Oral Surgeons in September 1975. 

In January 1975, Dr. Tarpley presented a lecture, "Non-Neoplastic Salivary 
Gland Swelling?/' to a group of oral pathologists participating in the U.S. 
Naval School Course in Oral Pathology. In March 197i>, he presented "Non- 
Neoplastic Salivary Gland Sialandenopathies" in the annual Oral Pathology course 
at the Armed Forces Institute of Pathology. 

As in previous years, but on a very limited scale, study sections conducted 
workshops and conferences to survey the status of research in their areas, 
enhance reviewer competence, and stimulate research in neglected areas. In all, 
eight conferences were held — two in September 1974, five in January 1975, and 
one in April 1975. Two have been planned for September 1975. 

Both of the conferences in September 1974 were held in Bethesda. On 
September 18, a workshop, "Goals in Population Genetics with Emphasis on Human 
Populations," was sponsored by the Genetics Study Section. A small group of 
population geneticists met with members of the Genetics Study Section to review 
the research objectives and current trends in population genetic studies, with 
particular attention to what such studies hope to accomplish and to what extent 
present methodologies are adequate to achieve these goals. Research proposals 
in this field are exceptionally variable in quality. Furthermore, the problem 
of scientific evaluation of such applications is accentuated by lack of agreement 
among population geneticists on the attainable objectives of many types of 
studies. A main objective of the workshop therefore was to provide members of 
the Study Section with a broader understanding of the basis for the divergent 



16 



viewpoints held by experts, and their assessment of what current methodologies 
can be expected to achieve. 

The discussion concentrated on three main questions in population genetics: 
1) the study by population genetics methods of the etiology of human traits, 
including disease and dysfunction; 2) the study of genetics variation in natural 
populations of various organisms, including man; 3) the study of the genetics 
and culture of "primitive" human populations. It is planned to publish a summary 
of the discussion and information that emerged from this workshop in Genetics — 
the journal of the Genetics Society of America. 

On September 25, 1974, a conference on "High Resolution Nuclear Magnetic 
Resonance Resource Facilities" was conducted by the Biophysics and Biophysical 
Chemistry B Study Section to survey existing facilities in the United States, 
their distribution and mode of operation, and to develop guidelines for optimal 
operation of such resources. A group of about 15 participants discussed high 
resolution NMR spectroscopy resources facilities, their basic components, current 
operations, and suggestions for improving them. Resource sharing and the 
levying of service charges were analyzed. Plans were described for developing 
ultrahigh frequency NMR spectrometers in the future. The group recommended 
establishment of an interagency (DRF-NSF) planning committee to inventory 
existing NMR facilities for biomedical research in the United States and to 
assess the need for additional resources. They also recommended that resource 
instruments displaced by more advanced spectrometers should be made available to 
other institutions where they could still give valuable service. An annual 
meeting of resource directors with NIH staff was recommended to exchange infor- 
mation on resource operation and service to the biomedical community. 

The first January 1975 workshop "Current Activity and Areas of High 
Potential and Bioinorganic Chemistry," was conducted in New Orleans on January 6 
and 7. At the sessions, which were sponsored by the Medicinal Chemistry B Study 
Section, the National Science Foundation, and the University of New Orleans, 26 
scientists participated directly in the program and about 20 other persons 
attended. The primary purpose was to give the study section an overview of 
bioinorganic research areas most likely to be in the forefront of progress 
during the next decade and hence representing future heavy proposal activity for 
the study section. Areas covered included metal ion transport and storage, 
trace metals, toxic and carcinogenic metals, organometallic antitumor agents, 
nitrogen (and other small molecule) fixation, macromolecular probes and models, 
metalloproteins, and coenzymes. Results of the workshop are to be published 
informally by the National Science Foundation. 

All of the other January workshops were held in Bethesda. Earliest of 
these was the January 10 workshop on "Growth Hormone and Growth Factors," 
sponsored by the Endocrinology Study Section and attended by about 35 persons. 
A variety of peptide factors that promote cell growth have recently been 
described, mostly in areas of investigation not traditionally associated with 
endocrinology. The discovery that a closely related factor is dependent upon 
hormone and may indeed mediate some of the actions of growth hormone has prompted 
an increasing number of investigators to explore the endocrinological implica- 
tions of these new growth factors. The purpose of the meeting was to familiarize 



17 



M 



members of the study section with this new body ot information and its implica- 
tions for understanding hormonal control of growth. 

The morning session of the meeting was devoted to a discussion of growth 
hormone and a possible relationship of its biological actions to those of 
somatomedin, a growth dependent peptide that appears in the plasma several 
hours after injection of growth hormone. The afternoon session was devoted to 
a discussion of a series of other peptides that appear to be related both to 
somatomedin and to processes of growth. The general discussion provided a 
wealth of informational background for members of the study section to aid them 
in evaluating the increasing number of research proposals that deal with this 
new, important, and rapidly developing branch of endocrinology. 

On January 15, a conference on "Evaluation of Large-Scale Nutrition 
Interventions," sponsored by the Nutrition Study Section, was attended by about 
5U participants. Both in this country and throughout the world, large-scale 
nutrition interventions have been made and are being made without serious 
attempt to assess the benefits to the recipients. There is now a growing 
concern in both government and scientific circles about this deficiency. The 
New York Prenatal Project was presented as a point of departure for a discussion 
of the various aspects to be considered in planning, carrying out, and inter- 
preting the results of nutrition interventions. Following a description of the 
prenatal project in New York City, discussions of various aspects were presented. 
Topics included study design, statistical evaluation, ethical considerations, 
and design comparisons with the Guatemala study. 

A workshop on "Behavioral Toxicology," was held on January 16 under 
sponsorship of the Toxicology Study Section. Two main themes were discussed by 
the participants: (1) the current status of methods in behavioral toxicology, 
and (2) the problem of selection of appropriate animal tests for evaluation of 
hazards to humans. Five invited speakers covered a variety of methods and 
research results in their presentations on the following subjects: (1) the role 
of operant conditioning techniques in precise behavioral assessments, particu- 
larly where sensorimotor discrimination may be affected by toxic substances; 
examples of tests in animals and humans exposed to carbon disulphide were given; 
(2) methods of detection of reversible hyperkinesis in rats exposed to carbon 
monoxide as neonates; activity of permanent groups of animals monitored in a 
residential maze equipped with photocells was discussed; (3) importance of 
social behavior and development studies using the example of young rhesus 
monkeys given lead in their diet; such studies are of particular importance for 
comparisons with humans; (4) neurophysiological methods that can be used to 
detect toxic effects of compounds in animals; the visual system is particularly 
sensitive to some pesticides; and (5) tests in rodents that can be carried out 
throughout development when the animals are exposed to toxicants during gesta- 
tion or early postnatal life. Sensitivity to low levels of toxicants occurs in 
swimming tests and open field activity. 

In the discussion which followed, the participants discussed the problems 
of selection of appropriate tests for screening for hazards. It was generally 
agreed that the developing organism is more sensitive to behavioral alteration 
than the adult. The precise tests which are most useful are difficult to 
select, but sufficient knowledge is probably available to make a start. Publi- 
cation of conference material is planned. 



18 



On January 16 and 1/, the Reproductive Biology Study Section held a work- 
shop on "The Glycoprotein Hormones and Their Receptors." About 100 persons 
attended this workshop at which 10 program participants presented the following 
topics: (1) the glycoprotein hormones, their origin, chemistry, use, and 
metabolism; (2) human follicular stimulating hormone, its subunits, and their 
structures; (3) immunologic relationships among the gonadotropins; (4) testicular 
and relevant receptors, and (5) clinical applications and comparison of these 
reactions in the human and sub-human primates. 

A conference on "Matching Needs and Resources in Epidemiology and Biometry," 
was sponsored by the epidemiology and Disease Control Study Section, National 
Cancer Institute, National Heart and Lung Institute, Fogarty International 
Center, Epidemiology Section of the American Public Health Association, 
Epidemiology Program Directors of Schools of Public Health, Association of 
Teachers of Preventive Medicine, and the National Center for Health Statistics 
of the Health Resources Administration. About 60 people attended the conference, 
which was held in Los Angeles on April 7 and 8. 



During its first decade, the Epidemiology and Disease Control Study 
Section has observed a dearth of productive epidemiologic research in all 
categorical areas. Two problems seem to characterize the rejected research 
proposals in most every instance: (1) they were presented by excellently 
trained clinicians who lacked epidemiologic concepts and methodological competence, 
and (2) they failed to involve trained and experienced epidemiologists and 
biometricians for the planning and ultimately the execution of the research. 
As the Study Section contemplated various approaches to the problem, it found 
its colleagues in other organizations were equally concerned. The result was a 
broadly-based sponsorship for the workshop including both the consumers and 
the producers of this specialty for biomedical research. The meeting was 
then to examine needs, problems, and approaches to their resolution. Its agenda 
was neither comprehensive nor conclusive. 

Three of the principal position papers, therefore, provided insight and 
illustration of the dynamics of the problem from the viewpoint of the program 
areas of cancer, heart and lung, and infectious diseases. These presentations 
gave focus to requirements for epidemiologists and biometricians in compre- 
hensive centers, intervention and control trials, specialized centers of 
research, clinical trials, surveillance and end results programs. Three other 
papers were then presented that dealt respectively with the research training 
opportunities in local, State, and Federal public health agencies; the current 
situation in schools of public health with regard to faculty, research personnel, 
and students; and the interrelationship of epidemiology with biometry, bio- 
statistics, and health statistics. Each of the papers attempted to include 
hard data definitive of the problem area, and yet were thought-provoking 
regarding internal needs of the disciplines of epidemiology and biometry. 
Moreover, they provided substantive material for discussions, which carried 
to the second day in the deliberations of small working groups who were 
attempting to reach a consensus regarding needed follow-up. It is planned for 
the proceedings to be reported as part of the Fogarty International Center 
Series on Preventive Medicine. 



o 

TO 
73 



I I 

fl! „ 

nil . 



_JJ 



19 



September conferences in Bethesda are planned by the Medicinal Chemistry B 
and Tropical Medicine and Parasitology Study Sections. "Ionization, Chemical 
Ionization, and Field Desorption" is the subject of the conference being 
sponsored by Medicinal Chemistry B Study Section. "Intracellular Parasitism: 
Status, Concepts, and Speculations in Research on Leishmania and Trypanosoma 
Cruzi " is the subject of the second conference. 






V 



20 



APPENDIX 



APPLICATIONS PROCESSED BY REFERRAL BRANCH, OADSR 
Fiscal Year 1975: March 16, 1974 - March 15, 1975 



COUNCIL 


NOV 74 


MARCH 75 


JUNE 75 


TOTAL FY 75 








COMPETING 






Types 1, 2, 3 NIH 


3 


,831 


3 


,865 


3,987 


11,683 


FDA 




40 




36 


22 


98 


HS 




112 




85 


138 


335 


OH 




31 




21 


25 


77 


ADAMHA 




934 




694 


1,088 


2,716 


Subtotal 


4 


,948 


4 


,701 


5,260 


14,909 


Construction 












6 


6 


PL 480 




6 




5 


4 


15 


Training 




87 




869 


349 


1,305 


Career Development 




929 




80 


327 


1,336 


Fellowships 

Subtotal 


1 
2 


,025 
,047 






954 


2,022 
2,708 


3,047 
5,709 



TOTAL, COMPETING 



Type 5 

Interim (Administrative) 

Cross Fiscal 



6,995 5,655 

NON-COMPETING 



3,085 

350 

45 



TOTAL, NON-COMPETING 3,480 



COMPETING 
NON-COMPETING 



6,995 
3,480 



GRAND TOTAL 10,475 



2,655 

287 

78 

3,020 

TOTAL 

5,655 
3,020 

8,675 






7.968 



2,751 

265 

33 

3,049 



7,968 
3,049 

11,017 



20,618 



8,491 
902 
156 

9,549 



20,618 
9,549 

30,167 



I 
1 











4 1, 

'"'I • 



IT 



21 



DRS 







o 



73 



STATISTICS AND ANALYSIS BRANCH 

Fiscal year 1975 was characterized by increased demands on the Statistics 
and Analysis Branch for information services and data processing support. 
During the year, the Branch provided review and award support services for a 
record breaking number of competing applications. Similar increases occurred 
in virtually every other measure of existing SAB operations. 

In addition to these increases in routine activities, the SAB met demands 
for such new services as the development and operation of a system of tracking 
applications involving human subjects through the review and award process. 
Another major new project is the Manpower Report which collects information on 
personnel paid under research grants and contracts . 

To meet these and other demands the Branch is continuing to seek out, 
particularly through application of the latest technology, ways and means by 
which productivity can be improved. There is, for example, a study currently 
under way which will consolidate the various data-capture processes into one 
single method with a significant improvement expected in the utilization of 
resources. 

The Branch, in collaboration with the American Association of Medical 
Colleges (AAMC) , presented to medical school representatives at the November 
1974 AAMC meeting in Chicago a proposed system for a medical school/NIH 
interface on extramural information. Following this presentation, eight schools 
have participated in a pilot study of such an interface system. A meeting with 
the participating medical schools, as well as the AAMC, to evaluate the system 
is planned for June 1975. 

Management support and employee interest in training and development for 
better job performance and career development purposes continued to remain 
high with 73 Branch employees participating in 55 different training courses j '[> ■• 
and seminars. In addition, a number of courses were applied for but were 
oversubscribed; employees will pursue this training as spaces become available. ii, 
A wide spectrum of training was covered including computer-related training, 
administrative and managerial, communications and office skills, EEO and 
management sciences. Special training programs in which Branch employees were 
involved included the Upward Mobility College and attendant workshops and 
seminars, the STEP Continuing Education Program, the NIH Manager Development 
Program, the Federal Executive Institute, and the Symposium on the Freedom of 
Information Act. The three Student Trainees recruited under the Federal Junior 
Fellowship Program in 1973 continued their third year of training. Also, 
during FY 1975 the Branch acquired a trainee under the Project Stride Program. 

1. Office of Systems Planning . The Office of Systems Planning in collaboration 
with the other Sections of the Branch, continued its activities for expansion 
of the NIH extramural central data system and for the design and implemen- 
tation of new applications. Systems design and procedural development connected 
with the entry into the system of new accounting numbers established by the 
Division of Financial Management (DFM) , establishment of a human subjects 



23 



tracking system, a link with DFM to permit balancing of contract and interagency 
and intraagency agreement information contained in the IMPAC system, and the 
processing of Core Center applications for the National Institute of General 
Medical Sciences were undertaken. These projects are discussed in detail in 
the individual section reports that follow. 

2. Data Processing Section 

Document and Entity Numbers . The Section converted several data items in 
the IMPAC System this year to conform to the following new Division of Financial 
Management (DFM) accounting numbers : 

Document Number - This number replaces the Transaction Number on PHS 
extramural grant award statements and approval lists. It is used by 
DFM as the obligation number in the NIH Central Accounting System and 
the DHEW Federal Assistance Financing System. The new Document Number 
will assure consistency in the assignment of obligation numbers in 
various DHEW systems. It contains several characters of the grant 
number permitting each number to be cross-referenced to its related 
grant. 

Entity Number - This number replaces the PHS Account Number on PHS 
extramural grant award statements and approval lists. It is used by 
the DFM as the payee number in the NIH Central Accounting System and 
DHEW Federal Assistance Financing System. The DHEW Central Registry 
office is responsible for establishing standarized codes to uniquely 
identify all entities dealing with the Department. An entity is broadly 
defined as an individual or organization or as a segment, division, 
school, or component of the organization. The standard organization 
code is derived from the Internal Revenue Service Employer Identification 
Number (EIN) with the Social Security Number (SSN) assigned as the 
standard code for individuals. Use of codes became mandatory 
for all agencies on July 1, 1974, for any award to entities included 
in the Central Registry System. 

Core Center Grants . DRG agreed to assign and review Core Center applica- 
tions for NIGMS beginning with the June 1975 review cycle. Data relating to 
these applications were available in the IMPAC pending file in April. The 
procedures established for processing these applications provided for recording 
the full range of Initial Review Group, National Advisory Council, and Awarding 
Unit actions for both the Core Center and the related individual projects. 

Human Subjects Tracking System . A computerized tracking system has been 
installed in the Section to identify projects involving human subjects. The 
system was implemented in May 1975 for applications assigned for September 
review by DRG Study Sections. The system documents the fact that review of 
questions involving human subjects has taken place, decisions reached, and 
problems resolved in the following manner: 

- At the time a pending application is received, an entry is 
made in the IMPAC computer record indicating whether human 
subjects are involved in the proposed project. 

24 



- If human subjects are involved, the Study Section will 
determine whether there is adequate protection or if possible 
risks exist. This distinction will also be recorded in the 
IMP AC computer record. 

- In the case of possible risks, awarding unit staff are 
responsible for resolving the problem and issuing a 
Grant/Application Change Notice to that effect. 

No award statements will be produced by the IMP AC System until all possible 
risks have been resolved by the appropriate awarding unit. 

Contracts . A link between the Division of Financial Management ' s Central 
Accounting System and the IMPAC System, similar to the grant link between the 
two systems, is being developed for research contracts and interagency and 
intraagency agreements. Under this system, DFM will provide SAB monthly tapes 
on these contracts and agreements containing dollars encumbered, entity number, 
object class codes, and document numbers to permit reconciliation between the 
NIH Central Accounting System and the IMPAC contract files. The system will 
be fully operational in fiscal year 1976 and will provide increased control 
over data in the contract file. 

Approval Lists . The Section has assumed additional operating responsi- 
bilities associated with a system being programmed to provide the Division of 
Financial Management with IMPAC grant-award data on magnetic tape. This system 
will result in major procedural changes in the grant award process. Under the , o 
new procedures, the awarding units will forward the original signed grant-award :» 
statements and approval lists directly to the Data Processing Section Control 
Point. On receipt, the staff will update a special IMPAC file, and, from this 
file, will create an encumbrance transaction tape for DFM. DPS will then 
forward the signed approval lists to DFM. Once operational, considerable I 

manpower and time savings will be realized in DFM because they will no longer ,u" 
have to keypunch approval lists. 

IMPAC Tech Notice . DPS has developed a new informational bulletin called 
"IMPAC Tech Notice" to notify users of the IMPAC system of current and proposed •,„. 
changes in the system. It will be issued on an "as needed" and not periodic mt | g> 

basis. 

„'li ! 

System for Computer Retrieval of Information of Scientific Projects (CRISP) . 41 
A total redesign of the CRISP system has been initiated to permit the generation 
of an increasing number of reports, to improve the accuracy and contents of 
these reports, to provide more flexibility in reporting, aid to reduce operational 
costs. All aspects of. the system's maintenance and reporting procedures have 
been considered, data collection methods have been reexamined, and input formats 
have been simplified and combined as appropriate. Record contents have been 
altered, internal coding of data changed, and the number of on-line files and 
records have been reduced to speed procession and facilitate use of the system. 

Expansion of Record . IMPAC Master File records have been expanded from 
1138 to 1378 bytes. This expansion will allow for future development as follows: 



25 



o 



- Expansion of research contract records to include the collection ^ 
and maintenance of certain data from the Request for Proposal 

(RFP) form. Commitment information on incrementally funded 
contracts will also be added. 

- Development of a telecommunications system which will permit 
awarding units to have direct access to the IMPAC System's 
files and produce grant award notices via remote terminals. 

- Expansion of IMPAC records to identify grants awarded under \ 
Public Law 93-348, National Research Act. One of the conditions 

of the National Research Service Award Program is that no trainee 
will be appointed unless he or she has signed and submitted 
a statement of intent to meet the service or payback provisions 
required under this law. It is expected that the IMPAC System 
will be used to monitor this compliance. 

3. Research Documentation Section (RDS) . The Section maintains a 
computerized disk storage and retrieval system, CRISP (Computer Retrieval 
of Information on Scientific Projects) containing scientific data on the 
research grants and contracts supported by the Public Health Service. 
Through this medium, RDS functions to service ad hoc and recurring requests 
for scientific information from Government administrators, scientists, 
and information personnel for purposes such as analysis and evaluation of 
research programs, specific scientific areas, and preparation of reports. 
In similar fashion, the Section responds to inquiries from grantee and 
non-grantee institutions and scientists, the news media, and other non- 
Government individuals engaged in, concerned with, or reporting on medical 
research. 

RDS publishes annually as a "spin off" of the CRISP file: 

1. The Research Grants Index , prepared in two volumes. Volume I is a 
scientific subject index with associated project numbers and titles. 
Volume II contains three sections (a) project identification data 

(b) research contract identification data and (c) project investigator 
information. 

2. The Medical and Health Related Sciences Thesaurus , the vocabulary 
authority list of subject headings used by the RDS Indexing Staff 
in indexing the research projects. 

CRISP has the query capability of providing information ranging from a 
straightforward listing of grants pertaining to a single scientific subject 
term to a compendium of projects relating to any number of terms, using a 
combination of Boolean search logic. Select queries for providing individual \ 
institutes with tapes or hard copy of their projects by subject, project 
(sub-project) number or investigator, and individual institute listing or 
projects with indexing terms (Scientific Profiles) can be provided. Query 
capability limiting subject searches or Scientific Profiles to certain program 
(R, M, N, P, S) or IPF Codes is available. 



26 



A specially designed CRISP subroutine provides for furnishing grantee 
institutions or NIH institutes possessing appropriate computer capabilities 
with specially formatted tapes with which they can search the scientific 
subject content of their own research grant and contract records. This 
subroutine called CESI (CRISP Extract System for Institutions/Institutes) 
is updated monthly and can furnish select tapes on an ad hoc or recurring 
basis. 



In addition, performing subject searches and producing Scientific 
Profiles or Investigator Listings on subprojects of program projects, 
center and other large grants is a unique feature of the CRISP System. 

New features of the CRISP system include : (1) the CESI System described 
above; (2) a narrative file termed CRISP File 5 (Format F) which offers the 
capability of furnishing research grant and contract narratives in response to 
grant or subject queries, and provides users with summaries of project 
objectives in addition to previously existing formats describing fiscal or 
subject heading information; and (3) Principal Investigator Indexer Records 
(computer printouts of individual project Scientific Profiles) which have 
been modified to eliminate the need of typing address labels. The innovations 
described above have been made possible largely through the efforts of the SAB 
System Planning and Data Processing Groups. 

Research Grants Index . Linotron tapes for the fully automated printing 
of this two-volume set were submitted to the Government Printing Office in 
January for publication (DHEW Publication No. (NIH) 75-200) in May 1975. 

Medical and Health Related Sciences Thesaurus . In addition to its in- 
house use, the revised edition (DHEW Publication No. (NIH) 75-199) was 
distributed on a request basis to research analysts, information specialists 
and other individuals who have responsibility for scientific communication 
systems. 

CRISP Services . In addition to responding to hundreds of requests on a 
wide range of subjects, the Section (1) prepared Linotron tapes used in the 
creation of extract Indexes for three institutes; (2) provided Scientific 
Profile data reports and/or CESI tapes for numerous Grantee Institutions; and 
(3) furnished NIH-wide scientific area data to responsible institutes. 

In attempts to improve SAB personnel utilization, RDS Technical Information 
Specialists have assumed responsiblity for professional editing operations 
involving thousands of approved research project applications during the 
current fiscal year. This activity was formerly conducted by other members of 
the SAB staff. 



mil ... 




"•" , 




H 


O 




73 


Hill; 


GO 



Intramural research projects . Efforts are well underway to develop a 
system for incorporating the keyword indexing of individual intramural research 
project reports into the CRISP System. This will allow for uniform reporting 
of intramural research using the full capacity of Boolean logic heretofore 
available only on queries for information on extramural research. 



27 



Training . A total of li employees participated in NIH training programs. 
The courses included WYLBUR, CPS, System/3/0, Mag Card, IRS Query, STEP Module y 
6, Supervision, and Science, Technology & Government. In addition, one 
employee continued in Upward Mobility College. 

4. Reports, Analysis, and Presentations Section . The primary function of 
the Section is to satisfy the information requirements of NIH and PHS 
centralized extramural activities. In fulfilling this function, the Section 
utilizes the IMPAC system as well as other data sources. Its responsibilities 
include: design, maintenance, and operation of computer reporting systems; JT 
training and technical assistance in data retrieval; planning and coordination 
of NIH responses to annual surveys covering Federal obligations for R&D; 
preparation of formal publications such as the PHS "Blue Books" and the NIH 
Basic Data Book; statistical analysis to compile and present visual materials 
dealing with extramural trends or other topics; and the development and 
implementation of special evaluation projects. This Section also works closely 
with the Data Processing Section in maintaining and extending the IMPAC system, 
and has direct responsibility for establishing institution classifications and 
related computer files, as well as ensuring the accuracy of selected key data 
items for publications or reports. 

Publications . The following volumes of the annual multi-volume series 
on PHS Grants and Awards were issued: 

(1) Public Health Service Grants and Awards, Part VI, FY 1973 Health 
Services and Mental Health Administration. (DHEW Publication No. 
(NIH) 74-500). 

(2) Public Health Service Grants and Awards, Part I, FY 1974 and FY 1973/ 
1974. Research Grants. (DHEW Publication No. (NIH) 75-494). 

(3) Public Health Service Grants and Awards, Part III, FY 1974 and FY 
1973/1974. Research and Development Contracts. (DHEW Publication 
No. (NIH) 75-496). 

(4) Public Health Service Grants and Awards, Part IV, FY 1974 and FY 
1973/1974. Health Planning and Health Services Grants. (DHEW 
Publication No. (NIH) 75-497). 

Data for the pocket reference book, Basic Data Relating to the NIH-1975 , 
were compiled in cooperation with the NIH Office of Program Planning and 
Evaluation. This publication presents information on the programs and resources 
of the NIH. 



Special Statistical Presentations . The Section compiled and analyzed 
extramural program statistics for fiscal year 1967-1974, and participated wi 
the Chief, Statistics and Analysis Branch, in developing a set of overhead 
projection slides illustrating key extramural trends. These slides were 
presented formally to the Director, NIH, and other officials in August 1974, 
and subsequently to various additional audiences. The data were also issued 
with an accompanying analysis, in a chart-book entitled NIH Extramural Trend 
Fiscal Years 1967-1974 prepared for administrative use. 



th 



28 



Reporting Activities . There are several major reporting activities which 
are recurring or cyclical and consume a large portion of the man-hours 
available in this Section. The annual survey conducted by the National Science 
Foundation, entitled Federal Funds for Research, Development, and Other 
Scientific Activities , is coordinated and prepared by this Section for the 
entire NIH. In general, the survey covers all the NIH intramural and 
extramural research activities for the past fiscal year along with estimated 
obligations for the next 2 fiscal years by performer, field of science, 
geographic area, basic and applied research and development, and combinations 
of the above. A segment of the report is also devoted to "Scientific and 
Technical Information Activities." 

The CASE Report summarizes support to institutions of higher education 
and other nonprofit organizations. The NIH response to this survey is 
coordinated and prepared by this Section. It requires an institution-by- 
institution report of all NIH extramural support, by program, for most 
nonprofit organizations, with an individual report for each health professional 
school. In addition, data by field of science grouping and program are also 
requested for institutions of higher education. 

The Section assisted other PHS agencies by compiling their CASE Reports 
for those programs that are regularly processed by DRG. 

Obligations for Medical and Health-Related Research and Training Activities 
is an annual survey of all Government-sponsored medical research and training. 
The NIH response to this survey is also coordinated and prepared by this 

Section and requires data on intramural and extramural research and development I £§ 
by field of sciencs, performer, programs, and state. Additional NIH data 
required include manpower statistics related to graduate training grants, 
fellowships, and research career program awards by degree sought, institution, 
field of science and institutional versus individual support. 



At the beginning of each review cycle for research and training grant 
applications, statistical reports are prepared which present data on the 
number and dollar value of applications received for review. The presentation 
is by institute, fiscal year of support, and type of application. Copies are 
distributed to each institute/ division. In addition, statistical tables 
showing summaries of initial review group actions on research and training 
grant applications are prepared twice during each review cycle for use by the 
Division of Financial Management, the institutes/divisions, and the Office of 
Research Manpower, DRG. 

The Section supplies material each month for the NIH Management Data Book , 
published by the Associate Director for Administration to provide top 
management with a comprehensive view of the resources, status, and trends of 
major programs and operations. 

Inquiries . The Section responds to hundreds of requests for information 
each month from Federal agencies, NIH officials, other Government and non- 
Government organizations. These requests are primarily for statistical and 
analytical information concerning the NIH extramural programs and characteristics 
of grantee institutions contained in the IMPAC system. The response to these 



29 



'"I! i, 



inquiries frequently requires analysis and compilation of historical data jk 
covering several years, design of special computer reporting files, providing ™ 
consultation services to requesters concerning available data, and assisting 
in developing specifications for the output. The Section is responsible for 
supplying magnetic tape extracts from the IMPAC system to several institutes 
and outside organizations for special research projects, or as inputs to 
existing management information systems. 

The Section has devoted considerable effort to the development of shelf, ^- 
or reference listings, unpublished reports, and microfiche, to answer routine v 
inquiries covering support to individual investigators or specific institutions. 
The Inquiry and Reporting System (a computer software facility) is the primary 
method for data extraction, manipulation, and hard-copy presentation requested. 
More than 9,000 queries were processed by the Section during fiscal year 1975. 

Institutional Research . The Section has the responsibility for establishing 
and maintaining the Institution Profile File (IPF) . The IPF is the central 
registry of names, locations, geographic and other selected data for 
organizations participating in the Public Health Service extramural programs. 
This file is the single source for organizational information established 
to assure uniform reporting and to eliminate the necessity for storing similar 
information in individual grant and award files. In fiscal year 1974, over 
1,000 new institutions were added to the IPF. The IPF now contains about 
21,500 records on institutions participating in NIH programs, as well as the 
programs of other agencies of the Public Health Service. 

Annual Manpower Report . The Section participated in planning and 
designing the annual report form for personnel working on NIH research grants. 
This report will supply needed information on the manpower used in the 
performance of biomedical research funded by NIH. It will build upon and 
supplement the data from the 1970 manpower sample survey conducted by the 
Section. The initial distribution of the form to principal investigators and 
program directors was made in December 1973. 

The Section has coordinated responses to grantee correspondence concerning 
completion of the form, and also has helped to solve processing and systems 
design problems. A computer file containing data for fiscal year 1973 grants 
was developed by the Section during fiscal year 1975. 

Research Grant Expenditures . A computerized data base of the Report of 
Expenditures (ROEs) for fiscal year 1972 NIH research grants was established. 
The data base combines, with pertinent data from the IMPAC file, information 
reported to NIH on the ROE form by grantees. Data input and table programming 
were performed by a contractor funded under the NIH Health Evaluation Program. 

Retrieval Methodology . Two basic IMPAC Inquiry and Reporting System (IRS) 
courses were offered by the Section. A total of 45 persons attended these 
courses. IRS is the primary instrument for extracting and reporting IMPAC 
data. 



30 



About eight consultations are handled each day for DRG and institute/ 
division personnel needing assistance in debugging queries, developing more 
advanced queries, and applying new techniques. 

Retrieval Applications and Procedures . RAP was continued as an informal, 
technical series to provide users with accurate information and instructions 
on how to apply new or more efficient retrieval procedures, and to correct 
recurring IRS problems. About 60 copies of each issue are distributed to 
DRG and institute/division personnel responsible for compiling IMPAC data. 

Graphic Arts . Approximately 3,000 pieces of graphic art work and 
photographies were completed by the Illustrator in fiscal year 1975. This is 
a considerable increase over the 1,100 pieces of work completed in fiscal year 
1974. The bulk of this work included: cover designs, charts, certificates, 
slides, signs, visuals, special exhibits, and illustrations for flyers and 
handbooks. Other major assignments involved the development and preparation 
of slides for various statistical presentations by the Director, NIH, and 
other officials. The Illustrator was also responsible for the artistic 
preparation and assembly of the chartbook entitled Extramural Trends , Fiscal 
Years 1967-1974. 






"'I " 



31 



1 



I 



ANNUAL REPORT 

FISCAL YEAR 1975 
(July 1, 1974-June 30, 1975) 

DIVISION OF RESEARCH RESOURCES 



National Institutes of Health 
Bethesda, Maryland 20014 



I 



TABLE OF CONTENTS 

Report of the Director 1 

Report of the Assistant Director 5 

Animal Resources Branch 11 

Biotechnology Resources Branch 27 

Chemical/Biological Information Handling Program 57 

General Clinical Research Centers Branch 83 

General Research Support Branch 103 

Program Analysis Branch 121 

Office of Science and Health Reports 125 



iii 



REPORT OF THE DIRECTOR 
Dr. Thomas G. Bowery 



Report of the Division Director 



Fiscal Year 1975 has been a significant year for the Division of Research 
Resources (DRR) . The DRR Self-study, initiated over a year and one-half ago, 
has resulted in the formulation of a contemporary goal for the Division — 

TO IDENTIFY AND MEET THE RESEARCH RESOURCE NEEDS 
AND OPPORTUNITIES OF THE NIH. 

This concept was affirmed by the Director, NIH, in October 1974, in a statement 
to the Director, DRR — 

"The functions of the Division of Research Resources have 
a particular relationship to the totality of the NIH 
mission in contradistinction to the more segmented 
relationships of the categorical Institutes. Thus the 
programs of DRR have a special relationship to the concerns 
of the Office of the Director, NIH. ' 

"As NIH examines its ever changing responsibilities in the 
support of biomedical research, it is appropriate that the 
critical question of its role in providing research resources 
should be studied." 



Therefore, the Division has been actively involved this year in determining 
whether the contemporary goal can better serve the total NIH, whether 
necessary DRR/Institute interfaces can be established and maintained, and 
whether the DRR can realign its internal and external resources to accomplish 
the new goal. A series of meetings have been held with the top program staff 
of five of the Institutes (NIAID, NICHD, NINCDS, NIDR, and NHLI) to portray 
our contemporary goal, display the extent and impact of DRR resources on each 
of the Institutes' programs* and explore further mutual programmatic 
opportunities. We plan to hold similar interface sessions with the remaining 
Institutes in the near future. 

With respect to internal realignment so as ". . . to better utilize management 
resources and assure coordination of programs" as directed by the Office of 
the Director, NIH, four internal work groups have been established to examine 
the several essential functional areas of the Division: 

Resource Development 

Grants and Contracts Management 

Technical Merit Review 

Program Data and Information Management. 

These work groups have submitted recommendations and it is anticipated that 
implementation of several new systems will begin within the next few months 
following a submission of an organizational plan to the OD, NIH. 






111 .. 








1 1 

i 
in 


o 

73 




! 
J 











Additionally, the Director, NIH, has charged the Division with undertaking an 
examination of the scientific missions of the various program components of 
the Division. A Request for Proposal for such an evaluation has been issued 
and a contract will be signed by the end of this fiscal year. We anticipate 
that the mission study will take place over the next fifteen months. The 
study hopefully will provide the Director, NIH; the Director, DRR; and the 
National Advisory Research Resources Council information necessary in 
determining how effective the Division's programs are in relation to the NIH 
mission and what, if any, program changes are called for. 

The Division looks forward to Fiscal Year 1976 as an opportunity for 
strengthening the role of the DRR within the National Institutes of Health. 



REPORT OF THE ASSISTANT DIRECTOR 
Dr. James F. O'Donnell 







__,. 



Report of the Assistant Director 



As detailed within the accompanying pages of this report, Fiscal Year 1975 
has been a highly significant year for program accomplishments in the Division 
of Research Resources. These accomplishments were met, in no small measure, 
by the conscientious efforts of all members of the Division. Critical 
staffing problems remain and have been exacerbated by the loss of several key 
Health Scientist-Administrators and the absence of four support personnel who 
were on maternity leave. Dr. Benjamin Alexander, Acting Chief of the General 
Research Support Branch, left to become President of Chicago State University 
in July, and in November, Dr. William Raub, Chief of the Biotechnology 
Resources Branch, left the Division to become the Associate Director of the 
National Eye Institute. In June, Dr. William Goodwin, Director of the Primate 
Research Centers Program of the Animal Resources Branch, retired from the 
Commissioned Officers Corps of the U.S. Public Health Service. 

The loss of these key staff members combined with increases in project site 
visiting activities has resulted in less than optimal amounts of time available 
for strategic program planning and program evaluation. 

Fiscal Year 1975 marked a milestone for the Division in relation to the 
National Advisory Research Resources Council. This was the first time in over 
four years that the Council was at full strength. This should now provide us 
with the necessary advisory function we seek as we move forward to implementing 
our contemporary goal. 



Critical program decisions face the Division in this coming year attendant 
with the severity of fiscal constraints which may be imposed. Unless the 
Congress restores funds to the General Research Support Grant Program, this 
program will be terminated in Fiscal Year 1975. Decisions will have to be 
made concerning the number and location of General Clinical Research Centers 
across the Nation which will have to be phased out unless significant budgetary 
increases are provided. This crisis has occurred chiefly because of the rapid 
inflationary spiral in hospitalization costs which have occurred in the past 
few years. The supply of nonhuman primates for biomedical research investi- 
gators, and the costs necessary to maintain the physical facilities of the 
seven primate centers are major problems affecting the Animal Resources Branch 
programs. Both additional staff and fiscal resources are necessary for the 
Biotechnology Resources Branch to optimally extend the resource sharing concept. 
Additional fiscal resources are also essential if the Minority Biomedical 
Support Program is to be extended beyond the limited communities it is now 
serving. The American Indian community is one which the program is especially 
anxious to have as participants in this program. 

Internal reorganization of the Division with the anticipated better utilization 
of our scarce personnel resources and a participative "governance" process 
will hopefully provide us with the ability to meet the programmatic challenges 
of Fiscal Year 1976. 



DRR BRANCH REPORTS 




Fiscal Year 1975 Annual Report 

Animal Resources Branch 
Division of Research Resources 

INTRODUCTION 

The overall objective of the Animal Resources Branch (ARB) is to support 
resource projects that provide, or enable biomedical scientists to 
effectively use, animals in human health related research. Special attention 
is given to those animal resource activities that are broadly supportive 
of the missions of the various NIH components. The Branch objectives are 
accomplished through a Primate Research Centers Program, a Laboratory 
Animal Sciences Program, and Research Contracts. 

PRIMATE RESEARCH CENTERS PROGRAM 

The Primate Research Centers were established with Federal funds in the 
early 1960's to provide special research environments for the use of 
primates in many important areas of biomedical research. The seven 
centers, operated by Federal grant funds, continue to provide national and 
international leadership in biomedical primatology. During this year, 
significant research contributions were made in numerous areas including 
carcinogenesis, kidney diseases, drug addiction, and infant respiratory 
diseases. 

The core grant support provided by this program permitted the 152 core 
staff scientists to conduct research on a total of 111 grants and contracts 
with a total funding of $6.6 million. In addition, the 432 collaborative 
scientists from a number of universities utilized the facilities to conduct 
research on 127 grants and contracts with a total funding of $11.0 million. 
.The Centers also provided the research environment for 163 graduate students 
to undertake their thesis research. The program provided salary support 
for 170 doctoral level staff and 706 technical and administrative personnel. 

During this year, the problem of obtaining sufficient primates for research 
purposes reached a critical stage; therefore, it became necessary to 
significantly increase the domestic production of the primate species 
commonly used in the research programs . The Centers have provided the 
necessary basic knowledge required in the establishment of large primate 
breeding programs and are developing plans to expand their breeding 
programs in order to become self-sufficient in the production of primates 
for their own needs . They are currently producing approximately 50 percent 
of their annual requirements for experimental primates with a total of 
1055 infant primates being produced during this year. The missions and 
examples of research accomplishments at each of the Centers are as follows : 

OREGON PRIMATE RESEARCH CENTER 

The missions of this Center are reproductive biology, cardiovascular 
diseases, and metabolic and immune diseases. The following is an example 
of their research accomplishments : 



11 



Effects of Development and Early Nutrition on Brain Composition: 

In all species, aging is accompanied by a sequence of changes in the 
composition of the different parts of the central nervous system. During 
the period of most rapid change, a given area is usually susceptible to 
various insults, including nutritional deprivation. The rhesus monkey 
has been used for a correlative biochemical, histological and behavioral 
study of the effects of maternal and infant protein malnutrition on the 
development of the young. It was found that protein malnutrition during 
early development reduced the size of the brain, particularly the brain 
stem. 

DELTA PRIMATE RESEARCH CENTER 

The primary mission of this Center is infectious disease research and an 
example of their research activities is as follows: 

Potential Developments of a Vaccine for Chickenpox: 

There were 121,985 cases of chickenpox in the United States during 1974 
and 90 percent of these occurred in children under 10 years of age. 
Currently, there is no effective vaccine available as a suitable animal 
host for the development and testing of a vaccine has not been identified. 
A recent outbreak of a disease among a colony of monkeys at this Center 
has been identified as being caused by a virus almost identical to the 
chickenpox virus (varicella) in man. It is believed that the monkey will 
serve as a model for the development and testing of vaccines against 
this human disease. In addition, it will provide an opportunity to study 
the manner in which this virus can remain dormant in human tissue and 
then reactivate years later to cause diseases like zoster and shingles. 

YERKES PRIMATE RESEARCH CENTER 

The missions of this Center are neural and behavioral research and the 
study of neoplastic diseases. This Center has the largest colony of 
great apes available anywhere in the world for biomedical research. 
The following is an example of their research: 

Development of a Remotely-Controlled Injection and Blood Withdrawal System: 

In a number of research and clinical problem areas, there are needs for 
assessing variations in blood constituents in unanesthetized, ambulatory 
animals. Scientists at this Center have designed an instrument that can 
be worn by humans and primates that is remotely controlled through a 
radio link. This device enables them to withdraw blood samples through 
an indwelling catheter, flushing the catheter between samples to achieve 
separation. Telemetry is incorporated into the design of the instrument 
so that the temporal sequence of events is signalled to the investigator 
without any cue to the subject. The infusion capabilities of the device 
enables the investigators to inject, intravenously, biologically active 
substances and to then measure their subsequent blood levels or effects. 
This device is now being used in research on alterations in endocrine 

12 



activity that are induced as consequences of stimulation of the central 
nervous system and in response to the stress of social environments. 

WASHINGTON PRIMATE RESEARCH CENTER 

The mission of this Center is research in neurophysiology relating to the 
cardiovascular system and the support of 'an extensive collaborative 
research program involving a number of scientists in many disciplines. 
The following is an example of the research conducted at this Center: 



Sudden Infant Death Syndrome: 

This research using infant monkeys is directed toward identifying factors 
which may be involved in human crib deaths. These studies are focused on 
observations made by pathologists and others who have done extensive autopsy 
studies on crib death babies. Baby monkeys can be brought to the point of 
death by stimulating the nerves controlling the muscles of the larynx. 
In addition, the reflex pathways which serve to protect the larynx and the 
balance of the airways can be stimulated in a manner which results in 
death of the infant monkey. This result cannot be obtained in adult 
monkeys. This would indicate that the upper airways of infants can be thrown 
into a spasm which impairs respiration and other vital functions. These 
investigations also suggest that infant monkeys are sensitive to reduced 
oxygen in the air, and breathing a low-oxygen mixture alters their sensi- 
tivity to other stimulation. This indicates that changes in the composition 
of the air breathed by human infants can produce adverse effects upon the 
respiratory system. These studies are important for the identification 
and investigation of factors which could not otherwise be evaluated in human 
infants as potential contributors to crib death. 

WISCONSIN PRIMATE RESEARCH CENTER 

Neural and behavioral sciences and reproductive biology are the basic 
missions of this Center. An example of their research accomplishments is 
as follows: 

Primate Ecology 

A new program in primate ecology was established during this year and is 
the only activity of this nature in the Primate Research Centers Program. 
A senior investigator will undertake extensive field studies in Cameroon 
on a number of African primate species. These studies concern the con- 
servation of some of Africa's endangered species and the determination of 
whether the more common species of African primates can play a greater 
role as subjects in future biomedical research. The latter goal is 
especially important due to the reduced imports of primates from India 
and other countries . 

NEW ENGLAND PRIMATE RESEARCH CENTER 

The core staff of this Center is conducting research in areas of infectious 
diseases and primate pathology. In addition, a number of collaborative 






13 



scientists from several institutions conduct a major portion of their 
research activities at this Center. The following is an example of the 
research activities undertaken at this Center. 

New Technique for the Identification of Microfilaria: 

A technique has been developed which allows precise identification of 
circulating parasite larvae in peripheral blood. Identification of these 
parasites, heretofore, was exceedingly difficult and, in some cases, 
impossible. The method utilizes the location of the enzyme, acid 
phosphatase, within the parasite. This method has been used to identify 
two filarial parasites of humans which were almost impossible to tell apart 
with other techniques. Their differentiation is important as one causes 
disease and the other does not. 

CALIFORNIA PRIMATE RESEARCH CENTER 

The mission of this Center is in the area of infectious diseases and 
environmental health sciences, and one of their research accomplishments 
is as follows: 

Effects of Ozone on Pulmonary Function: 

In these studies, monkeys were exposed to 0.2, 0.35, 0.5, and 0.8 ppm 
of ozone for 8 hours per day on 7 consecutive days. These concentrations 
of ozone range down to the oxidant level not uncommon in regions severely 
affected by air pollution. Lesions were produced in lungs of all ex- 
perimental monkeys with more severe lesions caused by the higher 
concentrations of ozone. Most of the damage occurred in the respiratory 
bronchioles; the response being characterized by hyperplasia and hypertrophy 
of nonciliated bronchiolar epithelial cells. Large conducting airways 
were also affected, but in a more random pattern. The similarities in the 
morphology of distal airways in man and the monkey, and the localization 
of the ozone-induced lesions in the respiratory bronchioles of the latter, 
make the monkey particularly useful for studies concerning the long-term 
relationships between air pollution and respiratory diseases In man. 

LABORATORY ANIMAL SCIENCES PROGRAM 

The Laboratory Animal Sciences Program (LASP) assists institutions in 
developing and improving animal resources for biomedical research and 
training through the award of research and resource grants. Currently 
active program areas include support for animal colonies of unusual and 
special value for research; studies directed at finding animal models 
which are needed for research on human diseases; projects to assist 
institutions to comply with the legal and policy requirements for care of 
laboratory animals; laboratories for the diagnosis and control of disease 
of laboratory animals; research related to improving health care and 
determining environmental requirements of animals used in research; 
reference and information centers dealing with selected problems; and 
training of specialists in the field of laboratory animal medicine. 
The program awarded funds totaling $7,782 million in fiscal year 1975, 

14 



which supported 88 discrete animal research and resources projects, 
5 training programs, 6 fellowship awards, and 10 contracts. 

ANIMAL MODELS AND SPECIAL COLONIES 

The major objectives of this program area are (1) to define, characterize 
and exploit the relevant biological attributes of selected animals which 
display potential for use in several areas of biomedical research; 

(2) to establish, improve or expand special colonies of well characterized 
animals which are of proven value for specialized areas of biomedical 
research, but which are not generally available from other sources; and 

(3) to preserve unique and valuable stocks and strains of animals which 
may otherwise be lost due to particular circumstances. 

Support for projects related to the establishment of special animal 
colonies and animal model development has remained rather static during 
the past several years. Twenty-one projects in these categories were 
supported during FY 1975 (approximate total of $1,267 million), as 
compared to 22 projects supported during FY 1974 (approximately $1,250 
million) and 20 projects supported during FY 1973 ($1,141 million). 

The majority of the currently active projects in these categories are 
related to vertebrate species (e.g., rats, mice, guinea pigs, hamsters, 
dogs, rabbits, nonhuman primates, armadillos, degus , etc.). One of the 
projects very recently funded relates to the investigation of systems 
for the laboratory culture and maintenance of sea urchins. Support has 
also been provided for model development and/or special resources of 
several species of invertebrate animals, e.g., rare species of Drosophilia 
and Xyleborus (wood-boring beetle) . Two contracts were awarded during 
the past year for development of laboratory mariculture techniques to 
rear and maintain species of Aplysia (sea-hare) and two related species 
of marine gastropods (i.e., Hermissenda and Pleurobranchaea ) . Both 
studies have reported good progress to date. If successful, methodology 
will become available for the cultivation and rearing of these marine 
invertebrate species in any laboratory, thus precluding problems of 
uncertain health status and seasonal availability from their native marine 
habitats which currently confront researchers. 

Projects devoted to the definition, characterization and development of 
new types of animal models have generally been limited to those species 
or strains which evidence good potential for use in several disciplines or 
disease categories. Full exploitation of the potential usefulness of 
such animals normally requires the efforts of investigators in several 
disciplinary areas over an extended time period. 

Examples of model development projects currently supported by the LASP 
include: 

1. Studies at Washington State University on inherited neurological 
types of diseases including leukodystrophy, an autosomal recessive 
trait in cats; progressive myoclonic epilepsy (La Fora's Disease) 



15 






. !- 



in dogs; Ehlers-Danlos syndrome, an autosomal dominant disorder in 
dogs and mink; a lower motor neuron disease in dogs; and a lysosomal 
disorder of cats similar to the mucolipidoses of children. 

2. The characterization of eight strains of germfree mice and three 
strains of germfree rats for use in several research areas, including 
gerontology, cancer therapy and environmental pollutants at the 
Lobund Laboratory, Notre Dame University. 

3. The biological characterization and development of 10 new inbred 
lines of Syrian hamsters which were derived from the first animals to 
be brought to the United States from their native source in Syria 
since 1930. These new inbred lines have good potential as 
appropriate models for many areas of health-related research, 
including studies of viruses, aging, hibernation, dental caries, 
transplantation, tumor induction, myopathy, etc. 

4. A colony of PBB/Ld mice at the University of Alabama Medical 
Center which have high concentrations of plasma cholesterol and 
triglycerides are being characterized and developed as a potential 
model of familial hyperlipoproteinemia, Type IV (Fredrickson) , 
This inbred mouse strain also shows considerable promise as a model 
of obesity and dental caries. 

5. A colony of squirrel monkeys at the Bowman Gray School of 
Medicine which are being studied as potential models of cholelithiasis, 
chronic glomerulonephritis and the nephrotic syndrome, and lactose 
intolerance. 

Examples of ongoing projects which provide support for the maintenance of 
special colonies and serve as institutional and/or national resources 
include: 

1. A colony of genetically obese rats (Harriet G. Bird Foundation, 
Stow, Massachusetts) which serves as a resource for many 
investigators in nutritional and metabolic research. 

2. A resource of gnotobiotic mice, rats, guinea pigs and rabbits 
which is being made available from the Lobund Laboratory of Notre 
Dame University to the biomedical community for studies including 
cancer induction and chemotherapy, immunosuppression, and bone 
marrow transplantation. 

3. A colony comprised of highly inbred lines of rabbits at the 
University of Illinois College of Medicine which are utilized as 
models for studies of transplantation, immune response and 
cancer immunotherapy. 

4. A colony of nine-banded armadillos at the Gulf South Research 
Institute, New Iberia, Louisiana, which has contributed sig- 
nificantly to recent breakthroughs in the use of this animal as 

a model for studies on human lepromatous leprosy and production 
of purified leprosy antigen for prognostic skin testing of human 



16 



lepers . 

5. A colony of Inbred strains and mutant-bearing stocks of rabbits 
at the Jackson Laboratory, Bar Harbor, Maine, which are made widely 
available to investigators of important human disease conditions 
including ataxia, epilepsy, buphthalmia, lymphosarcoma, hemolytic 
anemia, renal cysts and mandibular prognathism. 

6. A resource colony of degus (a South American rodent) at the 
University of Vermont which is useful for research in immundlogy 
and development of eye cataracts . 

7. A resource of rare Drosophila species at the University of 
Texas which is made available to investigators in research areas 
such as cytogenetics, biochemical genetics, behavior, evolution and 
taxonomy . 

During FY 1975, 14 of these special colony resources provided support 
for 70 NIH-funded research projects with a total funded value of 
$5,331,000 and 130 biomedical research projects which received funding 
from other sources (total research funding value of $3,400,000). 

Only one institutional nonhuman primate resource received support during 
FY 1975. Support for this area has gradually diminished over the past 
several years due to a general LASP policy that well established primate 
resources should become financially self-sufficient through charges to 
users for their maintenance operation. However, the initial establish- 
ment of primate resources at institutions for interdepartmental usage 
is of proven value and remains as an eligible area in the Program. 
The LASP has continued to assess its possible role in the support of areas 
which are experiencing critical shortages of experimental animals. For 
example, -the acknowledged national shortage of frogs from their native 
habitats prompted the organization of a conference on this subject under 
LASP auspices in March, 1975. The future role of the LASP in supporting 
studies to alleviate the shortage of frog resources for biomedical 
researchers is currently under active consideration. 

INSTITUTIONAL ANIMAL RESOURCE IMPROVEMENTS 

Upgrading of existing animal facilities and development of new centralized 
animal resource programs has continued to be the most active program area. 
Requests in this area usually include animal cages to meet current regula- 
tions, general sanitation equipment such as cage washers, renovation of 
animal facilities, and addition of trained professional and technical 
personnel. The projects are supported for one to three years after 
which time the applicant institution is expected to take over complete 
financial responsibility for its basic animal resource. The amount of 
funded research involving the use of animals and the sources of funding 
are important factors in establishing funding priorities. The Program 
Analysis Branch has identified 1433 projects ($90 million current 
annual funding) involving the use of animals which are supported by NIH 
at those institutions with currently active resource improvement projects. 



17 



Institutional improvement projects have been supported since the inception 
of the Laboratory Animal Sciences Program; however, they received in- 
creased emphasis beginning in FY 1972 when Congress appropriated an 
additional $1.5 million. These funds were added to the regular budget 
to help research institutions achieve compliance with the Animal Welfare 
Act of 1970 (P.L. 91-579). The NIH policy on "Care and Treatment of 
Laboratory Animals" (issued June 14, 1971) and the subsequent DHEW policy 
on "Animal Welfare" (issued May 14, 1973) also contributed to the overall 
response in this area. The following figures demonstrate progression of 
support : 



FY 1971 



FY 1972 FY 1973 FY 1974 FY 1975 




No. of Improvement Projects 14 24 28 46 38 
Dollars Awarded (in $l,000's) 673 2,169 2,318 3,217 2,582 
Percentage of LASP Budget 11% 35% 37% 55% 42% 

The number of new applications for developing institutional animal resource 
programs has continued at approximately the same level as last year 
(FY 74 - 19, FY 75 - 21). Seventeen projects were recommended for approval 
and 15 of these were funded. In addition, 4 of 7 projects from previous 
years were supported making a total of 19 new projects ($2,143,950). The 
three projects dating back nearly two years will be administratively with- 
drawn. Thus, the large backlog of unfunded projects in this area which 
developed over a period of several years has been reduced to two projects. 

DIAGNOSTIC LABORATORIES 

The objectives of these laboratories is to provide for improved animal 
health programs through investigation of naturally occurring laboratory 
animal disease, to support indepth studies resulting in new information 
on disease processes and their etiology, to aid in the elucidation of 
new laboratory animal models of human disease, and to develop resources, 
including tissues, slides, photographs, etc., for research and training 
in laboratory animal medicine and comparative pathology. There are 13 
programs which are currently being supported ($1,217 million - 20% of 
LASP budget) . A shortage of appropriately trained specialists (veterinary 
pathologists and microbiologists) has been a limiting factor, precluding 
any rapid establishment of new programs. However, two new laboratories 
were funded during FY 1975. Special attention is being given to 
laboratories which have the potential of serving more than one institution 
in the same metropolitan area. Unfortunately, several proposals of this 
type were not approved due to weaknesses in the projected staffing and 
basic animal care program of the participating institutions. 

By under girding an institution's animal health program, the laboratories 
make a direct contribution to approximately 885 NIH supported research 
projects using animals with total funding of nearly $56 million. In 
addition to the service aspects of diagnosis, the laboratories have been 
productive in terms of new information and techniques. In-depth studies 
of laboratory animal disease problems resulted in over 70 publications 
and presentations during the past year. The value of routine surveillance 



18 



activities continues to be demonstrated. Various suppliers of rats were 
evaluated for the incidence of respiratory pathogens at one institution. 
Providing this information to investigators coupled with changes in the 
sources of supply resulted in a much lower incidence of disease in rat 
colonies. Early recognition of Tyzzer's disease in newly received rabbits 
resulted in modifications in quarantine procedures and control of this 
potentially serious problem. One laboratory has continued its close 
association with a major amphibian facility. Various disease problems 
have been investigated and a number of publications have resulted. The 
importance of diet as a source of aerobic gram negative bacteria isolated 
from cloacal contents was established. These bacteria originated in 
arthropods being fed as live food. A serious disease problem was reported 
in one group of Rana pipiens due to naturally occurring infection with a 
pigmented fungus. The fungus was transmitted experimentally to healthy 
Rana pipiens , demonstrating a potentially serious clinical problem in 
laboratory housed frogs. Several laboratories have been investigating 
regional enteritis, a well known enzootic disease of hamsters. One 
laboratory was able, for the first time, to establish conditions for the 
experimental induction of this disease. Future studies to elucidate the 
etiology and pathogensis will be pursued under a recently funded research 
grant. A laboratory in Florida receives specimens from a number of 
exotic species including reptiles and marine mammals. It was noted that 
the BSP clearance time for healthy indigo snakes was 45-50 hours as 
compared to times of 30 minutes in rat snakes. This study shows 
promise in providing an important model for liver function studies. Another 
potential model for retinitis pigmentosa in humans was discovered following 
routine screening of an inbred colony of rats. The condition was found in 
100% of the rats and was characterized as a slow, progressive degeneration 
of photoreceptor cells. 

RESEARCH PROJECTS 

The Program has provided support to a relatively small number of discrete 
research projects over the past several years. This may be summarized 
as follows : 



Number of Projects 
Awarded (in thousands) 
Percentage of Total $ 



FY 71 FY 72 



FY 73 



FY 74 



FY 75 



4 


6 


8 


10 


9 


403 


449 


593 


591 


490 


9% 


7% 


10% 


10% 


8% 



Projects falling into this category generally have one of the following 
objectives: (1) to investigate the etiology, pathogenesis, and control 
of laboratory animal disease problems, (2) to determine various 
environmental requirements of laboratory animals. For example, currently 
active projects include studies of sialodacryoadenitis in the laboratory 
rat, definition of environmental conditions for laboratory animals, 
development of a vaccine to control feline viral rhinotracheitis, and 
diagnosis and control of mammalian encephalitozoonosis. Work during the 
past year on the latter project has resulted in the development of a new 
serologic test (complement fixation) for experimentally and spontaneously 



19 



■ '!. 



infected rabbits. The advantage of the complement fixation test is that 
it is more quantitative than the immunfluorescence test and is applicable 
to a variety of antigenic fractions. A study currently in progress is 
comparing the sensitivity of skin tests and serological tests. Comparative 
studies from human material resulted in the observation that two 
spontaneous human cases of microsporidosis were due to microsporida be- 
longing to the genus Nosema rather than to the mammalian genus 
Encephalitozoon . These observations suggest that more emphasis should 
be given to using immunologically incompetent animals in the safety testing 
of insect Nosema intended for use as biological pesticides and for dis- 
tribution into the environment. It is possible that the important 
human pathogen is the genus Nosema rather than Encephalitozoon as 
previously assumed. 



REFERENCE CENTERS AND INFORMATION PROJECTS 

The Program has continued to support several reference centers and 
information projects. Examples of these are: 

1. A Simian Virus Reference Laboratory at the Southwest Foundation 
for Research and Education, San Antonio, Texas. The Laboratory 
now has a working repository of over 60 virus reference reagents 
and reference antiserums. Ongoing activities of the project are 
designed to give information regarding the immune status of sub- 
human primates and the possible cause of outbreaks of overt 
diseases. Institutions throughout the country have taken 
advantage of this program. For example, during the past year, 

48 laboratories submitted nearly 2400 specimens for antibody 
surveys or virus isolation and identification. 

2. The Registry of Comparative Pathology, located at the 
Armed Forces Institute of Pathology (AFIP) . The Registry 
has continued to augment its collection of specimens from 
primates and other laboratory animals, domestic and wild 
animals, fish and birds. Material has been made available 
to others and utilized for the preparation of exhibits, 
lantern and microscopic slide sets, and as the basis for a 
number of publications. In addition to publication of a 
quarterly "Comparative Pathology Bulletin," the Registry 
sponsors publication of an animal model in each issue of the 
American Journal of Pathology. A handbook entitled "Animal 
Models of Human Disease" has been prepared for sale. Three 
fasciles covering 45 models have been published so far and a 
fourth containing 15 additional animal models plus an index 
is planned for 1975. An annual short course (3 days) in 
Comparative Pathology was offered for the second time this May. 

3. The Laboratory Primate Newsletter, which now has a mailing 
list of about 1,700 individuals and organizations. The Newsletter 
provides information on maintenance, breeding, and procurement of 
nonhuman primates for laboratory studies. It also serves as a 
general source of information through announcement of meetings, 



20 






nomenclature changes, etc., and aids investigators by publishing 
requests for materials. 

TRAINING 

Training in laboratory animal medicine is intended to prepare individuals 
to provide professional care of the many species of laboratory animals, 
to manage central animal resources, and to give special assistance to 
investigators through superior knowledge of laboratory animal biology 
and understanding of research methods. In addition, the trainees are 
prepared to participate in the teaching of graduate students and young 
investigators and to pursue their own research interests either as 
independent investigators or as a member of a research team. 

The Animal Resources Branch has supported training programs in laboratory 
animal medicine since 1967. Seven programs and approximately 20 trainees 
were supported during the current fiscal year . The programs are all 
located in medical research environments. Diagnostic laboratories are 
also supported in each. of these locations, and the laboratory resources 
have provided major input to the training experience. In addition to the 
training grant mechanism, the Branch supports training through the award 
of individual postdoctoral fellowships (six currently active Fellows). 
In some cases, these individuals have enrolled in ARB training programs. 
Approximately half of the individuals seek more specialized research 
training. These fellows have engaged in in-depth studies in a discipline 
or specialty such as surgery, pathology, virology or physiology, through 
which they can contribute to research animal resources. 

Currently available figures indicate that 110 trainees and fellows have 
completed training since the inception of training grants and fellow- 
ships in laboratory animal science and medicine. Forty (40) of these 
are employed by medical schools and 50 by other academic, research or 
governmental organizations. The majority (62) are functioning as 
directors or staff members of a vivarium; 41 are engaged in research 
or are obtaining additional training; and 7 are engaged in public health 
and other activities. Retention in the field of laboratory animal 
medicine has been excellent, emphasizing the career orientation 
provided by the training and the continuing need and opportunities 
available for such individuals. 

The attraction of well qualified and motivated individuals to the field 
of laboratory animal medicine has been a continuing problem, particularly 
over the past several years. In an effort to help this situation, the 
Branch, this year, has encouraged existing training programs and 
diagnostic resources to employ veterinary students during their summer 
break. It is hoped that this work experience will result in greater 
knowledge and interest in the field. Development of a "pool" of such 
individuals for future postdoctoral training should result in long term 
benefits to the field. Reaction during the first year is highly 
encouraging as some 41 students inquired about opportunities and 
approximately 20 will be employed at 11 different institutions. 



21 



In the fall of 1974, a new National Research Service Award Program was 
announced. This program replaces all previous training authorities 
which terminated July 12, 1974 with the passage of the National Research 
Service Awards Act (Public Law 93-348) . As currently active training 
programs reach the end of their project period, they will have to 
compete under the provisions of the new authority. The main changes 
in the new authority are a requirement for recipients (institutional or 
individual fellows) of NRS Awards to engage in biomedical research or 
teaching for a period equal to their period of support and a limitation of 
25% of the total award for other than trainee costs (institutional programs) 
Two programs submitted institutional applications for the June Council 
competition. Additional receipt dates have not been announced and the 
future of institutional programs supported by NIH is somewhat uncertain 
since the authority resulting from PL 93-348 was limited to one year. 
Additional questions to be resolved include the desirability of limiting 
the proportion of funds awarded to institutional programs compared to 
individual fellowship awards and the manpower requirements in various 
research fields that would justify federal training support. The changes 
and uncertainties surrounding the training programs have made it difficult 
for them to plan programs and attract well qualified students. If this 
continues, it will adversely affect research animal resources. 

RESEARCH CONTRACTS 



The Animal Resources Branch has used the research contract mechanism as 
an adjunct to its resource grant programs to support specific essential 
services or to initiate activity in vital resource areas that have not 
responded or are not eligible to respond to the grant mechanism. Research 
contract funds for ARB in FY 1975 were about $1,300,000, including $300,000 
transferred from The National Institute of Neurological and Communicative 
Disorders and Stroke (NINCDS) for support of the Caribbean Primate Center. 
Ten projects were supported. These contract projects are in the following 
area: 

PARTIAL SUPPORT FOR THE INSTITUTE OF LABORATORY ANIMAL RESOURCES 

The Institute of Laboratory Animal Resources (ILAR) is a subsidiary of 
the National Academy of Sciences, established as a coordinating agency 
to disseminate information, survey existing and required animal resources, 
establish standards and promote education in the field of laboratory 
animal science. Since July 1953, ILAR has received financial support 
from NIH. These activities are a valuable adjunct to the Animal Resources 
Branch program. The ILAR meets ARB needs for writing standards and guide- 
lines for animal facilities and care, furnishing information on sources 
and users of laboratory animals, and providing survey information on the 
status of animal resources. Special activities include an information 
service on the sources and availability of over 450 animals models and 
genetic stocks and a field survey on the abundance and distribution of 
primates of biomedical interest in selected areas in South America. A 
special activity, completed this year, has been a survey and analysis of 
use of primates for research and a study to provide information for 
planning numbers and species of primates which should be bred in this 



22 



country. The final report has been received and it will be very useful 
in planning primate supply programs. 

AMERICAN ASSOCIATION FOR ACCREDITATION OF LABORATORY ANIMAL CARE (AAALAC) 

The Animal Resources Branch is providing, through a small contract, partial 
support for site visits that are conducted as part of the AAALAC accreditation 
program. This effort is important to maintain quality in the accreditation 
program. NIH officially recognizes AAALAC accreditation as meeting the 
requirements of its policy on the care and treatment of laboratory animals. 

MARICULTURE OF MARINE INVERTEBRATES 

The Animal Resources Branch has awarded two complementary contracts for 
laboratory breeding. and rearing of Aplysia and related species. These 
marine mollusks are used in a variety of biomedical studies and are 
becoming increasingly difficult to obtain from nature (the principal 
supplier now "rations" the animals to researchers). It is felt that, with 
two or three years' effort, it is feasible to establish laboratory culture 
of these species, thereby assuring a supply of high quality animals. Both 
contractors, Pacific Biomarine Inc. and The University of Hawaii, are 
making good progress toward this goal. 

CARIBBEAN PRIMATE CENTER 

This primate resource is being supported by funds transferred from NINCDS 
which formerly supported the Center. The Center includes several 
semi-free ranging primate colonies on islands off the coast of Puerto Rico. 
The Center is a valuable resource for research on social behavior and 
neurologic behavioral relationships and has the potential to be an 
important breeding center. The breeding potential is, in part, being 
realized as the Bureau of Biologies, FDA, awarded a contract which 
supports production of 500 rhesus monkeys per year, and additional 
animals are being bred under contract from NINCDS. 

RHESUS MONKEY BREEDING 

The Animal Resources Branch has awarded three contracts for the domestic 
production of rhesus monkeys. This is part of an effort to assure a 
supply of primates for essential biomedical activities in the face of 
drastically curtailed importation of wild caught animals. When they come 
into full production in three to four years, these colonies are expected 
to produce about one-third of the rhesus monkeys required for NIH extra- 
mural programs. The oldest and largest of these three colonies is the 
Charles River Breeding Laboratories in the Florida Keys. This free 
ranging island colony currently has 800 breeding animals and about 125 
infants were born this year. The colony is targeted for 1500 breeders 
producing 1000 animals annually. The second colony is the Hazelton 
Laboratories colony in Texas. The breeders of this colony are housed in 
corn crib structures. It presently has 300 breeding animals and is targeted 
to have 900 breeders producing 500 offspring annually. The third colony 
is the Litton-Bionetics colony in South Carolina. This colony is housed 

23 



! 
i 









in sheltered outdoor runs. It currently has 260 of an anticipated 620 
breeders which will produce 400 animals annually. About 50 babies were 
born this year. 

SQUIRREL MONKEY BREEDING 

Late in the fiscal year, the Animal Resources Branch awarded two contracts 
for domestic breeding of squirrel monkeys. Next to the rhesus, squirrel 
monkeys are the most commonly used primate in biomedical activities. 
The prime sources of these animals, Peru and Colombia, have virtually 
stopped exportation of them in the past year. Animals can still be 
obtained from Guyana and Bolivia but these sources are not secure. The 
ARB contract projects are expected to produce 400 squirrel monkeys 
annually . 

ADMINISTRATION 

Primate supply problems continued to be a focus of administrative activity 
in Fiscal Year 1975. Bans on exporting of animals from Brazil, Colombia, 
and Peru continued in effect. Late in the fiscal year, we were informed 
that the Government of India was reducing the quota for export of rhesus 
monkeys from 30,000 to 20,000 annually. Other nations are considering 
restriction of primate exports, and chimpanzees will probably be placed 
on the endangered species list. All this has made development of plans 
for domestic production, agreements with foreign governments for primate 
supply, and conservation of use of primates of critical importance. In 
order to co-ordinate various primate supply activities, the Assistant 
Secretary for Health has appointed a Primate Steering Committee with NIH 
as the lead agency. This Committee will also co-ordinate with other 
government agencies that use primates. The Committee was fortunate to 
obtain the services of Dr. Benjamin Blood to provide staff leadership. 
The Animal Resources Branch is providing office space and secretarial 
assistance to Dr. Blood, and is in the forefront of domestic breeding 
and conservation of use programs . 

Another administrative activity has been the establishment of a Research 
Career Development Award (RCDA) program. The Branch received approval to 
announce such a program in January, 1975, and the first applications 
were received on May 1, 1975. The RCDA provides salary support for 
individuals that have had at least three years post doctoral experience 
and have demonstrated potential for development into creative independent 
investigators. The purpose is to increase the number of first rate 
investigators who have, as their career goal, research on laboratory 
animal resource problems. 



24 



TABLE I - Primate Research Centers Program Applications , FY 1975 

Number Amount Number Amount Number Amount 
Type Received Requested^ ' Approved Approved^ -' Funded Funded^ -' 

New - - - - - - 

Renewal 1 1,727,156 1 1,504,552 1 1,452,228 

Supplemental - - - - • 

Continuation 6 12,876,984 6 11,404,435 6 9,693,772 

Totals 7 14,604,140 7 12,908,987 7 11,146,000 

1/ Direct Costs Only 

2/ Includes Indirect Costs 

TABLE II - Laboratory Animal Sciences Program Applications , FY 1975 





Number 


Amount 


Number 


Amount 


Number 


Amount 


Type 


Received 


Requested^' 


Approved 


Appro vedi' 


Funded 


Funded?/ 


New 


45 


4,053,288 


28 


2,314,848 


27 


2, 836, 766^ 


Renewal 


8 


1,099,216 


5 


329,476 


5 


438,795 


Supplemental 


9 


201,372 


8 


188,357 


8 


240,847 


Continuation 


48 


2,705,679 


48 


2,004,424 


47 


2,665,236 


Totals 


110 


8,059,555 


89 


4,837,105 


88 


6,180,844 



1/ Direct Costs Only 

2/ Includes Indirect Costs 

_3/ Includes 5 Prior Year Approvals at $451,199 

TABLE III - T raining Grant Applications in Laboratory Animal Medicine , FY 1975 





Number 


Amount 


Number 


Amount 


Number 


Amount 


Type 


Received 


Requested^' 


App 


roved 


Approved^/ 


Funded 


Funded?/ 


New 


2 


163,523 




2 


95,406 


2 


103,038 


Renewal 


- 


- 




- 


- 


- 


- 


Supplemental 


- 


- 




- 


- 


- 


- 


Continuation 


4 


313,092 




4 


247,153 


4 


256,621 


Totals 


6 


476,615 




6 


342,559 


6 


359,659 



1/ Direct Costs Only 

2/ Includes Indirect Costs 

TABLE IV - Fellowship Applications in Laboratory Animal Science , FY 1975 





Number 


Number 


Number 


Amount 


Type 


Received 


App 


roved 


Funded 


Funded 


New 


5 




3 


1 


27,738 


Renewal 


- 




- 


- 


- 


Supplemental 


- 




- 


- 


- 


Continuation 


5 




5 


5 


21,111 


Totals 


10 




8 


6 


48,849 



25 



TABLE V - Laboratory Animal Sciences P rogram Resource and Research Grants , 
Project Distribution , FY 1 975 



Number 



Amount 



Number 



Amount 



Number Amount 



T^oe 

Basic Improvement 
Special Colonies 

and Models 
Primate Resources 
Resource Research 
Diagnostic Labs 
Reference & Info. 



Received Requested— ' Ap proved Approved— ' Fund ed Funded— ' - 



3/ 



42 3,188,025 



26 
1 

17 

18 

6 



1,645,629 

22,195 

1,265,469 

1,559,287 

378,951 



Totals 110 8,059,555 



37 

22 
1 
10 
13 
_6 
89 



2,145,733 

1,095,217 

11,098 

380,496 

851,322 

353,239 

4,837,105 



38 

21 
2 
9 
13 
_5 
88 



2,581,834 

1,267,019 

118,615 

490,115 

1,216,661 

50 6,600 

6,180,844 



1/ Direct Costs Only 

If Includes Indirect Costs 

3/ Includes Prior Year Approvals 

TABLE VI - Laboratory Animal Sciences Program , Research Utilization of 
Selected Animal Resource Colonies, FY 1975 



No. of 
Colonies 

14 



No. of 
N IH Grants 

70 



Dollar Amt. of NIH 
Grants in $1, OOP's 

$5,331 



No. Other Dollar Amt. Other 
Projects Projects in $1, OOP's 

130 $3,400 



26 






Fiscal Year 1975 Annual Report 
Biotechnology Resources Branch 
Division of Research Resources 

The Biotechnology Resource is a vehicle through which the physical sciences, 
mathematics, and engineering are interfaced to biology and medicine. Such a 
resource combines expensive equipment, complex methodologies, and scarce ex- 
pertise to facilitate the solution of important medical problems. A continuous 
effort to meet program goals is maintained within each resource by (1) providing 
services to the biomedical research community; (2) engaging in collaborative 
research arrangements with appropriate scientists; (3) engaging in core research 
and development designed to provide new technological opportunities for the 
research community and/or increase the usefulness of existing technology; and 
(4) providing training opportunities to the user community so that they can 
better understand the technology and apply it more effectively to their own 
research problems. 

During the past few years it has become increasingly apparent that even some of 
the most distinguished biomedical research institutions throughout the country 
are unable to provide their member scientists with either up-to-date, health- 
relevant, research tools or the opportunity to collaborate with innovative 
experts at the technology /medicine interface. Accordingly, a concerted effort 
in Biotechnology Resource Sharing was initiated and promoted during FY 1974 and 
will continue for the foreseeable future. The objective is to effect a more 
nearly equitable distribution of highly specialized research support capabilities 
in the nation, including especially those institutions having limited biotech- 
nology capabilities but strong biomedical research programs and compelling bio- 
technology needs. 



STATE OF THE PROGRAM 

BASIC DATA 

The variety of supported Biotechnology Resources and the diversity of assistance 
they provide the research community are shown by the following classification of 
the 47 grants and five contracts active during FY 1975. 

17 computer resource grants 

17 biomolecular characterization resource grants 
1 resource-related project in biomolecular 

characterization 
6 biomedical image and image processing resource 

grants 
1 resource-related project in biomedical image 

and image processing 
5 biomedical engineering and other resource grants 
1 electron microscopy services contract 
4 clinical research data management and analysis 
developmental contracts 



27 



■ 



The aggregate annual expenditure level for these activities is approximately 
$12 million. A listing of the BRB sponsored activities active during FY 1975 
is given in Table I. A brief description of each Resource's capabilities, 
highlighted with an example of its application, is included in Table Ila-d. 
The interaction of the Biotechnology Resources Program with other NIH programs 
is shown in Table III . 

It is particularly interesting to view the Biotechnology Resources Program in 
historical perspective. In 1967, for example, 61 resources were supported at 
a cost of $12.2 million. These resources fell into the following categories: 

48 computer resources 

10 biochemistry instrumentation resources 
3 biological materials resources 

Both the numbers and the substantive nature of each type of resource have changed 
greatly during the intervening years, especially in the computer resource cate- 
gory. Compared to the 28 batch-processing or off-line, general-purpose computer 
installations in 1967, the Program had only one resource of this type in 1975. 
Whereas in 1967 the average annual award for a computer resource was about 
$174,000, it was approximately $346,000 in 1975. There seems to be little doubt 
that the ever more sophisticated computational needs of biomedical scientists 
are requiring highly specialized resources and not general-purpose ones. 

Rapid and far-reaching change is not limited to the computer resource category. 
For example, as the requisite talent becomes available to manage mass spectrom- 
eters in a variety of biomedical settings, there is a strong trend toward the 
use of these instruments in clinical investigation, such as the study of meta- 
bolic errors in infants. It is also of interest to note that, unlike even a 
few years ago, all of the biochemistry instrumentation resources now contain a 
dedicated computer for reduction of data to a manageable form. Similarily, 
almost exclusively as a result of efforts by the Biotechnology Resources Program 
in the past several years, high voltage (i.e., one-million volt) electron 
microscopy services have become a reality in the United States and are now being 
applied for such purposes as obtaining stereo micrographs of thick-sectioned 
biological material and examining the surfaces and contacts of intact wet cells 
in a hydration chamber. 



BIOTECHNOLOGY RESOURCE SHARING 

The succeeding sections will describe representative biotechnology resource 
activities in several areas. It is obvious that these biomedical research 
activities are of great value to their respective research communities. It is 
also apparent that these research communities are especially fortunate in having 
these excellent opportunities immediately available. 

Because these highly specialized resources are both expensive and dependent on 
critical assemblies of scarce talent, only a few medical research centers having 
needs for them can be accommodated by the BRB, using traditional program support 
mechanisms, within present and foreseeable funding constraints. 



28 



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36 



Table Ila 

Resource Characterizations 

Computers 






Grant No. 



RR-03-14 



RR-07-12 



RR-15-13 



RR-249-10 



RR-259-09 



RR-267-10 



RR-276-10 



RR-291-09 



RR-326-09 



RR-374-08 



RR-396-08 



Capability 

Batch processing, timeshare. 
and graphics 



Image Processing and 
analysis 



Time sharing and batch 
processing 

Stand-alone minicomputers 



Batch processing and tele- 
processing 

Batch processing and time- 
sharing 

Dedicated systems and time- 
sharing 



Batch processing or 
dedicated digital analog 
system 

On-line interactive 
laboratory computing 

Experiments hardwired to 
resource computers plus 
time-sharing 

Dedicated computers and 
macromodule systems 



Illustrative 
Applications 

Biostatistical research; 
modelling cell cycle 
dynamics 

Non- invasive monitoring 
of cardiac function via 
roentgen video 
densitometry 

Biochemical kinetics 
modelling 

On-line real-time control 
of neurophysiology 
experiments 

Patient record management 



EKG analysis 



Computer assisted 
pulmonary function 
testing 

Biomathematical modelling 



Acquisition and processing 
of neurophysiology data 

On-line control and analysis 
of physiology experiments 



Cardiac rhythm monitoring; 
biomolecular modelling 



37 



Computers (continued) 

Grant No. Capability 



RR-576-04 



RR-578-05 



RR-643-04 



RR-757-03 



RR-785-02 



RR-898-01 



Remote job entry to insti- 
tution's computers; stand- 
alone minicomputer 

Stand alone medium computer 
and graphics 



Access to timesharing 
systems 



Computer-based automated 
laboratory systems 



Remote access through 
computer networks 



Interactive graphics and 
modelling 



Illustrative 
Applications 

On-line real-time control 
of biomolecular character- 
ization devices 

Biomolecular modelling 
and computer-assisted 
design of organic 
systhesis 

Application of artificial 
intelligence to clinical 
decision making 

Image processing, on- 
line acquisition and 
processing of X-ray 
crystallography data 

Applications of artificial 
intelligence in biology 
and medicine 

Displaying and mani- 
pulating molecular 
mo el e 1 s . 



38 



Table lib 

Resource Characterizations 

Siomolecular Characterization 



Grant No. 



RR-273-10 



Capability 

Gas chromatography/low 
resolution, mass spectrom- 
etry/gas flow proportional 
counter 



Illustrative 
Applications 

Metabolic profiles 



RR-292-10 



High-frequency NMR, Multi- 
nuclear capability 



Structure and function 
of hemoglobins and other 
molecules 



RR-317-08 



Mass spectrometry-High 
resolution, gas chromatog- 
raphy/ mass spectrometry, 
chemical ionization 



Drug identification, 
structure determination 
of unknown biomaterials 



RR-330-08 Mass spectrometry-High Structure determination 

resolution, gas chromatography/ of potential anti-tumor 

mass spectrometry drugs 

RR-355-08S1 Mass spectrometry - High Structure determination 

resolution, gas chromatography/ of antibiotics 
low resolution 



RR-356-08S1 



RR-480 T 07 



RR-542-05 



Mass spectrometry - High 
resolution, low resolution, 
NMR - Carbon- 13, Proton, 
High performance chromatography 



Separation and detection 
of mucleosides 



Mass spectrometry - High Structure determination, 

resolution, gas chromatography/ Lipids of biomedical 

mass spectrometry, field importance 
desorption mass spectrometry 



High-frequency NMR 



Enzyme /substrate 
interaction mechanisms 



rr-574-04 



NMR-multinuclear capability 



Carbon- 13 labeled 
macromolecules 



RR-612-05A1 Resource related research 
Mass Spectrometry 



Application of artificial 
intelligence to mass 
spectrometry 



39 



Biomolecular Characterization (continued) 



Grant No. Capability 

RR-636-03 NMR-multinuclear capability 

RR-63y-02 NMR-Proton, Carbon-13 



Illustrative 
Applications 

Structure and function 
of peptide hormones 

Carbon-13 studies of 
nucleoside bases 



RR-665-02 



Mass spectrometry - high Structure identification 
resolution, gas chromatography/ of natural products 
low resolution, chemical 
ionization 



. 



RR- 708-01 



RR-711-02S1 
-03 



Mass spectrometry, gas 
chromatography/low resolu- 
tion, NMR-220MH„ 



NMR - 360MH, 



Metabolic studies, 
structure and function 
of biomolecules using 
stable isotopes 

Structure and function 
of macromolecules 



RR-719-02 



Mass spectrometry - high 
resolution, gas chromatog- 
graphy/high resolution, low 
resolution 



Application of mass 
spectrometric techniques 
to clinical problems 



RR-798-01 



RR-862-02 



NMR - 270MH Z ; Proton, carbon- 
13; deuterium; swept and 
fourier transform modes 



Mass spectrometry-chemical 
ionization 



Membrane structure, drug 
and hormone action, 
immune responses , 
carcinogenic activity 

Application of mass 
spectrometry to medical 
problems 



40 



Grant No. 
RR-442-06 

rr-443-06 

RR-570-05 

RR-592-05 

RR-679-03 

RR-715-03 
RR-754-01 



Table He 
Resource Characterizations 
Biomedical Image and Image Processing 

Capability 
Image processing and displays 



Image processing 

One-million volt electron 
microscope 

One-million volt electron 
microscope 

Electron Microprobe 



Scanning electron microscope 
Image processing 



Illustrative 
Applications 

Neuroanatomical 
modelling 

Electronmicrographs and 
medical images 

Structure and function of 
chromosomes 

Structure and function 
of the nucleolus 

Histochemistry - 
quantitative analysis 
of renal cell 
composition 

Under development 

More sensitive systems 
for recording images in 
the high voltage 
electron microscope 



41 



Table lid 
Resource Characterizations 
iiomedical Engineering and Others 



Grant No. Capability 

RR-12-13 Activities hardwired 

to resource computer 

RR-657-01A1 Production of radiochemicals 
that incorporate short-lived 
radionuclides 



Illustrative 
Applications 

Patient monitoring; 
medical record management 

Nuclear medicine 



RR-716-07 



RR-759-02 



RR-857-01A1 



On-line real-time integra- 
tion methods; on-line real- 
time display 



Serology, toxicology, 
histology 

Microelectronics fabrication, 
packaging, and evaluation 
capabilities 



Interfacing of laboratory 
instruments to computers; 
acquisition of electro- 
physiological and other 
biological data under 
computer control 

Forensic pathology 



Microelectronics devices 
for biological and 
clinical research 



42 



Table III 

Number & Dollar Amount, by NIH Institute, of Projects 

Receiving Technological Support from a Sample of 30 of the 47 

Biotechnology Resources 



Active During FY 1974 



Institute 



Allergy and Infectious Diseases 

Arthritis, Metabolism and 
Digestive Diseases 

Cancer 

Child Health and Human Development 

Dental Research 

Environmental Health Sciences 

Eye 

General Medical Sciences 

Heart and Lung 

Neurological and Communicative Disorders 
and Stroke 







Dollar Value 


Number 


of 


of Project 


Project 


s 


(in millions) 


26 




1.5 


57 




4 


64 




9.7 


45 




2.8 


4 




.1 


6 




.4 


7 




.6 


140 




7.9 


226 




8.5 


59 




5 



634 



40.5 



Projected Totals for all 47 Active Grants 
Number = 993 
Value = $64 million 



43 



Moreover, these specialized resources usually must have great capacity in order 
to function effectively. At the same time such great capacity may exceed the 
needs of a single institution, yet could be of even greater value with specific 
supplementation. 

The logical solution to these problems of high costs, scarce talents, needs for 
broad and versatile resource support, and inter-institutional collaboration, 
lies in linking and sharing resources. 

Because of the varied natures of sharable resources, specific appropriate admin- 
istrative arrangements are needed. Some biotechnology resources, such as com- 
puters which can be linked by telecommunication networks, are readily adapted 
to the shared mode. Others, e.g., the HVEM resources, presently require that 
the investigator and the problem be brought to the resource facility, under 
suitable arrangements assuring effective management, participation of qualified 
researchers, needed training, and ongoing evaluation of effectiveness as a 
shared resource. 

Assembly of related but dissimilar biotechnology resources into shared networks 
offers the advantage of pooling diverse talents and instrument capabilities to 
produce levels of capability superior to those of any component. 

The pooling effect has special benefits for those investigators and institutions 
with potential, but who for lack of opportunity have inadequate training and 
experience in the exacting skilled fields encompassed. Sharing of resources 
therefore offers opportunities for disadvantaged institutions and isolated 
investigators. However, the linking of institutions and investigators of 
grossly dissimilar levels of sophistication poses new problems of program 
management to assure equitable involvement of the "have" and "have not" compo- 
nents in shared resource systems. Both the review and the ongoing management 
by NIH staff must enter a new dimension. 

The benefits of shared biotechnology resources are obvious. These include: 

(1) the support of a larger and more varied body of investigators and problems, 

(2) fuller utilization of expensive instrumentation, (3) increased collaboration 
between investigators in different institutions who have research interests in 
common, and (4) the increase in numbers and quality of researchers and insti- 
tutions able to benefit from sophisticated biotechnology approaches to their 
biomedical activities. 

Although shared biotechnology resource programs are still in comparative infancy, 
the potential for expansion is impressive. The experience gained in developing 
and managing these arrays may well establish patterns of wide applicability in 
biomedical research. 



COMPUTER RESOURCES 
CLINICAL DECISION MAKING IN GLAUCOMA 

Research on the management of medical knowledge relevant to glaucoma diagnosis 
and therapy at Rutgers University and Mt. Sinai School of Medicine is now making 

44 



clinically significant contributions. A conceptual model of how this knowledge 
is organized for computer-based problem solving is an iceberg: the visible 
portion is the set of observed signs and symptoms; at the water line are 
descriptions of disease states appropriate to the specific patient; and under 
the water are found the detailed normal and pathophysiological models containing 
most of what is known about glaucoma-related ocular mechanisms and functions. 
This system is designed to trap inconsistent observations, to be restructured 
and rebased from new knowledge acquired from the experts in glaucoma as they 
interact with the system, to provide the rationale for each action recommended, 
to simulate how each of several glaucoma experts would handle a' difficult case, 
and to provide advice on diagnosis and therapy through the stages of glaucoma. 
Linkages between experts at different institutions and the Rutgers group are 
being developed to broaden and deepen this effort and its impact. 

At present the system contains about 80 causal states associated with glaucoma. 
This number seems to be approaching the optimum for an effective yet efficient 
clinical consultation tool for those dealing with this disease. Future work 
will strengthen the linkages between the disease state and the pathophysiolog- 
ical models and explore how knowledge of the disease and computer-predicted 
consequences of candidate therapeutic actions can be organized and presented 
in the most compact but comprehensive form. 



SUMEX-AIM 

During FY 1974 the BRB awarded funds for the creation of SUMEX, Stanford Uni- 
versity Medical Experimental facility. This resource is the first and only 
such installation expressly devoted to research on Artificial Intelligence in 
Medicine (AIM) . The SUMEX computer has 50 per cent of its capacity devoted to 
AIM activities within the Stanford University Medical School and the remaining 
50 per cent of the capacity allocated to AIM activities throughout the country 
via computer networks. The initial SUMEX/AIM community included mass spec- 
trometry data interpretation studies at Stanford, the glaucoma activity at 
Rutgers University, and X-ray crystallography studies at the University of 
California at San Diego. National solicitation to identify additional qualified 
participants began in FY 1975 and is currently well underway. 

The intellectual ties among the SUMEX-AIM participants are expected to serve 
as a key element of the shared resource function. Benefits should accrue 
through exchange of ideas and techniques, and these interactions should lead 
to further strengthening biomedical research through collaboration both within 
the artificial intelligence community and between the computer scientists and 
their medical research counterparts. 



AIM WORKSHOPS 

Health researchers outside the SUMEX-AIM activity have expressed interest in 
learning more about these advanced computing techniques and their potential 
biomedical application. As a result, a series of AIM workshops are planned. 
These workshops are to be an arena where biomedical scientists with significant 
health research problems can interact with advanced computer scientists who 

45 



are stimulated by the methodological challenges of the biomedical milieu. The 
Biotechnology Resource at Rutgers University will be the focus for these work- 
shop activities. The first workshops were held at Rutgers University June 14-17, 
1975. 



CANDIDATE NEW TOOLS FOR PROGRAM MANAGEMENT 

There have been many subjective indicators over the years suggesting that the 
BRB Program best serves the biomedical research community by encouraging the 
development and use of specialized computer resources rather than general-purpose 
ones. Therefore, it is important to assess the relative costs of specialization 
and generality. Measures of total costs to create both generalized and special- 
ized computer centers have, interestingly enough, shown little difference; and, 
in most cases, those computer systems especially developed for the research 
community are more vigorously utilized than general-purpose ones, i.e., utili- 
zation by the research community is much higher when their needs are addressed 
directly by the staff and system of a Biotechnology Resource. 

Utilization of computer system capacity can be evaluated effectively by various 
metrics . The computer systems supported by the BRB Program have in common the 
mission to diffuse technology into health research. The proposed selection of 
talent and equipment to do this is reviewed prior to the initiation of each 
resource. The progress of the resource in serving qualified investigators can 
be examined by observing the ratio between this utilization and the size of the 
systems and applications programming staff. It is important that both systems 
and applications work be included in this analysis, for the more effectively 
the systems programmers bend the machine to serve man, the less need there is 
to provide applications programming support to the user community. After a 
resource has achieved mature and stable capabilities, strong effort is required 
to maintain a competitive edge with the constantly emerging new computer tech- 
nology. The BRB diffusion metric (user hours /computer programming FTEs) is 
sensitive to these variations and strengths. 

Cost measures also are central to this analysis. BRB interests in cost measures 
stem from the programmatic goal of having biomedical computer technology con- 
tribute optimally within the funds available. The strategy has been to create 
and nurture resources and then to see at least their routine service components 
sustained without further BRB funds. Costs obviously play an important role 
here, for if a resource is to become self-sustaining, it must be able to compete 
for computing dollars within its own environment. Thus, a cost measure such as 
total production time in hours per year divided by the average annual BRB award 
dollars per year gives a measure through the BRB-support stages. Average annual 
amounts are used to cover rental /purchase variations introduced by alternative 
procurement methods selected by the grantees. Total computer production time 
is the total core research and user time interacting directly with the computer 
as is indicated in the annual resource usage summaries, i.e., total man/machine 
interaction time. 

When this cost measure and the above diffusion measure are graphed and examined 
together for a single resource, year-by-year changes show the development of 
that resource in time. 



46 



When the diffusion metric and cost metric are plotted for all computer resources 
(Figure I) , a general separation of resources into highly successful and moder- 
ately successful operations is observed. Should this observation prove to be 
consistent in time, it can become a valuable management tool for this Program. 

When taken separately over the entire computer resource program, the cost measure 
shows the effectiveness in moving from batch-processing systems to specialized 
systems developed for specific research needs, as shown in the cost/effectiveness 
metric during the years 1968-1974. 



BRB Dollars Per 



1968 



1969 



1970 



1971 



1972 



1973 



1974 



Computer Pro- 
duction Hour $91/hr. $70/hr. $72/hr. $52/hr. $32/hr. $27/hr. $20/hr. 



WORKSHOP ADMINISTRATIVE ASSISTANCE 

Workshops and related activities represent a potentially indispensable mechanism 
to facilitate both the planning and communication activities associated with 
resource sharing. By assembling scientists in groups of various sizes, NIH 
staff can simultaneously encourage the interchange of ideas and draw upon expert 
technical advise. Moreover, by having individual scientists visit shared bio- 
technology resources, use the capabilities offered on research problems of their 
choice, and furnish a written report on the experience, NIH staff can build the 
kind of data base the workshop participants will need for their efforts to be 
most effective. A continuing workshop series could be the principal forum 
through which NIH staff and the biomedical research community jointly bring about 
successful sharing of highly specialized biotechnology research resources. The 
BRB is initiating a contract to provide administrative assistance for these 
activities. 



CLINFO 

The CLINFO project is a scientific inquiry sponsored by the BRB and General 
Clinical Research Centers Branch. It is aimed at identifying and characterizing 
the information analytic tasks and the information flows in human clinical inves- 
tigation and at developing methods for facilitating these tasks and flows. The 
first phase of the inquiry gathered information about and characterized the 
investigative processes, identified potential roles of computer technology in 
facilitating clinical research, and identified existing and potential systems 
to fill these roles. 

CLINFO is currently being effected by a consortium comprised of clinical con- 
tractors at Baylor College of Medicine, the University of Oklahoma, and the 
University of Washington, information scientists at The Rand Corporation, and 
staff members of DRR.. The clinical contractors have been contributing knowledge 
about clinical research, the information scientists have been contributing expe- 
rience in computer technology and knowledge of information science, and DRR 
staff members have been providing overall direction. 



47 



1 

1 

i C3 

1 







U Cd 

OS E 



23 

CO u 
P O 



>• to 

j o 



7000 1- 



5600 



1400- 
O 



<D O 



OBSERVATION ON RESOURCE 
EFFECTIVENESS FROM FY' 74-75 DATA 



(#» phased-out ) 



7TW 



1.2 



COST EFFECTIVENESS METRIC- 
TOTAL COMPUTER PRODUCTION HOURS /ANNUAL AVERAGE BRB FUNDS 



48 






The CLINFO project has thus far 

• broadly characterized clinical research activities, 

• identified research data management and analysis as 
major problems in clinical research, 

• shown (through an extensive survey of clinical inves- 
tigators) that these problems are widespread, and 

• examined a number of existing systems that might 
alleviate these problems. 

The present goal is to increase the quality and effectiveness of clinical re- 
search by developing an economical, readily accessible, widely usable computer 
system that, together with specially trained personnel, will help clinical inves- 
tigators to collect, organize, store, retrieve, and analyze their research data. 
Past attempts to develop useful computer systems have often failed because devel- 
opment projects have been uncoordinated and inadequately staffed, because they 
have not had an adequate understanding of the hardware, software, and personnel 
requirements, and because they have not adequately tested the systems with a 
variety of users in a variety of situations. Plans for the next phase include 
a well staffed, well tested, evolutionary approach which will 

• implement an initial prototype system; 

• install copies of this system at the three clinical- 
investigator contractors' institutions where they will 
be used by several investigators during the course of 
their execution of approved protocols; 

• investigate the use of the prototypes, and (as unobtrusively 
as possible) modify the systems functional characteristics 
to maximize their acceptability and utility to a broad 
variety of users; 

• estimate the benefits and operating costs of the prototypes; 

and ,' ^^ 

• test the conclusions reached by installing a stable version '! "l ^^ 
of the system at and providing personnel to an additional 
clinical research center where there is no CLINFO contractor 
and by (passively) observing its use there. i } 

I ^° 
en 
Thus in the next two years the project is to develop a prototype clinical re- 
search data management and analysis system and test it with several clinical 
investigators at each of four sites, including one where there is no CLINFO 
contractor. The expected results are 

9 a tested, practical system which can continue to operate 
at the four sites and which can be duplicated and further 
distributed in a straightforward fashion; 

• documentation of the requirements for, and benefits of, a 
system designed to have wide applicability; 

• knowledge about how to introduce such systems into new 
institutions, how to promote their use, and how to assist 
and educate their users; 

• information about the requirements for both on-site and 
centralized personnel to perform these functions; 

49 



a dispersed, trained group of such personnel; and 
a number of newly uncovered problems whose solution 
could benefit clinical research. 



BIOMOLECULAR CHARACTERIZATION RESOURCES 

During FY 1975 the Biomolecular Characterization Resources Program encompassed 
a broad range of capabilities within the areas of mass spectrometry and nuclear 
magnetic resonance spectroscopy. As illustrated in Table lib, each Resource is 
a unique complement to the total program. 

For example, a significant impact has been made in the area of clinical mass 
spectrometry through the Biomolecular Characterization Resources Program. Al- 
though the technology has not reached the status of a routinely usable tool 
for the clinical chemistry laboratory, sufficient experience was gained during 
FY 1975 to encourage continued emphasis in this area. 

At the Michigan State University Mass Spectrometry Facility computer-based 
techniques have been developed in combination with gas chromatography/mass 
spectrometry to allow rapid simultaneous identification and quantification of 
a large number of compounds in urine or other biological fluids as an aid to 
disease diagnosis and metabolic studies. 

A unique and powerful tool, a combined gas chromatograph/mass spectrometer/ 
gas flow proportional counter system, has been developed at the University of 
Pittsburgh's Mass Spectrometric Facility for Biomedical Research. This instru- 
ment makes it possible to separate the components present in an extract of cells 
or growth medium, identify them, quantitate each component, and assay their 
isotope content. From such information an accurate metabolic profile can be 
determined. The system is being applied to a model study designed to diagnose 
muscular dystrophy at the embryonic level. The availability of such prenatal 
information would be invaluable in helping to make a decision whether or not to 
terminate a pregnancy. 

In the area of nuclear magnetic resonance spectroscopy, a 360 MH Z instrument, 
funded jointly with the National Science Foundation, was acquired by the High 
Frequency NMR Biotechnology Resource at the Stanford University Medical School 
and in the near future will be widely available to scientists with appropriate 
problems. A 270 MH Z instrument was recently installed at Yale University. This 
spectrometer has proton, carbon-13, and deuterium capabilities and will be 
available to scientists in the Eastern part of the United States. 

As part of the BRB commitment to resource sharing, steps have been initiated to 
develop a coordinated national effort in mass spectrometry and nuclear magnetic 
resonance spectroscopy. Each center is being encouraged to specialize according 
to expertise, primary fields of interest and experience, and hardware capability 
to maximize its effectiveness and impact on important medical problems. The BRB 
has undertaken the development of a Resource Directory for distribution to NIH 
grantees and contractors to aid them in identifying sources of highly special- 
ized analytical support available through the program. 



50 



HIGH VOLTAGE ELECTRON MICROSCOPY RESOURCES 

The High Voltage Electron Microscopy Resources at the University of Wisconsin 
and the University of Colorado — and the contract with U.S. Steel Corporation 
to purchase time on their one-million volt electron microscope — are another 
part of the shared resources program in BRB. These resources are national in 
scope and are available to qualified biomedical investigators throughout the 
country. Administrative mechanisms have been established to insure that the 
community of potential users outside the resources' institutions know about 
the installations and of their opportunity to make application for their use. 
An ad hoc advisory group to BRB assists in the review of applications for beam 
time from these scientists, and BRB staff informs these applicants of the results 
of the review. 

During the past year approximately 55 per cent of the microscopes' operating 
time at the Universities of Colorado and Wisconsin HVEM Resources was allocated 
to off-campus users. Time purchased by the BRB on the U.S. Steel million volt 
microscope is used completely by outside scientists. About 70 scientists used 
the microscopes in a wide variety of investigations. 

Considerable progress has been made in the Resources in developing applications 
of HVEM in biomedical research. The greater penetration and higher resolution 
gained by the use of the HVEM presents some important advantages to electron 
microscopists. Small cellular structures such as chromatin fibers, microtubules, 
microfilaments , and ribosomes are seen with clarity in thick sections at 1000 kv 
with spatial relationships between structures preserved. The ability to observe 
whole cells is proving important in studying the interaction of virus and cell. 
The probability of finding virus particles suspected to be present in small 
numbers is greatly enhanced when viewing thick sections and whole cells in the 
HVEM. Using thick sections for autoradiography experiments shortens the exposure 
times by a factor of 10 to 20. Grain densities that take months to form in the 
thin sections required in 100 kv microscopes are obtained in two to three days 
with thicker sections in the 1000 kv instrument. The reconstruction of three- 
dimensional structure and organization of intracellular systems from stereo 
images of thick sections in the HVEM is proving to be more accurate and less 
tedious than has been possible using serial thin sections. The ease with which 
thick sections can be cut and handled is another practical advantage of high 
voltage electron microscopy. 

BIOMEDICAL ENGINEERING RESOURCES 

A biotechnology resource specializing in microelectronics for health research 
was funded last year. This resource is based upon an established program at 
Case Western Reserve University focused on strengthening biomedical engineering 
capabilities; the goal of the new resource is to interact with health scientists 
in ways that lead to new and improved capabilities of general applicability to 
health research and patient care. The role of the biomedical engineer in this 
setting is to reduce the research overhead of medical scientists by providing 
ways to gain information which is attainable only with microelectronics tech- 
niques. 



51 



_ — 



This resource, through its past experience and present capabilities, provides a 
base to develop telemetry devices which can be 

• implanted in the human body to study stress and strain 
of orthopedic appliances, 

• implanted to monitor intercranial pressure, cerebral 
spinal fluid pressure, and p0£ of neurosurgical patients 
and hydrocephalic children, and 

• implanted for chronic monitoring of a patient's condition 
after organ transplant or other critical surgical procedures; 

and implant stimulation devices which can effect 

• pain suppression by stimulation in spinal cord or periphery, 

• blood pressure control of hypertensive patients, and 
o control of central nervous system functions. 

Using the above devices, systems may be developed to operate an internal signal 
to control and study the regulation of body functions. Ameliorative steps such 
as providing a bypass for a damaged neural network is possible with a system of 
implanted sensors and stimulators. 

The collaboration activities of this resource in the past have been with single 
collaborators on each research area. Extension to other collaborators is desir- 
able to test the efficacy of the ideas in a number of research environments; it 
is important that the commonality of research needs met by the engineering 
product be determined and the number of sites for its potential diffusion be 
multiplied. 

The opportunity to examine the processes of pursuing these goals through the 
resource mechanism is offered in this activity. Two measures of progress can 
be identified. Early in the resource's life progress may be measured by the 
strength and geographical range of the resource's collaborative activities. 
Later, successes may be evaluated in terms of the range and value of the 
resource's services that are subscribed to by outside users and the appearance 
and national diffusion of its "finished products" in the commercial marketplace. 

"INTERFACE" RESOURCES 



In order to make the benefits of highly specialized and expensive biotechnology 
research resources more widely available to potential health researchers, the 
sharing of these resources is being encouraged and supported. This sharing 
makes possible the broader availability of specialized abilities between 
resources, permits concentration on individual problem areas, and most impor- 
tantly, brings new investigators and institutions into the national array of 
biotechnology research activities. 

An "interface" resource is designed to make the capabilities of nationally 
shareable resources available to local or special groups of the biomedical re- 
search community. An "interface" resource would need to meet the following 
criteria: 



52 



1. The activity must emphasize a dynamically evolving health-relevant technology 
such as computer mass spectrometer capabilities, biomedical engineering 
capabilities, and molecular modelling capabilities. The Resource Director 
will participate in technical innovation to upgrade capabilities of the 
resource which he uses. 

2. The service and collaborative capabilities rendered by the "interface" 
resource staff must exceed those which are exploited by a single user. 

3. The operating costs of the "interface" resource (i.e., expenditures for 
personnel, supplies, travel, communications) must be at a level which 
cannot be justified by a single research effort. 

An example of "interface" resources is found at Rutgers University where that 
resource's staff collaborate and provide service for glaucoma investigators at 
Mt. Sinai Medical School in New York, Washington University, and Johns Hopkins 
through the capabilities of the BRB supported computer resource at Stanford 
University. 

Such sharing results in a more equitable distribution and effective use of 
limited resource support funds and in the inclusion in the national program of 
promising talented individuals in institutions now isolated from the capabilities 
of expensive and specialized equipment developed for biomedical research. 



RESOURCE SHARING - SUMMARY 

The following table displays and summarizes the nature, status, and projected 
future of shared resource programs. Shared biotechnology resources must meet 
the present four essential criteria for BRB resources and in addition must 
include inter-institutional collaboration in research, policy, and management 
activities. Presently active BRB shared resources are described above. Shared 
BRB resources under development or planning are listed in Table IV. Potential 
sharing of resources need not be limited to biotechnology. 

In the development and on-going management of shared resources several consid- 
erations must be kept in mind in addition to those that pertain to traditional 
research resource support programs. The preparation by applicants of requests 
for support of shared resources will need consultation and advice by staff to 
ensure that plans for inter-institutional sharing are described clearly. The 
peer merit review of proposals must include, in addition to the traditional 
considerations, evaluation of the need for and the feasibility of the proposed 
sharing arrangements . 

The management of NIH-supported shared resources must take into account the 
increased complexity of multi-institutional relationships, geographical sepa- 
ration, and unequal sophistication of participants. This management must be a 
partnership among components, including an on-going role for the staff of the 
supporting agency. 



53 



TABLE IV 
SHARED BIOTECHNOLOGY RESOURCES UNDER DEVELOPMENT OR CONSIDERATION 

Biomolecular characterization resources 

High resolution mass spectroscopy 
Nuclear magnetic resonance spectroscopy 
X-ray crystallography 
Activation analysis 

Biomedical computer specialized resources 

Modeling of biological processes 

Molecular modeling 

Image processing 

Biomedical graphics 

Biostatistics 

Chemical-biological information-handling 

Electron probe resources 

Biomedical engineering resources 

Diffusible products -- computer, instruments, and sensors 
Programmed console for radiation therapy 
Clinical monitoring systems 



54 



The management must provide for 

• equitable responsibilities and opportunities for all 
participants — both suppliers and users of services, 

• justified expansion of opportunities — including 
training for inexperienced candidates needing to 
participate, 

• equitable funding support among components, 

• appropriate participation by funding agency, and 

• on-going inter-institution management ("interface" 
resource) . 

In planning and setting up national networks of shared resources, the need for 
subsequent evaluation of effectiveness must be recognized. This evaluation can 
be done most dependably if incorporated into the original design, so that records 
will reflect the basis for and consequences of decisions made. It will then be 
possible to make comparative measurements of relative effectiveness in terms of 
program and costs. 

These considerations hopefully will evolve into an agenda for action insofar as 
further biotechnology resource sharing is concerned. But meaningful action on 
the agenda will take place only if both the letter and spirit of these concepts 
are embraced by leaders in the biomedical research community. BRB staff and 
advisors look forward to playing at least a small role in catalyzing the testing 
and elaboration of these concepts in the real world of biomedical science. There 
is little doubt that the key contributions of biotechnology resources toward 
fulfilling the NIH mission will be even more visible in the future than they have 
been in the past. 



55 



Fiscal Year 1975 Annual Report 

Chemical /Biological Information-Handling Program 

Division of Research Resources 



"PROPHET encourages the investigator to ask more searching questions of 
(his) data, and to look at it from perspectives he ordinarily would not 
explore " 

— PROPHET user working in human 
clinical investigation 

PROPHET "...permits ideas and research to continually and daily be redirected 
in the most promising directions. Notions that would have been too extrava- 
gant to pursue, in terms of the investigator's time, can now be taken up and 
rapidly settled." 

-- PROPHET user working in molecular 
biology 

"Bill, the ?*!*? thing really works We now can do data analysis so much 

faster, the difference is not just quantitative, it's qualitative! We never 
were able to test so many hypotheses before." 

-- PROPHET user working in 
neuropharmacology 



BACKGROUND 

Better understanding of the interrelationships between chemical substances 
and living systems is of critical importance to almost eyery area of biology 
and medicine. Whether the focus is drug development and evaluation, endocrine 
function, toxic compounds present in the environment, or antigen-antibody 
interactions—to name only the more prominent examples--, significant advances 
invariably depend upon the acquisition of detailed new knowledge about how 
specific molecules affect and are affected by life processes. Nowhere are 
insights into molecular mechanisms more actively sought or more urgently 
needed. Nowhere is there research more relevant to the cure and prevention of 
disease in humans and animals and to the improvement of the quality of life. 
It hardly is surprising that chemical/biological interactions are featured 
among the research activities of every one of the National Institutes of 
Health (NIH) and the Institutes comprising the Alcoholism, Drug Abuse, and 
Mental Health Administration (ADAMHA). 

The Chemical /Biological Information-Handling (CBIH) Program has a special 
mission with respect to the rest of the NIH and to ADAMHA. The CBIH Program 
(a) designs and develops computer-based information-handling tools for the 
study of chemical/biological interactions; (b) makes these tools available 
to the national scientific community in an easy-to-use and highly reliable 
form; and (c) collaborates with the users of these tools not only to refine 



57 



1 

1 


DRS 







and extend them but also to understand better the investigative process 
itself. Throughout this work, emphasis is placed on discovering where and 
how computer technology and information science can help scientists learn to 
predict how chemical substances and living systems will interact under various 
circumstances. In this way, the CBIH Program strives to be a resource for 
many other programs throughout NIH and ADAMHA, undertaking technological 
innovations that no one Institute generally could justify doing alone and 
sharing the results wherever they are needed. 

All of the activities of the CBIH Program involve a specialized computer 
resource called the PROPHET System. PROPHET is accessible from essentially 
anywhere in the Nation by means of digital telecommunications facilities and 
is capable of serving several users simultaneously. It features tools for 
data management, data analysis, and molecular modelling via the medium of an 
English-like command language and an interactive graphical display. PROPHET 
is the most nearly comprehensive array of information-handling tools for the 
study of chemical/biological interactions ever to be integrated into a single 
system and made available to laboratory and clinical scientists in national 
competition. The evaluation and refinement of the PROPHET System is the means 
by which the CBIH Program carries out its mission. 

Substantial documentation exists regarding PROPHET and its research uses. The 
features of the System are explained in detail in several manuals (1,2). The 
principal characteristics of PROPHET'S architecture have been reviewed from 
several perspectives (3,4,5). There are accounts of specific research pro- 
jects involving PROPHET (6,7,8,9), as well as a discussion of issues associ- 
ated with the management and administration of the resource (10). 

The paragraphs which follow summarize the progress of the CBIH Program and 
its PROPHET System during Fiscal Year 1975. 

PARTICIPANTS IN THE PROPHET PROJECT 

The continuing maturation of the PROPHET project and its ever-broadening 
impact upon biomedical research reflects a successful blending of the talents 
of many individuals. The bulk of the responsibility for the development and 
operation of the PROPHET System rests with two NIH contractors: Bolt Beranek 
and Newman Inc. (BBN) of Cambridge, Mass. and First Data Coproration (FDC) of 
Waltham, Mass. BBN is the focus for improvements to and maintenance of the 
PROPHET software, as well as being the principal point of contact with the 
PROPHET users. FDC houses and manages the PROPHET System computer facility 
(a Digital Equipment Corporation PDP-10) and arranges for the digital tele- 
communication services that make PROPHET accessible nationwide. Beth of 
these contractor organizations have distinguished themselves and tne project 
by exhibiting high technical competence and professionalism in carrying out 
their assigned tasks. 

The CBIH Program staff and contractors receive invaluable assistance in the 
planning, execution, and evaluation of PROPHET System activities from the 
Chemical/Biological Information-Handling (CBIH) Review Committee (see Table I). 
This group, a formally chartered DHEW advisory body, participates in four 



58 



basic ways. First, the Committee reviews position papers, draft Requests for 
Proposals, and other documents which deal with proposed PROPHET System 
activities. Second, the Committee assists the CBIH Program Director in the 
technical evaluation of the performance of the contractors. Third, the 
Committee reviews research prospectuses submitted by individuals or groups 
who wish to use the PROPHET System in their research and advises the CBIH 
Program Director as to the appropriate allocation of PROPHET System services. 
Fourth, the Committee, augmented by ad hoc consultants having special expertise 
in selected subject matter areas, helps NIH staff determine the relative tech- 
nical merits of contract proposals submitted in response to CBIH Program 
solicitations. The PROPHET project is fortunate to have the counsel and 
critique of this able and dedicated group of men and women. 

The third and final group of participants in the PROPHET project—the user 
community — in many ways is the most important. It is these scientists to 
whom everyone else in the project frequently turns for evaluation of present 
PROPHET System capabilities and for suggestions about new ones. It is these 
scientists through whom the significance of PROPHET is being made ever more 
visible in the milieu of laboratory and clinical investigation. It is these 
scientists and their applications of the technology, not the technology per se , 
that produces the benefits to society that taxpayers expect and deserve. 

The list of institutions presently having access to the PROPHET System is 
shown in Table II. At each location there is available either a graphic 
display terminal, a teletypewriter terminal, or both. The last four user 
sites listed began receiving PROPHET services during Fiscal Year 1975. There 
also was an increase in the number of users associated with each of the five 
installations established prior to Fiscal Year 1975. 

The growth in both number of user installations and number of users per site 
.is gratifying. It demonstrates that the results of years of system design 
and technological development are indeed being delivered to qualified scien- 
tists in laboratory and clinical environments essentially irrespective of 
their geographical location or institutional affiliation. It also insures 
that, in evaluating and refining the PROPHET System, CBIH Program staff and 
advisors are able to draw upon a considerable breadth and depth of expertise 
"at the bench" and "in the clinic"— i .e. , at the business end of biomedical 
inquiry. It is doubtful that anyone has ever been in a better position to 
blend the perspectives of computer scientists and biomedical scientists in 
producing powerful yet easy to use tools for the study of chemical/biological 
interactions. 

RESEARCH APPLICATIONS OF THE PROPHET SYSTEM 

The research uses of PROPHET are many and varied, reflecting the neterogeneity 
of studies involving chemical/biological interactions. PROPHET users range 
from molecular biologists and quantum pharmacologists concerned with the fine 
details of biomolecular mechanisms to epidemiologists and social scientists 
dealing with the use of alcohol and other drugs of abuse. The applications 
of the System range from (a) management of empirical data gathered in the 
laboratory and clinic through (b) statistical analyses and pharmacokinetic 
modelling to (c) the construction and manipulation of molecular models. 



59 



Tables III. A - III .H summarize the research uses of the PROPHET System during 
Fiscal Year 1975. In general, each table deals with one user installation. 
The principal exception is Table III. F which involves the collaboration of 
investigators at three sites. Additional discussion of this collaborative 
activity is given below. 

The format of the tables hopefully is self-explanatory. For the most part, 
the individuals identified are affiliated with the institution housing the 
PROPHET terminal. There are a few exceptions (e.g., scientists located at 
neighboring institutions), but these other institutions are not included 
explicitly in the interest of keeping the tabulations simple. The use of the 

phrase "same as number " under the heading "sponsor(s/' signifies not 

only the same funding source but also the same grant or contract award. 

AN APPLICATION OF THE PROPHET SYSTEM IN IMMUNOCHEMISTRY 

While Tables III. A - III .H give one some feeling as to the scope of PROPHET 
System uses, they necessarily are too brief to impart much about any one 
individual research project in terms of its significance, its intellectual 
excitement, or the ways in which PROPHET facilitates its progress. Accord- 
ingly, this section is devoted to a discussion in some detail of one investi- 
gation which made extensive use of PROPHET during Fiscal Year 1975. Perhaps 
this illustration will help the reader to appreciate how PROPHET functions 
as a national research resource. 

1 . The Problem 

This example deals with the research of E. A. Kabat and T. T. Wu of 
Columbia University and Northwestern University, respectively. Their joint 
investigations, which have been in progress for several years, are designed 
to elucidate the molecular bases of antibody specificity. Thus, the work is 
relevant to essentially any area of biology and medicine where an organism's 
immune system may play a role in combating (or, in some cases, causing) 
disease or dysfunction. Among the questions these investigators are concerned 
with are the following: (a) What structural features enable antibodies to be 
so incredibly specific in their associations with antigens, in some cases 
exhibiting an ability to distinguish one optical isomer from another? 
(b) What significance should be attributed to the fact that all immunoglobulin 
molecules have many structural features in common, irrespective of the antigen 
against which they are directed or the animal species from which they are 
obtained? (c) In view of the absence of detailed x-ray crystallographic 
findings as to the three-dimensional structure of immunoglobulin molecules, 
to what extent can one use knowledge of the primary structure of these proteins 
(i.e., the linear sequence of amino acids which comprise the polypeptide 
chains) to make predictions about an antibody's molecular conformation? 

Use of the PROPHET System to study these and related questions began during 
Dr. Kabat 's tenure as a Fogarty Scholar in residence at the NIH. Dr. Wu was 
provided access to PROPHET from his laboratories at Northwestern University 
as soon as the feasibility of this application was established. Because of 
the breadth and complexity of this effort, Dr. H. Bilofsky of BBN works closely 



60 



with Drs. Kabat and Wu, providing consultation in the use of PROPHET, develop- 
ing selected application programs, and participating in the mathematical and 
statistical analyses of the immunoglobulin sequence data which Dr. Wu amasses 
from the scientific literature. 

2. Predicting Polypeptide Conformation 

One major aspect of this research effort involves the development of 
techniques for predicting how polypeptide chains fold up. The objective is 
a method whereby one need know only the sequence of the amino acids which 
comprise a given polypeptide to identify where there are alpha helices, beta 
sheets, beta bends, and other secondary and tertiary structural characteristics 
of these molecules (11). The need for such a method, of course, is not limited 
to immunochemistry. Knowledge about the mechanisms of polypeptide folding is 
relevant, for example, to enzymology, to endocrinology, and to the studies of 
biological membranes; and investigators throughout the world are attempting to 
develop predictive methodologies (12). The need for predictive methods in this 
field is especially acute, for there are formidable problems involved in 
attempting to determine the three-dimensional structure of polypeptides 
directly via x-ray crystallography. 

Kabat and Wu approach the chain folding problem as follows. They focus on the 
tri peptide as their basic unit of interest. Using data on the few proteins 
whose three-dimensional structures have been solved x-ray crystal lographically, 
they determine how frequently certain types of theoretically possible struc- 
tural characteristics actually occur in nature. Concentrating on the first 
and third amino acids in each tri peptide and allowing the middle one to be anv 
one of the 20 normally found in proteins, they prepare a "20 by 20 table" (13), 
This specialized matrix serves to abstract selected features of the proteins 
whose three-dimensional structures are known and to represent the result in 
terms of amino acid pairs (i.e., the first and third members of each possible 
tripeptide). For example, the 20 by 20 table reveals how frequently the 
sequence glycine-x-alanine occurs (where x is any amino acid) and how fre- 
quently this sequence occurs in an alpha helix, a beta sheet, etc. Kabat and 
Wu use this specialized matrix to classify certain tri peptides as helix- 
permissive, helix-breaking, sheet-breaking, etc.; and, armed with this classi- 
fication, they then attempt to infer secondary structural characteristics of 
individual unknown polypeptides from their primary structures. 

The methodology described above can be extended further where sequence data 
on a homologous series of polypeptides is available (e.g., the cytochromes, 
the neurohypophyseal hormones , immunoglobulins, etc.). In these cases, 
evolutionary mechanisms have allowed changes to occur in the amino acid 
composition of some parts of the molecule while simultaneously preserving the 
overall three-dimensional shape (which presumably is indispensable to the 
molecule's normal function). Where data on a homologous series is available, 
Drs. Kabat and Wu have developed an algorithm for selecting values of phi and 
psi , the pair of rotation angles commonly associated with each juncture in a 
polypeptide backbone (14). Given these phi-psi estimates and assuming the 
peptide bond to be planar, one then can build a three-dimensional model of the 
backbone of the class of polypeptides. 



61 



The PROPHET System facilitates this work in several major ways. They are 
described sequentially below. 

a. Preparing the 20 by 20 tables . The first step in preparing a 20 by 20 
table is to get into useful form selected data on the proteins whose structures 
have been solved x-ray crystal lographically (approximately 20 proteins at this 
writing). This is accomplished by preparing a standard PROPHET TABLE for each 
protein using the MAKE TABLE command. Column 1 is designated to include amino 
acid residue names in standard 3-letter code, is named "residue," and is 
defined to be of data type "text." Columns 2 and 3 are designated to include 
the values of phi and psi , respectively, are named accordingly, and are 
defined to be of data type "number." The appropriate text and numeric values 
then are entered either row by row from the keyboard in response to prompting 
by PROPHET or in bulk if already available to PROPHET in machine manipulable 
form. The command 

MAKE TABLE PAPAIN, 

for example, invokes a dialogue which eventually results in a 212 row by 3 
column tabulation of the backbone structure of this proteolytic enzyme. 

Once the protein backbone data are in this form, they can be manipulated with 
PROPHET'S wide array of TABLE-handling commands. One such use is the prepara- 
tion of a classical Ramachandran plot for the protein (11). This is essen- 
tially a scattergram of phi (x-axis) plotted against psi (y-axis), and it can 
be used to characterize a protein with respect to its secondary structural 
characteristics. That is, one can determine at a glance if large numbers of 
phi -psi pairs fall within the alpha helical domain (just below and to the left 
of center), the beta sheet domain (upper left), etc. If, for instance, one 
wished to generate a Ramachandran plot for papain and to manipulate it sub- 
sequently under the name of PAPAINPLOT, this could be accomplished by giving 
the command 

MAKE GRAPH PAPAINPLOT FROM PAPAIN AS PHI VS PSI 

and then following it with the command 

DISPLAY PAPAINPLOT. 

Alternatively, one could invoke a small PL/PROPHET procedure written by 
Bilofsky to produce the plot with an overlay of the specific boundaries Kabat 
and Wu elect to use in determining whether or not a given value for a phi^-psi 
pair falls with the alpha helical domain or the beta sheet domain. Whichever 
way PROPHET is used to prepare the Dlot, a task which may require an hour or 
more by hand is accomplished in less than a minute. 

Using some or all of the protein TA3LEs , the user also can invoke another 
PL/PROPHET procedure to prepare the 20 by 20 table. The result is a 20 by 20 
PROPHET TABLE, where each cell corresponds to a different amino acid pair 
(the first and last members of a tripeptide), where each column is of data 
type "fixed array," and where each cell contains an array of 6 numbers. The 



62 



six numbers indicate the number of times this tripeptide sequence was found 
(1) in the alpha helical domain, (2) in the beta sheet domain, (3) outside of 
either domain, (4) the frequency with which four successive values occurred 
in the helical domain, (5) the frequency with which three successive residues 
occurred in the beta sheet domain, and (6) the frequency of a beta bend 
involving the middle amino acid. Because PROPHET reduces the time required 
to prepare this matrix from many days to a few hours, it not only can be more 
readily updated as new published protein structure solutions become available 
but also can be prepared in a variety of forms for the purpose of comparative 
evaluation--e.g. , using only proteins which are rich in alpha helix, using 
different definitions of what constitutes the alpha helical and beta sheet 
domains, etc. Hypotheses which once were impractical to test now can be 
addressed quite readily. 

b. Predicting secondary structural features . The PROPHET version of the 
20 by 20 table can be used via a PL/PROPHET procedure to predict the secondary 
structural characteristics of polypeptide chains. To do this one creates a 
PROPHET TABLE for the "unknown" polypeptide using a pre-existing empty 
template TABLE. The residue names (in standard three-letter code) are put 
into the cells of column 1; the other columns are left blank. Then one gives 
the command 

CALL METH0D1 

to invoke a procedure which, after prompting the user for specific items of 
information (e.g., the name of the TABLE containing the sequence data on the 
"unknown"), uses the summary data on the tripeptides to identify each residue 
as to whether or not it is helix-breaking or sheet- breaking. As an option 
one may also compute the probability of a beta bend occurring at each residue 
position. The procedure records its results by automatically filling in, 
where appropriate, cells in the empty columns of the TABLE. 

Through the medium of another PL/PROPHET procedure called DAYSEARCH, METH0D1 
also can be applied quickly and easily to polypeptide sequences in the file 
recorded and maintained by Dayhoff et al (15). The magnetic tape version of 
this file has been purchased and implemented on the PROPHET computer. The 
command 

CALL DAYSEARCH 

allows the user to interactively review the directory of sequences recorded 
in the file and select one or various combinations for inspection. Optionally, 
the user may specify that one or more selected sequences are to be read out 
of the file in the form of a PROPHET TABLE all ready for use with the METH0D1 
procedure. Thus, by "gluing together" some standard top-level PROPHET TABLE- 
handling functions with a few custom built PL/PROPHET procedures, it was 
possible to build an easy-to-use subsystem for evaluating successive versions 
of METH0D1 against the extensive collection of sequences which Dayhoff et al 
glean from the scientific literature. 



63 



c Const ructing models of po lypeptide backbones . In those cases where 
homologous series of polypeptide sequences are available for use in estimating 
phi-psi angle values (see above), additional PROPHET capabilities are ex- 
ploited. Wu has written a FORTRAN program embodying the angle selection 
algorithm. Not only can this program be run on the PROPHET computer; there 
also exists a standard interfacing procedure whereby this FORTRAN program can 
be made to appear to the user as if it were an integral part of PROPHET. This 
is an excellent example of PROPHET'S ability to absorb and integrate proce- 
dures that technically exist outside of it. 

One of the direct benefits of this integration is that the results produced 
by the "extra-PROPHET" procedure can be manipulated subsequently within the 
mainstream of top-level PROPHET functions. This is especially important in 
Wu's work, for the output of his program (estimates for phi-psi angle pairs), 
once recorded in PROPHET as part of an instance of the data type MOLECULE, 
can be operated on by PROPHET MOLECULE-handling commands to produce display- 
able and manipulable models of the polypeptide backbone. This opportunity 
to manipulate the computational results interactively in graphical form makes 
the continuing evaluation and refinement of the structure prediction algorithm 
much more efficient and effective than was previously the case when only 
manual methods or batch processing computing facilities were used. 

3. Tabulation and Analysis of Immunoglobulin Sequences 

The other principal area of interest to Kabat and Wu is the study of 
variations in the amino acid composition of immunoglobulin molecules. The 
existence of constant regions and variable regions in both the light chains 
and the heavy chains of immunoglobulins has stimulated considerable research 
regarding their significance, the underlying genetic mechanisms, etc. It 
seems clear that the key to antibody specificity is to be found in this area. 

Several years ago, Kabat and Wu developed a statistic with which to character- 
ize immunoglobulin variability (16). For any given collection of variable 
region sequences (e.g., human heavy chains), they arrange the sequences for 
maximum homology and then compute for each position in the chain a variability 
index. This index is defined as 

n- 
variability- = _ 



where ni is the number of different amino acids observed to occur at position 
i and fi is the frequency of the most common amino acid at that position 
(i.e., the number of times the most common amino acid occurs divided by the 
total number of sequences examined). With this statistic an invariant position 
has a value of 1; were all 20 amino acids to occur randomly at a position, the 
upper bound would be 400. This statistic has proved extremely useful in 
establishing the existence of discrete regions of hypervari ability in both 
light and heavy immunoglobulin chains. And this type of analysis has received 
added impetus in recent years by preliminary x-ray crystal! ographic evidence 
which suggests that these hypervariable regions play a principal role in the 
formation of an antibody's active site. 



64 



While conceptually and arithmetically simple, both tabulation and analysis of 
immunoglobulin sequences are tedious, error-prone tasks. In the absence of 
convenient information-handling tools, only a small subset of all the inter- 
esting hypotheses can be tested. Research options are seriously constrained 
by the sheer volume of data and the multitude of calculations. 

The PROPHET System has been used successfully to ease these constraints. 
Published immunoglobulin sequences and the associated literature references 
are recorded in PROPHET TABLES by Wu on a continuing basis. PROPHET'S inter- 
active mode and editing facilities do much to minimize transcription errors. 
Moreover, the data are immediately available to the other participants in the 
study, even though they are widely separated geographically from one another. 

Once available in the form of TABLES, the sequence data can be subjected to 
analyses in a yery convenient way. The calculation of the variability indices 
is carried out via a PL/PROPHET procedure called VARIAB; this procedure records 
its results by adding several new columns to each TABLE it operates upon, the 
last column containing the values of the variability statistic described above. 
A graphical representation of the variability then can be obtained by calling 
the PL/PROPHET procedure VARGRAPH. Once again, the combination of standard 
top-level PROPHET functions and a few custom-built PL/PROPHET procedures has 
done much to remove an information-handling bottleneck previously faced by 
Kabat and Wu and exposed to their creative energies targets that could not 
realistically be explored before. 

Within recent months this work has progressed to the point where virtually 
all of the immunoglobulin sequences that have appeared in refereed scientific 
journals have been recorded in PROPHET and enriched with calculated variability 
values, variability plots, etc. Thus, this unique data base has the potential 
of being a valuable resource in its own right; access to the collection no 
doubt could facilitate the work of many other investigators studying antibody 
structure and function. In recognition of this, arrangements now are being 
formulated whereby Kabat, Wu, and Bilofsky will undertake not only to maintain 
and update this data base as part of their continuing research but also to 
produce low cost printed versions of this collection in a form that will make 
broad distribution possible.. The power of PROPHET and its ease of use are 
responsible in large measure for a data compilation of this magnitude being 
amassed and distributed as a by-product of a single research project. 

NEW PROPHET SYSTEM FEATURES 

Just as PROPHET alters the research milieu and investigative opportunities 
of its users, so users' experiences cause PROPHET to change and grow. The 
users have, in fact, become a principal source of ideas for new and improved 
PROPHET features. This section highlights the major new capabilities which 
were introduced into service during Fiscal Year 1975. 

1. Tools for Data Analysis 

Since the introduction of PROPHET services three years ago, there has 
been a steady growth in the statistical functions available to PROPHET users. 



65 



These PROPHET procedures generally are based upon and incorporate code from 
programs made available by the UCLA Health Sciences Computer Facility and 
other leading centers of biostatistical research. PROPHET'S design allows for 
an essentially open-ended accretion of such programs and their graceful inte- 
gration into the System, with users' requirements being the major determinant 
of the pace and course of this growth. Among the results of recent activities 
are procedures for probit analysis and chi-square analysis and the elaboration 
of the collection of procedures for analysis of variance (2). 

Other broadly useful tools for data analysis are developed from time to time 
by individual PROPHET users and made public via the PROPHET public procedure 
exchange. During Fiscal Year 1975, for example, Dr. Carl Johnson of Mt. Sinai 
School of Medicine prepared and made available a number of programs for 
analysis of kinetic data emphasizing Michaelis-Menton kinetics and other 
methods useful in interpreting dose-response curves. 

In a related but more nearly comprehensive vein, PROPHET System contractors 
introduced MLAB into PROPHET within the past few months. MLAB (Modelling 
Laboratory) is a program developed at the NIH's Division of Computer Research 
and Technology for use in a wide array of situations where mathematical 
functions need to be fit to experimental data. MLAB can be invoked by the 
users either directly or through the medium of special PL/PROPHET functions 
which not only make it easier to use but also return its output as PROPHET- 
manipulable variables. MLAB can be used to fit functions of almost arbitrary 
complexity-i .e. , combinations of powers, exponentials, logarithms, and trigo- 
nometric and hyperbolic expressions. 

2. Molecule-Handling Tools 

Fiscal Year 1975 marked the addition of several new PROPHET features in 
the area of molecular modelling. As a result of collaboration between PROPHET 
users at the Medical Foundation of Buffalo and BBN staff, a procedure was 
developed whereby an instance of a PROPHET data type MOLECULE can be created 
directly from x-ray crystallography results. That is, using the measured 
atomic coordinates for all three dimensions and knowing the connectivity 
among the atoms, one can create MOLECULE variables in the standard PROPHET 
form and thereby take advantage of the wide array of pre-existing functions 
for manipulating such variables. Before this development, instances of 
MOLECULE variables could be created only one way--by sketching a two-dimensional 
structural diagram with the stylus and tablet in response to prompting asso- 
ciated with the MAKE MOLECULE command. Moreover, the only three-dimensional 
molecular models previously available for manipulation were those that had been 
derived from a representation of atomic connectivity using the COMPUTE MODEL 
command. Users now have two ways to create MOLECULE variables and, when the 
crystal lorgraphy data exists, can work with "observed" structure as well as 
"estimated" structure. 

The PROPHET users at the Medical Foundation of Buffalo also were instrumental 
in enriching the System's capabilities for molecular display. With the 
assistance of BBN staff, they modified and introduced the ORTEP program for 
producing perspective drawings of three-dimensional molecular models. This 
program was developed at the Oak Ridge National Laboratory about a decade ago 

66 



and is widely used in a variety of forms throughout the chemical research 
community, usually with computer driven plotters. Its accessibility via a 
simple procedure call now lets PROPHET users choose, for any given three- 
dimensional molecular model, whether they wish to visualize a stick figure 
or an ORTEP perspective drawing on their display terminal. 

There also was a major upgrading in the power of the COMPUTE MODEL command. 
In collaboration with Dr. W. Todd Wipke and his associates at Princeton 
University, PROPHET was fitted out with Dr. Wipke's procedure for building 
plausible three-dimensional molecular models for cyclic compounds of almost 
arbitrary complexity. Previously, the PROPHET System had relied exclusively 
on a "ring library" for such computations and consequently could construct 
models of only those cyclic compounds whose ring constituents were represented 
in the library in terms of their three-dimensional atomic coordinates. BBN 
staff now are collaborating with PROPHET users in order to establish better 
the limitations of the Wipke algorithm in this implementation and to determine 
how best to combine it with the "ring dictionary" approach. 

3. Remote Terminals 

The Tektronix 4010 graphic display terminal was added to PROPHET'S line 
of remote access devices during the past year. This terminal is based on 
essentially the same storage tube technology as the Computek 400 terminals 
originally used with PROPHET and is fully compatible with them. The new 
terminal and Tektronix 's nationwide array of field service installations 
should give PROPHET users and contractors alike greater flexibility with 
respect to maintenance of the devices in the field. In addition, the Tektronix 
4010 terminal is an important step toward the large screen storage tube devices 
that recently have become commercially available. 

There also was some emphasis during Fiscal Year 1975 on improving "teletype" 
access to PROPHET. Originally, use of PROPHET via teletypewriter devices was 
restricted to programmers at BBN. While almost all PROPHET features can, in 
fact, be exercised from a typewriter terminal, the task often is complex or 
tedious or both. In the early years of the PROPHET project (when all involved 
were uncertain as to just how "friendly" PROPHET had to be to attract computer- 
naive users), access by PROPHET users was limited to display devices. 

Within the last eighteen months or so, it has become clear that this proscrip- 
tion regarding low-performance terminal devices can be relaxed somewhat. User 
groups whose activities involve principally numeric and textual data (and not, 
say, molecular models) have found that PROPHET'S TABLE-nandling functions and 
computational capabilities are quite satisfactorily exercised from a teletype- 
writer device. This being the case, a number of improvements have been made 
(especially in the area of tabular and graphic output) to facilitate such use. 
Given the significantly lower cost and easier field maintenance of these 
devices (when compared with a graphic terminal), the goals of the PROPHET pro- 
ject are well served by making selective use of teletypewriter terminals as a 
principal access medium. 



67 



4. Dial -Up Telecommunications for Graphic Terminals 

During Fiscal Year 1975, dial-up access to PROPHET for users with graphic 
terminals became a realistic alternative to use of dedicated telephone lines. 
Two events brought this about: (a) the emergence during the last few years 
of telephone modems capable of transmitting 120 characters per second over 
a switched network and (b) the recent introduction of new telephone company 
tariffs which make the use of INWATS lines more attractive economically than 
had previously been the case. Several PROPHET terminal sites are or soon 
will be serviced via a dial-up arrangement. The additional flexibility 
afforded by dial-up access should become increasingly important as the 
PROPHET user community grows in the years ahead. 

5. Tools for Self Instruction 

As the PROPHET user community expands, so does the .importance of main- 
taining good communications between and among the participants in the project. 
This is especially true insofar as instruction in the use of PROPHET is 
concerned. While every effort is made to keep the User Manual and Public 
Procedures Manual accurate and clear and while a small cadre of BBN staff 
are available to users on a regular basis both via telephone and in person, 
this of course does not guarantee that every PROPHET user fully understands 
the strengths and limitations of the tools at his or her disposal. Evenin 
those several cases where a user group has one or more resident experts in the 
use of PROPHET, it is quite possible that individual users are not receiving 
all the assistance they should. If PROPHET were a static system, this would 
be problem enough. But the steady accretion of new functions only heightens 
the possibility that an inexperienced user will miss something of importance 
or fail to notice that a previously absent feature now exists. 

In recognition of the above, BBN staff have developed and introduced into 
service some tools for preparing on-line self instructional materials. One 
of these tools allows a user to "record" an actual PROPHET session; that is, 
it produces a script of both user commands and System responses in a special 
format. This script then can be "played back" via another command at a 
subsequent time, thereby allowing the user to proceed step-by-step through 
simulated recreation of the original session. The user is required to depress 
the GO key after each command appearing in the script in order to have some 
control over the rate of the presentation and to acquire some feeling of 
participation. Since the "play back" is in reality only the read-out of a 
disc file, the computational resources required in this step are almost 
trivial. Only when the session actually is being "recorded" is PROPHET being 
exercised and making appreciable demands on the computer hardware. And then 
the demands are essentially identical to those associated with normal System 
use. 

The strengths and limits of these programs for building self-instruction 
materials now are being assessed. BBN staff have prepared a number of 
scripts covering basic PROPHET operations such as making TABLES, GRAPHS, and 
MOLECULES. Some PROPHET users are studying the possibility that self- 
instruction scripts will be valuable as a medium for explaining how to use 
various public procedures and public data bases they have in preparation. 



68 



ADMINISTRATIVE CONSIDERATIONS 

Research resources have unique problems and special opportunities. Resources 
may be involved in important ways with a wide array of categorical disease 
problems, but they rarely receive the benefits of being identified with any 
one of them. Resources may be key ingredients in achieving Federal health 
objectives, but the significance of their contributions frequently may be 
overshadowed by issues more obviously aligned to the medical problems them- 
selves. Resources may succeed in opening up new opportunities for biomedical 
scientists, but judgments as to the value of the resources' accomplishments 
necessarily must wait until users have demonstrated that those opportunities 
are both wanted and needed. Like the rest of the Division of Research 
Resources, the CBIH Program must deal with and accommodate to these facts 
throughout its management and administrative activities. 

In the case of the PROPHET System, the mission of the resource is inextricably 
linked to the missions of the categorical disease programs elsewhere in NIH 
and ADAMHA. Computer tools for studying chemical /biological interactions have 
little value if they are designed and tested outside the mainstream of high 
quality biomedical science. And the significance of even the most exquisitely 
crafted tools generally will go unappreciated unless their use is directed by 
a prepared mind. The CBIH Program therefore places a premium on establishing 
meaningful ties to other Federal program activities in which chemical /biological 
interactions are being investigated and where modern information-handling 
technology is not at hand. 

The PROPHET System has special attributes as a research resource. First, it 
came into being as a result of a specific Federal initiative and is sponsored 
via the contract mechanism; most research resources are initiated by their host 
institutions in response to Federal program guidelines and are funded via the 
grant mechanism. Second, the continuing development and operation of the 
PROPHET System involve the efforts of several contractors, with coordination 
and overall direction being furnished by CBIH Program staff; most research 
resources involve only a single award and staff of the awardee provide the 
direction. Third, the PROPHET System is a nationally shared research resource; 
most research resources have a much more restricted geographic impact. Fourth, 
services of the PROPHET System are allocated on a national basis with the aid 
of a peer review mechanism; most research resources have considerably less 
formal procedures for this. Fifth, PROPHET users directly reimburse the CBIH 
Program for a portion of the costs associated with the services they receive; 
the majority of research resources furnish their services at no cost to the 
users. Because of these and other attributes, the PROPHET System may well 
become a paradigm for other specialized research resources in the future. 

PLANS 



The CBIH Program plans to continue the evaluation and refinement of the 
PROPHET System. Additional high quality users will be selected and thei . 
needs will be addressed along with those of the present users. Efforts will 



leir 



69 



be made to expand not only the physical capacity of the resource but also 
the array of powerful tools it contains. Special emphasis will be placed 
on pharmacokinetics, molecular modelling, and archival management. The 
prospects for further successful interaction with important research projects 
seem excel lent. 



70 



Table 1. Chemical /Biological Information-Handling Review Committee 

Fiscal Year 1975 

CHAIRMAN 

Amarel, Saul 

Professor and Chairman 

Department of Computer Science 

Livingston College 

Rutgers University 

New Brunswick, New Jersey 08903 



Abbott, Robert P. 

Leader, Applications Programming Div.II 
Computation Department 
Lawrence Livermore Laboratory 
University of California 
Livermore, California 94550 



Davi , Sumana K. 
Senior Investigator 
Dermatology Branch, DCBD 
National Cancer Institute 
National Institutes of Health, PHS 
Bethesda, Maryland 20014 

Grunewald, Joan 0. 

Assistant Professor 
. Dept. of Biochemistry and Molecular 
Biology 

School of Medicine 

University of Kansas 

Kansas City, Kansas 66103 



Miya, Tom S. 
Professor of Pharmacology 
Department of Pharmacology 

and Toxicology 
School of Pharmacy and Pharmacal 

Sciences 
• Purdue University 
Lafayette, Indiana 47907 

Pauker, Stephen G. 
Assistant Professor 
Dept. of Medicine (Cardiology) 
New England Medical Center Hospital 
Boston, Massachusetts 02111 



Woods, Eugene F. 
Professor 

Dept. of Pharmacology 
College of Medicine 
Med. University of South Carolina 
Charleston, South Carolina 29401 






EXECUTIVE SECRETARY 

Raub, William F. 
Program Director 

Chemical/Biological Information-Handling Program 
Division of Research Resources 
National Institutes of Health, PHS 
Bethesda, Maryland 20014 



71 



Table II. Prophet User Groups as of June 1975 



1. Department of Pharmacology 
School of Medicine 
University of Pittsburgh 
Pittsburgh, Pennsylvania 

2. Harvard University General Clinical Research Center 
Beth Israel Hospital 

Boston, Massachusetts 

3. Department of Pharmacology 
Mount Sinai School of Medicine 
New York, New York 

4. Molecular Biophysics Department 
Medical Foundation of Buffalo 
Buffalo, New York 

5. Research Institute on Alcoholism 

New York State Department of Mental Hygiene 
Buffalo, New York 

6. Technological Institute 
Northwestern University 
Evanston, Illinois 

7. Harborview Medicai Center 
University of Washington 
Seattle, Washington 

8. Biology Department 
Yale University 

New Haven, Connecticut 

9. Division of Research Resources 
National Institutes of Health 
Bethesda, Maryland 



72 



Table III. A. Applications of the Prophet System, at the School of Medicine, 
University of Pittsburgh, Pittsburgh, Pa. 



Project 

1. Drug interactions through 
depot formation 

2. Study of phenotypic resistance 
to tetracycline 

3. Hypertension screening protocol 
4.- Pharmacokinetics of bethanidine 

5. Kinetics of pyruvate kinase 

6. Discharge patterns in neuron 
populations of primate somato- 
sensory cortex 

7. Hallucinogenic drug action 
on the somatosensory system 

8. Kinetics of anticoagulant 
effects of warfarin in rats 

9. Pharmacodynamics of d-tubo- 
curarine in humans 



Investigator(s ) 
J. Anderson 

R. Connamacher 



Sponsor(s ) 

Medical Alumni Association, 
University of Pittsburgh 



c. 


Corder 


c. 


Corder 


L. 


Decker 


G. 


Werner 


G. 


Werner 


G. 


Werner 


L. 


Wingard 



Alfred P. Sloan Foundation; 
National Science Foundation 



National Institute of 
Mental Health 



73 



Table III.B. Applications of the Prophet System at 
Beth Israel Hospital, Boston, Mass. 



Project 

1. Error analyses of amino acid 
determinations 



Investigator(s ) 



R. 



Auty 
Ransil 



R. Auty 
B. Ransil 



R. Auty 
M. Lanner 

H. Benson 



Analysis of electrolyte 
interferences in pooled plasma 
by the method of additions 

Analysis of ultracentrifuge 
sedimentation rates 

Non-pharmacological approach 
to hypertension, anxiety, 
cardiac arrythmias, headache, 
and drug abuse in post- 
myocardial infarction patients 



5. Study of oral protein sparing G. Blackburn 
in human subjects 



6. Analysis of nutritional status G. Blackburn 
of hospitalized patients 



7. Determination of optimal G. Blackburn 
hyperalimentation infusion 

rates 

8. Metabolic response to severe G. Blackburn 
trauma 

9. Response of QT interval of H. Hartley 
the electrocardiogram to 

exercise 



Sponsor(s ) 

General Research Support 
Program, Division of 
Research Resources, NIH 

Same as #1 . 



Same as #1 



National Institute of Mental 
Health; National Heart and 
Lung Institute; Hoffman- 
La-Roche; General Clinical 
Research Center Program; 
Division of Research 
Resources, NIH; General 
Service Foundation of 
St. Paul , Minnesota 

MIT Center for Nutritional 
Research; General Clinical 
Research Center Program, 
Division of Research 
Resources, NIH 

National Institute of 
General Medical Sciences; 
National Institute of 
Arthritis, Metabolic and 
Digestive Diseases 

Deaconess Hospital 
Nutrition Support Service; 
Same as #6. 

Same as #7. 



National Heart and Lung 
Institute 



74 



10. Prevalence of premature H. Hartley Same as #9. 
ventricular contraction 

induced by exercise 

11. Effect of relaxation tech- H. Hartley Same as #9. 
nique on (L-uptake during 

exercise 

12. Effect of acute ozone exposure G. Huber 
on pulmonary host defense 
mechanisms 

13. Effect of acute and chronic G. Huber 
smoking on pulmonary host 
defense mechanisms 

14. Airway mechanics and relation G. Huber 
to smokinq artificial tobacco 
(Celanese) 

15. Subject variability of 24-hour B. Ransil 
urinary creatinines D. Greenblatt 



Tobacco Companies Grant 
#49906 



Same as #12. 



Celanese Corporation of 
America 



16. Pharmacological behavior of 
librium 

17. Debug of progesterone and 
aldosterone assay for 
progranmable calculators 

18. Effects of sodium salicylate 
in acute Chagasic myocarditis 
in mice 

19. Systolic time intervals during 
submaximal and maximal exercise 
in man 

20. Left ventricular ejection 
time by densitometry 



B. Ransil 

D. Greenblatt 

B. Ransil 



B. Ransil 
F. Duncanson 



Ransil 

Maher 

Beller 

Hartley 

Ransil 

Chi ri f fee 

Foerster 



Same as #1 



National Heart and Lung 



U.S. Army Research Institute 
of Environmental Medicine 



Same as #1 



0. Bing 



21. Cardiopulmonary resuscitation 
on medical and surgical wards 

22. Insulin clearance in pre- and 
post-nephrectomized subjects 



Ransil 
Go! dberg 
Rami rez 
Ransil 



23. The electron charge density B. Ransil 
basis of chemical reactivity 
and biological activity 



75 



._ 



24. Kinetics of K clearance in B. Ransil 
perfused rat kidney P. Silva 

25. Evaluation of the relationship F. Schiffer 
between emotional stress 

and ischemic heart disease 
with the quiz-electrocardio- 
gram technique 

26. Transport of potassium and P. Silva 
sodium by the isolated R. Solomon 
perfused kidney A. Besarab 

27. Potassium adaptation and P. Silva 
Na-K-ATPase activity in the R. Solomon 
mucosa of the colon A. Besarab 

28. Thiocyanate inhibition of P. Silva 
ATPase and its relationship R. Solomon 
to anion transport A. Besarab 

29. Metabolic adjustment of the P. Silva 
kidney involved in the R. Solomon 
adaptation to potassium A. Besarab 
loading 

30. Role of Na-K-ATPase in renal P. Silva 
function and relation to R. Solomon 
respiratory rate A. Besarab 

31. Role of platelets in mainte- P. Silva 
nance of endothelial integrity R- Solomon 

A. Besarab 



National Institute of 
Arthritis, Metabolic, and 
Digestive Diseases 

National Heart and Lung 
Institute 



Same as #24. 



Same as #24. 



Same as #24. 



Same as #24. 



Same as #24. 



National Heart and Lung 
Institute 



76 



Table III.C. Application of the Prophet System at Mount Sinai 
School of Medicine, New York, N. Y. 



Project 

Derivation of quantitative 
structure-activity relation- 
ships for tryptamines on 
the LSD-receptor of the 
rat fundus 



Investigator(s ) 
C. Johnson 



Sponsor(s ) 

National Institute of 
Mental Health 



Analysis of relationships S. Kang 
between peptide hormone 
conformation and pharmaco- 
logical activity 

Response of Renshaw cells S. Goldfarb 
to multiple input; changes 
with chronic spinal section 
and chronic drug administration 

Relationships between spatial S. Glick 
preferences and d-amphetamine 
effects on timing behavior 
in rats 



Same as #1 



National Institute of 
Neurological Diseases 
and Stroke 



National Institute of 
Mental Health 



Table III.D. Applications of the Prophet System at the Medical 
Foundation of Buffalo, Buffalo, N. Y. 



Project 

Dissemination of molecular 
data for biomedical use 



Investigator(s ) 

W. Duax 
V. Cody 
C. Weeks 



Sponsor(s ) 

National Library of 
Medicine 



2. Molecular structures of 
steroids 



W. Duax 
C. Weeks 
R. Rohrer 



National Cancer Institute 



3. infrastructure of the anti- H. Hauptman 
hypertensive prostaglandins G. DeTitta 

4. Cancer of the thyroid and its E. Volpert 
hormonal identity 

5. Molecular structures of thyro- V. Cody 
active compounds 



National Heart and Lung 
Institute 

National Cancer Institute 



Julia R. and Estelle L. 
Foundation of Buffalo; 
National Institute of 
Arthritis, Metabolic and 
Digestive Diseases 



77 



Table III.E. Applications of the Prophet System at the Research 
Institute on Alcoholism, Buffalo, N. Y. 



Project Investigator(s ) 

Analysis of subjectively J. York 

perceived effects of alcohol- 
barbiturate combinations by 
means of drug discrimination 
procedures 



2. Fetal alcohol syndrome: 
epidemiological study 

3. Effects of ethanol and bar- 
biturates on membranes and 
membrane-bound enzymes from 
drinking and non-drinking mice 

4. Effects of acute and chronic 
administration of ethanol on 
muscle afferent activity 

5. Survey of teenage drinking 
patterns 

6. Alcohol ingestion in lactating 
rats: effects on offspring 

7. Evaluation of the Erie County, 
N.Y. Driving While Intoxicated 
Program 

8. Correlates of alcohol-related 
drinking behavior in twins 

9. Evaluation of model sobering- 
up stations in New York State 

10. Alcohol-induced biochemical 

changes in the central nervous 
system 



M. Russell 

D. Lin 

D. Greenhouse 

G. Barnes 

E. Abel 

F. Hooper 

F. Hooper 

R. Cabral 

A. Chan 



Sponsor(s ) 

New York State Department 
of Mental Hygiene 



Same as #1 



Same as #1 , National 
Council on Alcoholism 



Same as #1 ; National 
Institute of General 
Medical Sciences 

Same as #1 . 



Same as #1 ; United Way of 
Erie County 

Same as #1. 



Same as #1 . 
Same as #1. 
Same as #1. 



78 



Table III. F. Applications of the Prophet System at the National 
Institutes of Health; Northwestern University, Evanston, 111., 
and Bolt, Beranek, and Newman, Inc., Cambridge, Mass. 



Project 

1. Prediction of polypeptide 
conformation 



Investigator(s ) 

E. Kabat 

T. Wu 

H. Bilofsky 



Sponsor(s ) 

National Cancer Institute; 
National Institute of 
Allergy and Infectious 
Diseases; National Science 
Foundation 



Tabulation and analysis of E. Kabat 
immunoglobulin sequence data T. Wu 

H. Bilofsky 



Same as #1 . 



Table III .G. Applications of the Prophet System at the Biology Department, 
Yale University, New Haven, Connecticut 



Project 



Investigator(s ) 



Sponsor(s ) 



1. Growth control by mem- B. Stowe 
brane matrix matching lipids M. Dotts 






79 



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<c 


O) 




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> 


U- 


•i— 


<4- 


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o 


+-> 


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oo 




l/l 


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80 



REFERENCES 



1. PROPHET System Users' Manual, Version 3.1, May 15, 1974. 
(Copies available on request.) 

2. PROPHET System Public Procedures Manual: A Program Exchange for 
PROPHET Users, March, 1975. (Copies available on request.) 

3. Raub, W.F. Automated information-handling in pharmacology research. 
AFIPS Conf. Proc. 40:1157-1165, 1972. 

4. Raub, W.F. The role of specialized data structures in computer- 
based management, analysis, and communication of pharmacological 
information. International Union for Pure and Applied Biophysics, 
Academy of Sciences of the USSR, pp. 307-312, 1973. 

5. Castleman,P.A.,C.H. Russell, F.N. Webb, C.A. Hollister, J.R. Siegel, 
S.R. Zdonik and D.M. Fram. Implementation of the PROPHET System, 
Proc. Natl. Compt. Conf. 43:457-468, 1974. 

6. Weeks, CM., V. Cody, S. Pokrywiecki, D. Rohrer, and W. Duax. 
Application of the PROPHET System in correlating crystal lographic 
structural data with biological information. Proc. Natl. Compt. Conf. 
43:469-472, 1974. 

7. Johnson, C.L. Application of the PROPHET system in molecular 
pharmacology - structure-activity relationships in monoamine 
oxidase inhibitors. Proc. Natl. Compt. Conf. 43:473-477, 1974. 

8. Ransil, B.J. Applications of the PROPHET System in human clinical 
investigation. Proc. Natl. Compt. Conf. 43:477-483, 1974. 

9. Ransil, B.J. Use of table file structures in a clinical research 
center. Fed. Proc. 33:2384-2387, 1974. 

10. Raub, W.F. The PROPHET System and resource sharing. Fed. Proc. 
33:2390-2392, 1974. 

11. Dickerson, R. E. and I. Geis. The structure and action of proteins. 
W.A. Benjamin, Inc. Menlo Park, California. 1969. 

12. Hunting the Helix . Nature 242:555. 1973 

13. Kabat, E.A. and T.T. Wu. The influence of nearest-neighboring amino 
acid residues on aspects of secondary structure of proteins. Attempts 
to locate a-helices and 3-sheets. Biopolymers: 751-774, 1973. 



81 



14. Kabat, E.A. , and T.T. Wu. Construction of a three-dimensional 
model of the polypeptide backbone of the variable region of 

kappa immunoglobulin light chains. Proc. Nat. Acad. Sci . 69:960-964, 
1972. 

15. Atlas of Protein Sequence and Structure, M„0. Dayhoff, editor, 
Washington, D.C. National Biomedical Research Foundation, 1972. 

16. Wu, T.T., and E. A. Kabat. An analysis of the sequences of the 
variable regions of Bence Jones proteins and myeloma light chains and 
their implications for antibody complementarity. J. Exp. Med. 
132:211-250, 1970. 



, 



82 



Fiscal Year 1975 
Annual Report 
General Clinical Research Centers Branch 
Division of Research' Resources 

I. Introduction and Goals of the Program 

In 1959, Congress expressed the view that the Nation should receive the bene- 
fits of basic research as rapidly as these became available. Passage of P.L. 
86-798 established the legislative basis for the General Clinical Research 
Centers (GCRC) Program, and in 1960 Congress appropriated $3 million for its 
establishment. The GCRCs were designed as loci for clinical investigation; 
they were created to supplement ongoing medical research in universities and 
hospitals. 

The GCRC Program has evolved in response to the need for specialized facili- 
ties and trained personnel to meet the complex demands required by high quali- 
ty clinical research. The fundamental study of human physiology and disease 
with its broad implications for the maintenance and restoration of health re- 
quires an optimal environment for human study. Repeated attempts to perform 
high quality clinical investigation in beds scattered in the general hospital 
environment have proven unsatisfactory. Furthermore, a single general re- 
search unit effectively meets the needs of many investigators studying a vari- 
ety of disease problems in a most effective and economic fashion. 

The primary goal of the GCRC Program is the establishment of a resource for 
clinical investigation to: 

Increase the knowledge of human physiology and pathophysiology 
by the investigation of the epidemiology, etiology, progression, 
prevention, control and cure of human disease by studies 
in man; 

Provide an optimal setting for controlled studies by clinical 
investigators supported through NIH and other research support 
programs; 

Encourage and foster disciplinary interaction; 

Contribute to the maintenance of a national core of qualified 
clinical investigators, and 

Develop technological and therapeutic advances in the expeditious 
translation of basic biological knowledge into effective patient 
care. 

A GCRC is defined as "a distinct organizational and physical entity provid- 
ing a continuing resource for clinical research efforts, including the nec- 
essary laboratory and supporting services." Specifically, a GCRC is a re- 



83 



source to a medical institution permitting quality clinical investigation. 
The research conducted in the GCRC derives its support from various Insti- 
tutes of the NIH as well as from numerous foundations and philanthropic organi- 
zations. Funds for the GCRC Program are intended primarily for the estab- 
lishment and maintenance of the separate discrete units in which clinical 
research is to be done. 

A GCRC consists of four to thirty beds, the average being eleven. Usually a 
GCRC contains bedrooms, treatment rooms, a core laboratory, diet kitchen, pa- 
tients 1 lounge, nurses' station, and conference room. Centers can usually ac- 
commodate both adults and children, but about one-fifth of the GCRCs are en- 
tirely pediatric. Several GCRCs specialize in areas involving premature in- 
fants, maternal-child, or acute surgical problems. 

Over 13,000 individuals are involved with GCRCs. GCRC grants provide salary 
support for staff, numbering approximately 1,800. Currently, the Program con- 
sists of 84 GCRCs, plus an outpatient GCRC, a special surgical unit, and pays 
76 percent of the extramural research patient care cost funded by NIH. 

Within the GCRCs, senior scientists, research fellows, and house staff are ex- 
posed to increasingly sophisticated methods and concepts of clinical research. 
Such training is essential for the continued development of competent investi- 
gators and improved medical care. An additional benefit of these GCRCs is that 
future medical practitioners develop knowledge that facilitates critical eval- 
uation of new medical discoveries with which they will be confronted in their 
careers. In addition, the GCRCs assist in the training of large numbers of 
paramedical personnel. 

Information concerning the research done in the GCRCs is distributed to the 

medical community in a variety of ways. For example, in fiscal year 1973 there 

were a total of 2,360 publications and 1175 abstracts (see table 1) which ap- 
peared in scientific books or journals. 

Table 1 
Center Publications 



Year 



Publications 



Abstracts 



1969 
1970 
1971 
1972 
1973 



1/ 

2/ 

3/ 



2,077 

2,341 

2,229±' 

2,462^ 

2,360 s -/ 



Includes 246 publications involving outpatients 
Includes 411 publications involving outpatients 
Includes 549 publications involving outpatients 



931 
996 

991 

994 

1175 



The GCRC Branch has also been active in anticipating the needs of the GCRCs 
and has continued to evaluate and develop resources which facilitate clinical 
investigation. The following is a list of major program modifications and in- 



84 



novations of the past seven years: 

..Outpatient Program 

..Service Patient Policy 

..Third Party Credits 

. . Clinical Research in Surgery 

..Discrete Unit Costing 

..Contribution papers (Atherosclerosis, Growth and Development, 

Drug Abuse, Narcotic Addiction, Diabetes, Sickle Cell Anemia, 

Cancer, Transplantation, Bed Occupancy) 
..Annual Ranking Procedures for GCRCs 
..Resource-Related Research Grants 
..Clinical Associate Program 
. .Mixed Centers 

The GCRC Branch staff is continuing to evaluate its Program and to modify pro- 
cedures where appropriate. The following areas are being studied: 

1. Occupancy 

GCRC Branch staff is preparing a manual so that all GCRCs 
can report their occupancy rates by using identical formulae. 

2. Physicians ' Fees 

A position paper is being written on whether to allow physicians' 
fees for certain types of patients admitted to the GCRCs. This 
practice is not currently allowable. 

3- Clinical Mass Spectrometry Resources (CLINSPEC) 

The field of mass spectrometry is being surveyed to determine 
applications to clinical research problems. The potential for 
a mass spectrometry resource program in clinical research in 
collaboration with the Biotechnology Resources Branch of the 
Division of Research Resources, is being explored. A two-day 
workshop was held in May 1975 to determine the feasibility 
of supporting this instrumentation as a resource to the GCRCs. 
Topics were developed to provide data and to assist in making 
programmatic decisions with regard to this instrumentation. 

4. Funding Sources for Clinical Investigators 

A pilot study is being done to determine the efficiency of 
proposed reporting procedures so that all supporting sources 
(e.g., NIH research project grants, philanthropic donations, 
foundation grants, etc.) can accurately be tabulated and 
analyzed. 



85 



5. NIH Clinical Research Coordinating Committee 

With representation from each of the Institutes at the NIH, this 
Committee has held six meetings since September 10, 1974 to 
inform itself of the clinical research activities at the NIH. 
The Committee is exploring several methods of coordinating the 
clinical research supported by each Institute. The Chief, 
GCRC Branch, is the Executive Secretary of the Committee. 

6. Program Directors' Meeting 

A national meeting of GCRC Program Directors is being planned. 
It is anticipated that not only will the GCRC Branch benefit 
by a discussion of Program needs and trends, but the Program 
Directors will also benefit by interchanging ideas and solutions 
in administrative or scientific problem areas. In addition, 
better communication in terms of coordinating the research of 
identical clinical problems is expected to occur. 



Jk 



CLINFO 

CLINFO is a collaborative scientific inquiry sponsored by the 
GCRC Branch and the Biotechnology Resources Branch. It is aimed 
at: 1) identifying and characterizing the intellectual tasks 
and flows of information occurring in clinical investigation, 
and 2) developing methods for facilitating these tasks and 
flows. The project was conceived because significant problems 
exist in the clinical investigative process which could be met 
by better information systems. Contracts have been awarded to 
develop a stand-alone minicomputer which will be designed, 
tested, and installed initially at selected GCRCs. 



National Association of Research Nurses and Dieticians 

The GCRC Branch has been working with the research nurses and 
dieticians of the Nation to encourage collaboration and to 
foster exchange of information. This past year, with GCRC Branch 
encouragement, a national meeting of the research nurses and dieti- 
cians was held, at which time scientific papers were presented 
and workshops were held in several scientific, nursing, dietary 
or administrative areas. Also at this meeting, the research 
nurses and dieticians agreed to meet every other year at seven 
regional workshops and to hold a national meeting during the 
year when no regional meetings take place. The GCRC Branch is 
continuing to encourage the research nurses and dieticians to 
involve themselves more intimately with GCRC programs. 



86 



9. Core Laboratory Evaluation 

The GCRC Branch is in the process of demonstrating the rationale 
and utility of the core laboratories within GCRCs. This study 
has a i second purpose, and that is to determine the feasibility 
of a collaborative exchange of technology and samples between 
GCRCs. Thus, the establishment of geographical core laboratories 
in certain areas might help to standardize testing, reduce the 
number of laboratories doing similar tests, and increase scienti- 
fic productivity of core laboratories. 

10. Principal Users of GCRCs 

A review of the use of GCRCs by Program Directors and Principal 
Investigators in terms of their patient-day involvement indicated 
that a few Centers appear to be dominated by their Program 
Director's or Principal Investigator's interest or projects. 
While many such studies are sound and of good quality, the GCRC 
Branch is reviewing such situations to insure that the GCRC is 
indeed a general institutional research facility available to 
all qualified investigators at the institution. 

II. Training 

Within the GCRCs, senior scientists, research fellows, and house staff are ex- 
posed to increasingly sophisticated methods and concepts of clinical research. 
Such training is essential for continued development of competent investiga- 
tors and for improved medical care. Moreover, the GCRCs are the primary hos- 
pital facility in which nurses, dieticians, and laboratory technicians gain 
practical experience in newly developed patient care techniques , generally 
resulting in better quality of hospital care. Table II shows the numbers of 
individuals receiving training in the GCRC during the past five years. 



Ill 







Table 


II 






Number and 


Types 


of Training in GCRCs, 1969 


-1973 




1969 


1970 


1971 


1972 


1973 


Medical Students 


2939 


3065 


2872 


3152 


2780 


Interns 


1019 


911 


921 


873 


733 


Residents 


1870 


1751 


1646 


1745 


1466 


Fellows 


1340 


1321 


1169 


1281 


1212 


Dietary Interns 


422 


487 


578 


460 


600 


Student Nurses 


1066 


1089 


914 


944 


799 


Fiscal Summary 













The GCRC Program grew at an almost constant rate between 1960 and 1967. In the 
past few years, however, rising costs and fiscal constraints have prevented ex- 
pansion and have forced support for fewer Centers and a decreasing number of beds. 



87 



GCRCs exist in about two-thirds of the teaching medical institutions in this 
Nation. A number of such institutions with great potential do not have a 
Center. Table III depicits the Program history since 1968. The Program has 
operated effectively despite sharp inflationary rises and modest budget in- 
creases through a number of adjustments, such as termination of a number of 
GCRCs, reducing the number of beds supported, savings realized through new 
discrete costing procedures, service patient policy, and some research done 
on an outpatient rather than an inpatient basis. 



Table III 







GCRC 


Program, 


FY 1968-1975 




Medical 








Full-Time 




Schools 








Equivalent 


Fiscal 


with a 


Number of 


Funded 


Patient 


Positions 


Year 


GCRC 


Centers 


Beds 


Days 


Funded. 


1968 


62 


91 


1051 


260,696 




1969 


64 


93 


1023 


245,943 


2,297 


1970 


64 


93 


940 


231,020 


1,920 


1971 


56 


82 


881 


218,716 


1,885 


1972 


58 


84 


907 


220,490 


1,801 


1973 


59 


83 


893 


204,993 


1,790 


1974 


62 


87 


888 


238,560 


1,812 


1975 


61 


84 


827 


212,831 


1,722 



Apportionment 
(in thousands) 

30,443 
35,004 
35,004 
38,004 
42,181 
41,300 
42,320 
42,300 



Despite budgetary constraints, the Program continues to support the best a- 
vailable resources for clinical research. More than half of all hospital 
beds in the Nation, specialized for research on humans, are supported by 
this Program. 



During 1967-75, a dynamic exchange of beds and GCRCs occurred within the Pro- 
gram. In 1967, 1,131 beds were approved in 91 Centers. In subsequent scien- 
tific reviews, 23 Centers with 192 beds were disapproved and NIH support ter- 
minated. An additional 251 beds, on the basis of limited scientific produc- 
tivity in 46 Centers, were eliminated with corresponding staff reductions. 
During this same period, 12 new Centers and six reapproved Centers (with re- 
vised applications of higher scientific merit) for a total of 161 beds were 
funded. In addition, six of the new Centers given two-year renewals worked 
to revise their program to compete successfully with programs of high scienti- 
fic merit. The net result has been a substantial improvement in the overall 
scientific quality of the Program and the funded beds now correspond closely 
with the bed needs of investigators holding NIH-sponsored grants and con- 
tracts. Despite these reductions and modest increases in appropriated and 
apportioned funds, rising costs have outstripped available funds. This dif- 
ferential has been met in part through appropriate collections from third 
party carriers, and in part by encouraging investigators to carry out some 
of their activities through less expensive outpatient protocols whenever fea- 
sible. Table IV shows the history of service patient credits that have been 
credited to the GCRC Program since 1972. 



Table IV 
Service Patient Savings 
to the GCRC Program 



FY 

1972 
1973 
1974 



Credits 

$3,350,927 
3,418,216 
4,100,000(est.) 



Table V shows the increase in outpatient visits since the outpatient program 
was initiated in 1970. 

Table V 
Summary of Outpatient Visits, 1970-1974 

FY Outpatient Visits 



1970 
1971 
1972 
1973 
1974 



1,175 
13,426 
24,658 
36,309 
48,845 



Figure I presents the National Advisory Research Resource Council's ceilings, 
gross Program expenditures, service patient credits, plus appropriations since 
1967. 



Table VI presents the cost increases for beds and personnel position in the 
GCRC Program, FY 1968-1976. 

Table VI 
Cost Increase for Beds and Personnel 
Positions in the GCRC Program 
FY 1968 thru FY 1976 





Percent 


Percent 




Percent 




Increase 


Increase 




Increase 




Cost/Posi- 


Over Pre- 


Cost/Pa- 


Over Pre- 


FY 


tion/Year 


vious Year 


tient Day 


vious Year 


1968 


$ 8,170 




$127.89 




1969 


8,335 


2.02 


135.53 


6.27 


1970 


9,244 


10.91 


148.78 


9.78 


1971 


10,228 


10.64 


156.67 


5.30 


1972 


10,985 


7.40 


165.10 


5.38 


1973 


11,746 


6.92 


182.89 


10.77 


1974 


12,755 


8.59 


194.72 


6.47 


1975 


13,763 


7.90 


209.35 


7.51 


1976 


15,139 est. 


10.00 est. 


230.29 est. 


10.00 est 






89 



AL CLINICAL RESEARCH CENTERS 

Ft 1957 - FY 1976 
(Dollars in Millions) 



FIGURE 1 



^^^ NARRC CEILINGS 
'////// EXPENDITURES 

SERVICE CREDITS + APPROPRIAT CONS 




W/^^^/ 




J_ 



I 



1967 1968 1969 1970 



1971 1972 1973 
FISCAL YEAR 



Estimate 



1974 1975 19 



90 



IV. Research Highlights 

Rheumatic Heart Disease 

Rheumatic heart disease commonly involves the mitral valve, resulting in inade- 
quate valve closure (mitral insufficiency) . The severity generally increases 
with age. In adults, replacement of the diseased valve with an artificial 
valve is the treatment of choice; in children, management has often consisted 
of continued medical treatment or artificial valve replacement. At one GCRC, 
an operation known as "annuloplasty," which consists of surgically making 
the base of the leaky valve narrower, has been found to result in marked 
clinical improvement in 11 children with mitral insufficiency. Leaking of 
the valve almost disappeared, and abnormal blood pressure in the heart re- 
turned to normal. These findings suggest that annuloplasty in childhood is 
corrective and may help avoid future valve replacement in adult life. 

Excessive Scar Tissue 

During the normal healing process following an infection or injury, scar tissue 
forms around the injured structure. When this occurs around the urethra, the 
tube carrying urine away from the bladder, the patient experiences pain, bleed- 
ing, and difficulty urinating. A drug called B-aminopropionitrite fumarate 
can cause a marked decrease in the amount of scar tissue which forms in pa- 
tients operated on for relief of a narrowing of the urethra. As a result, it 
is possible that relief can be offered not only to patients with disabling uri- 
nary symptoms as a result of scar tissue formation around the urethra, but also 
in other human ailments caused by formation of scar tissue. These include ad- 
hesions after abdominal surgery, scarring of the liver from hepatitis or alco- 
hol, scars in the esophagus from chemicals, and heart valves scarred from rheu- 
matic fever. 

Paget 's Disease 

Nearly 5% of the U.S. population over the age of 40 is affected by Paget' s dis- 
ease of bone. In many patients, this disease is painful and produces crippling 
deformities. Until recently, no effective treatment has been available, but 
work performed over the past two years at a GCRC and elsewhere has readied a 
new and promising drug, disodium etidronate, for clinical use in Paget' s dis- 
ease. Its effectiveness and safety have been documented by careful clinical 
and laboratory investigations, and the precise doses and amount of time re- 
quired to see a response have been worked out. 

Parkinson's Disease 

The treatment of Parkinson's disease was revolutionized about seven years ago 
by the introduction of L-dopa, an amino acid which calms the tremor and im- 
proves the mobility of Parkinson patients, usually spafiing them from surgery. 
Much of the work in developing L-dopa was performed on a GCRC. Work has con- 
tinued to combat the increasingly common problems with L-dopa: the recurrence 



91 



of uncontrollable movements and long-term resistance to the drug. On this 
GCRC new drugs have been tested which are modifications of L-dopa designed 
specifically to improve its potency. One drug, Piribedil, has been found to 
be particularly beneficial to many patients. By use of such a drug, the ex- 
traordinary but often temporary benefits of L-dopa may be extended into per- 
manent control of Parkinsonism. 

Childhood Hypertension 

Although much is known about hypertension (high blood pressure) in adult 
life, little is known about childhood hypertension and its course through 
adolescence. The causes of childhood hypertension are particularly mysterious. 
Recently, investigators at a GCRC have discovered several forms of hypertension 
caused by adrenal hormones, including one caused by a hormone which was previ- 
ously unknown. By understanding the underlying hormonal causes of high blood | 
pressure in these patients, investigators have been able to design treatment 
which can reverse the hypertension. This has profound implications in the pre- 
vention of adult hypertension, a leading public health problem. 

Growth Hormone Deficiency 

Growth hormone deficiency causes dwarfism. Treatment with human growth hormone 
accelerates growth so that dwarfed children can achieve socially acceptable 
heights. Yet only a small fraction of the children with growth hormone defi- 
ciency can be treated because of the scarcity of human growth hormone which 
is obtained from human pituitary glands. However, recent results on a GCRC 
indicate that the metabolic response to recently modified fractions of bovine 
growth hormone i.s similar to that of human growth hormone. This could mean 
a great relief to families who now often learn that although human growth hor- 
mone is a successful means of treatment, inadequate supplies may prevent their 
children from receiving it. 

Thyroid Cancer 

Patients with cancer of the thyroid gland have a much greater chance of survi- 
val when this disease is diagnosed at an early stage. A GCRC is currently re- 
fining a new diagnostic test with the capability of detecting this disease be- 
fore the thyroid becomes sufficiently large to be recognized clinically. Inves- 
tigators there have discovered that a protein of the thyroid gland, thyroglobu- 
lin, occurs in the blood in high concentration in patients with cancer of the 
thyroid, thus permitting early diagnosis. This unique diagnostic test may prove 
to be of considerable value in the early treatment and subsequent cure of this 
lethal disease. 

Gallstones 

Gallstones are a common health problem in the United States with an estimated 
10 percent occurrence in this population. Other countries, such as Japan, 
have a very low incidence of gallstones. Because these stones are composed 
primarily of cholesterol and because of the disparity in the incidence from 



92 



country to country, the possibility exists that gallstone formation is relat- 
ed to dietary cholesterol content. One GCRC has demonstrated that high die- 
tary cholesterol can alter the composition of bile, making it more likely to 
precipitate cholesterol and form stones. This suggests that gallstone formation 
can be retarded or prevented by dietary measures. Preventive measures are very 
important because once stones have formed they must either be removed surgical- 
ly or dissolved medically, a very slow process. 

Studies of Patients with Defective Defense Mechanisms 

Over 100 children and adults with a variety of immunodeficiency syndromes re- 
sulting in frequent severe infections have been studied and treated in one 
GCRC. 

These patients provided the opportunity to develop a number of laboratory 
tests which should be useful to others. A potent antigen (bacteriophage 0X 
174) accurately measures the ability of patients to make antibody and identi- 
fies those patients who may benefit from gamma globulin injections. In ad- 
dition, this antigen permits the diagnosis of infantile X-linked agammaglo- 
bulinemia during the newborn period before clinical symptoms and life-threat- 
ening infections develop. Recently a World Health Organization Committee 
recommended this antigen as a standard for diagnosis and classification of 
immune deficiency syndromes. This GCRC, with support from the National Foun- 
dation, assists other Centers in the United States and abroad by performing 
the assay. 

In addition, a simple and accurate microtest to detect chronic granulomatous 
disease (an illness in which white blood cells cannot kill certain bacteria, 
resulting in life-threatening infections) and to identify symptom-free car- 
rier females of this inherited disease has been devised. The test requires 
only one drop of blood and large numbers of patients can be screened. Six 
new cases have been detected and extensive studies at a GCRC provided impor- 
tant and valuable information about normal and affected white blood cells. 

The treatment of immunodef icient patients is complicated and often unsatis- 
factory. During the past year pilot studies in 14 patients have been done 
using a new, modified gamma globulin preparation which can be given by the in- i ?° 
travenous instead of the intramusclar route, causing less pain, insuring bet- 
ter absorption and allowing the infusion of larger doses at regular intervals. 

Arterial and Venous Angiotensin II, Plasma Renin Activity, 
and Aldosterone in Mild Hypertension 

High blood pressure affects about one of ten American adults. Untreated, it 
plays significant roles in the genesis of heart disease, stroke, kidney fail- 
ure, and eye disease. Adequate treatment, leading to the prevention of these 
important complications, hinges upon a thorough knowledge of the underlying 
mechanisms of its development. The cause of the vast majority of cases, the 
category of so-called "essential hypertension," is undetermined. An under- 
standing of a well-known kidney and adrenal gland hormonal complex, the renin- 
angiotensin-aldosterone system, is helping to shed light on the mechanisms 



93 



o 



which lead to the generation of essential hypertension and which at the same 
time give rise to a scientific basis for appropriate treatment. 

Studies presently conducted in an outpatient GCRC are showing that, marked 
suppression of the renin-angiotensin - aldosterone system occurs in mild hy- 
pertension prior to the initiation of therapy, as evidenced by the finding of 
subnormal concentrations of plasma renin activity, arterial and venous angio- 
tensin II, and aldosterone. Both renin and aldosterone levels consistently 
and progressively decrease as the levels of blood pressure increase in this 
group of patients. The findings are most pronounced in blacks, who are known 
to develop hypertension more frequently and of generally greater severity 
than whites. 

In contrast to previous interpretations that hypertension associated with low 
plasma renin activity suggests a special subgroup of these patients with a dif- 
ferent and less ominous prognosis, the current studies indicate that renin and 
aldosterone supression represents a sequence of events in the evolution of hy- 
pertensive disease. Complete understanding of such hormonal suppression will 
likely pave the way for appropriate treatment and avoidance of morbid complica- 
tions of this highly prevalent disease state. 

Evaluation of Influenza A Georgia 65-1 (E) Virus in Normal Adults 

The aim of this research is to develop improved vaccination materials against 
pandemic influenza. Current influenza vaccination which uses killed influenza 
virus offers only incomplete protection against pandemic influenza. Using re- 
cently developed methods which can combine various strains of viruses, investi- 
gators at the NIH have recombined an influenza virus strain which stops growth 
at normal body temperature of the "wild type" virus. In preliminary tests such 
a strain provokes a very mild respiratory infection, but provides substantial 
protection against wild type (epidemic) virus. During the past 9 months such 
a hybrid live virus vaccine has been administered to 31 volunteers in one GCRC. 
The vaccine induced complete resistance to influenzal disease produced by chal- 
lenge with virulent wild type virus. Work is now being done to confirm the 
efficacy and safety of a newer live virus vaccine which may provide broad 
protection against recent virus mutations. 

Intractable Diarrhea of Infancy 

Most infants and children with diarrhea recover spontaneously after an illness 
of three to five days duration. Intractable diarrhea of infancy is a term used 
to describe a diarrheal syndrome occurring in the first two months of life and 
associated with a prolonged course of weeks to months with a mortality of up to 
80%. The cause of this syndrome is unknown and it has remained refractory to 
the usual treatment for diarrhea and dehydration. Development of total paren- 
teral nutrition therapy, which allows feeding by vein of all essential pro- 
tein, calories and vitamins, has resulted in survival of these infants and 
allowed study of the causes of the syndrome. 

Bile acid malabsorption as a cause of diarrhea in the adult has been well docu- 
mented. Bile acids are cholesterol derivatives which are excreted from the 
liver in bile and which function as detergents to allow dietary fat to be made 



94 



water miscible so that it can be digested and then absorbed. After this func- 
tion is performed in the upper small intestine, bile acids are reabsorbed in the 
lower small intestine (terminal ileum) and conserved to be recycled and uti- 
lized again. 

Bile acid diarrhea results from loss of the terminal ileum from disease or sur- 
gery so that bile acids enter the large intestine (colon) . Here they induce 
secretion of water and electrolytes with resultant severe watery diarrhea. 
One GCRC is studying bile acid kinetics in children with intractable diar- 
rhea of various types. Labeled bile acid was administered by mouth to 15 in- 
fants with diarrhea of various types. The two patients with the "intractable 
diarrhea syndrome" were found to have markedly increased excretion of bile 
acid similiar in magnitude to that of four infants with the short gut syn- 
drome resulting from surgical resection in which the terminal ileum had been 
removed. Infants with steatorrhea (failure to absorb fat) and self-limited 
diarrhea had no increased bile acid loss. This study documents bile acid mal- 
absorption as one factor in the causation of intractable diarrhea in infancy. 
Rational treatment in infants with intractable diarrhea with bile acid-se- 
questering resin is suggested by the results. Further studies to determine 
the value of such treatment are in progress. Without the GCRC such a study, 
which involves careful collection of stool and urine specimen in infants who 
simultaneously require total parenteral nutrition to maintain life, would not 
be possible. 

Obesity 

Obesity and its attendant diseases such as diabetes, atherosclerosis, and hy- 
pertension represents one of the major health hazards in this country. In 
addition to the physical disability attributable to obesity, the mental anguish 
of these obese patients is noteworthy in that they must live in a culture that 
places great emphasis upon slimness and physical attractiveness. 

All currently available modalites of weight control have failed. However, a 
relatively new procedure has appeared. This is the intestinal bypass whereby 
90% of the small intestine is bypassed from the normal passage of food. Studies 
begun in the one GCRC are attempting to define some of the basic metabolic ab- 
normalities which lead to body weights of from 300 to 850 pounds. 

Surgical technique was carefully controlled and to date there has been but a 
single operative death (from a pulmonary embolus) in 160 operations. This 
means that one can operate upon and care for massively obese patients with a 
high degree of safety whereas previously they were denied surgical therapy of 
serious lesions because of obesity alone. 

Present studies are confined to two separate aspects of obesity; first, the 
obese state per se and, secondly, a careful follow-up of the patients who have 
undergone intestinal bypass surgery at this institution. 

Studies performed in the obese state have demonstrated that a percentage of 
obese individuals require a tremendous protein intake (3 to 5 times normal) to 
be in proper nitrogen balance. This means that the patient must consume a high 
number of calories to provide his body with its nitrogen requirements. This is 

95 



one of the first metabolic clues to the etiology of the insatiable appetites of 
some of these individuals. 

Intestinal bypass surgery for obesity is still experimental because relatively 
little is known about the long-term safety of having undergone the procedure. 
All patients operated upon at this GCRC must agree to return to the GCRC at in- 
tervals for a period of five years. During these visits many tests are per- 
formed, but the most important one may be a liver hiopsy, where changes are be- 
ing seen that are indistinguishable from alcoholic cirrhosis in some patients. 
These changes are quite serious. 



Radiation Therapy 

From about 1930 to 1958, radiation therapy was commonly employed for a variety 
of benign conditions in children, principally for enlargement of tonsils, ade- 
noids and thymus glands. About 1951, it became apparent that at least some of 
the patients who had been exposed to head and neck radiation were developing 
abnormalities, including malignancies, of the thyroid gland. More recent stu- 
dies suggest that there is a latent period which may extend beyond 20 years fol- 
lowing radiation to the head and neck before clinically evident thyroid malignan- 
cies are detected. Because of the widespread use of head and neck radiation 
and the uncertainty of the incidence and mechanisms of related disorders, the 
endocrinology group along with radiation biologists and immunologists of a 
GCRC began a large scale screening program for individuals who had received 
such radiation. Thus far 1,100 patients have been studied. Several broad con- 
clusions can be formulated. About 20% of the irradiated subjects had developed 
some thyroid abnormality. About 250 patients had thyroid scans to detect no- 
dules; however, this technique was not found to be superior to a careful physi- 
cal examination. The patient's blood was also assayed for thyroid stimulating 
hormone (TSH) and for the two circulating thyroid hormones. Thyroid antibodies 
were also measured along with skin tests for various fungi, to assess whether 
any abnormalities of the immune system had developed as a result of the head 
and neck radiation. There are some investigations which suggest that this may 
occur. Of the 110 patients who were found to have discrete thyroid nodules, 
thus far, 42 have undergone surgery. Of these, 25% have been found to be malig- 
nant. Some of the patients who presently do not have nodules may ultimately 
develop nodules, some of which may be cancerous. Since growth of thyroid malig- 
nancies is supported by TSH , efforts are now underway to examine whether pa- 
tients taking thyroid replacement therapy will be protected from developing thy- 
roid malignancy. To answer this question, one group of patients has voluntari- 
ly agreed to take thyroid replacement therapy to suppress TSH, amd another 
group no therapy. These patients will be followed on a yearly basis. Attempts 
are also underway to correlate the dose of the head and neck radiation with the 
likelihood of developing thyroid abnormalities. 



96 



Damage to Red Blood Cells Caused by Artificial Heart Valves 

Cardiologists have studied patients with hemolytic anemia following the inser- 
tion of a heart valve prosthesis. It is believed that the hemolytic anemia is 
due to trauma to the red cells based on physical contact with the prosthetic 
valves. The early model prostheses, particularly for the aortic valve, were 
especially likely to produce hemolysis . Change to clothcovered prostheses has 
distinctly decreased the magnitude of the problem of hemolytic anemia. However, 
it does persist. It has been found that in patients with either the original 
or the improved clothcovered prosthesis that when the heart rate is slowed with 
propranolol, there is increased red cell survival as demonstrated by slower 
turnover of isotope labeled red cells. 

Medullary Carcinoma of the Thyroid Syndrome 

One type of cancer of the thyroid, medullary carcinoma, is a familial disease 
frequently associated with pheochromocytoma, a tumor of the adrenal glands. 
One large family with several members having medullary carcinoma has been lo- 
cated. Genetically, half of the members of this family are at risk for develop- 
ing this cancer in their lifetime. Investigators at a GCRC have developed a 
test which enables them to identify this disease before it has become clini- 
cally detectable. Thus, when identified, these individuals can have their thy- 
roid removed before the cancer has metastasized and become life-threatening. 

Renal Transplantation 

Renal transplantation is now an accepted form of therapy for chronic renal fail- 
ure. Despite the apparent success, a number of problems remain which can best 
be thoroughly examined and solved in a GCRC environment. 

Approximately 45 percent of renal transplants from cadaver donors are unsuccess- 
ful and a second or even a third transplant (retransplant) is often necessary if 
the patient is to avoid chronic dialysis for the remainder of his life. Cadaver 
kidney retransplants have successfully supported patients for more than nine 
years, but they have been most successful when the cause of failure of the first 
transplant was either technical, or chronic rejection. When the loss of the first 
transplant was due to a high state of immunization manifested by early rejection 
of the transplant or the presence of cytotoxic antibodies in the recipient , the 
success rate of retransplantation has been poor. After prolonged study of the 
problem, two discoveries have been made which now make it possible to perform re- 
transplantations successfully in these high risk patients. The first observa- 
tion was that the withdrawal of immunosuppressive therapy prior to the removal 
of the previous transplant seriously prejudices the outcome of a subsequent 
transplant. The second discovery was the development of a kidney cell cross- 
match which supplements the standard lymphocyte crossmatch. This technique 
helps to avoid both the hyperacute and chronic types of rejection due to anti- 
bodies which were frequent causes of failure in this group of patients. It is 
now possible to perform retransplants in this high risk group of patients with 
the same degree of success that is achieved in recipients of first cadaver kid- 
neys. 



97 



o 
1 <s> 

1 




j 


i 





Treatment of Acute Leukemia 
by Marrow Transplantation from Identical Twins 

Leukemia is a cancer originating in the bone marrow . It interferes with produc- 
tion of red blood cells, white blood cells, and platelets, with resultant ane- 
mia, susceptibility to infections , and bleeding. Although acute leukemia of 
childhood is increasingly responsive to chemotherapy, more than half such chil- 
dren and virtually all adults with acute leukemia ultimately die with recur- 
rent disease despite chemotherapy. Such refractory leukemia might still be 
susceptible to vigorous doses of drugs or total body irradiation; however, 
this treatment also destroys all normal marrow elements and is therefore it- 
self lethal. Therefore, it has been proposed that patients with resistant 
leukemia might be treated with extraordinarily large doses of drugs and total 
body irradiation if they could thereafter receive a transplant of bone marrow 
from a normal donor . 

The rare leukemia patient who has a normal, genetically identical twin presents 
the opportunity to attempt such an approach under conditions in which the trans- 
planted marrow is not foreign to the host and will not be rejected. According- 
ly, patients with end-stage leukemia resistant to conventional therapy have 
been admitted to a GCRC and treated by a combination of drugs, a supralethal 
dose of total body irradiation , and transplantation of marrow from a normal 
genetically identical twin. The marrow was obtained by multiple needle aspira- 
tions from the donor's pelvic bones under spinal anesthesia and was infused in- 
travenously into the patient. The procedure required only one day's hospitali- 
zation and was associated with no complications to the normal donor. The nor- 
mal marrow usually established itself and produced normal marrow elements with- 
in two to three weeks. 

The principal problems encountered have been persistence of leukemia despite 
the radical therapy and several instances of major or fatal infections. How- 
ever, a large majority of patients exhibited disappearance of leukemia and 
went into complete remission. Although leukemia recurred in three to seven 
months in several patients, seven patients thus treated (about one-third of 
the total) are free of disease and leading normal lives without any additional 
treatment or hospitalization at seven to fifty-two months after the transplant. 

The importance of these results, made possible by access to a GCRC, is not 
only the good health and survival of these unique patients but also the oppor- 
tunity to obtain information which will permit applications of this approach 
more effectively to the treatment of leukemia patients who do not have geneti- 
cally identical twins , and conceivably to patients who have other kinds of ma- 
lignancies. Thus, the twin marrow transplant program provides important infor- 
mation relevant to the rather large ongoing study involving treatment of leu- 
kemia by marrow transplants from non-twin siblings. 

Renal Failure 

Chronic renal failure is a major medical problem in the U.S.A. The financial 
problem associated with maintaining patients lacking kidney function is one 
which is growing and will continue to grow as long as an effective, but expen- 



98 



sive, life-supporting technique is available. Dialysis is such a technique. 
A patient who is committed to dialysis in most cases can look forward to a long 
life, but there is usually no hope of terminating this treatment. The rate 
of successful kidney transplantation is 50 - 75% over the first few 
post-operative years. The patients frequently remain on high doses of immuno- 
suppressive drugs, and the entire transplant procedure cannot be considered as 
a totally satisfactory answer to renal failure. It has been the aim of one 
GCRC to develop inexpensive, but effective, techniques of prolonging useful 
life in uremic patients without resorting to dialysis. If each patient can be 
maintained for one to five years in a comparatively comfortable and active 
state before being required to go into dialysis, the savings in physical and 
emotional trauma, as well as money, will be considerable. 

Advantage has been taken of reports that oxidized starch when taken orally will 
absorb various uremic toxins. Patients can be maintained in relatively good 
health without dialysis, with only minimal renal function, if they ingest the 
starch product. The scope of this study has been enlarged and investigators 
are looking at the effects of charcoal and charcoal-oxidized starch mixture 
on the metabolism and general condition of moderately uremic individuals. Ba- 
lance studies are necessary to determine the objective effects of the intes- 
tinal absorbents. These studies measure the entire input and output of a large 
number of nutrients and excretion products . Only in a GCRC can such balance 
studies be performed. 

As of now, investigators have studied a large number of patients on starch a- 
lone and have reported this to the American Society for Artificial Internal 
Organs. Initial studies have established that ingested, oxidized starch low- 
ers such parameters of uremia as elevated blood urea nitrogen. Indeed, some 
return towards a more normal nitrogen metabolism was noted. In addition, the 
patients reported a reversal of many of the clinical signs of uremia, such as 
nausea, drowsiness and lethargy. Control studies with unoxidized starch, as 
placebo, indicates that these results could be attributed to ingestion of the 
specific sorbent. 

Renal Disease in Children 

Renal disease among young children is in many way more devasting than in a- 
dults. Because children's bones are forming, the ill effects of acid-base dys- 
function and disordered calcium and phosphorus metabolism in children with 
poor kidney function are magnified. In fact, the syndrome of "renal rickets" 
is well recognized by pediatricians . Vitamin D is metabolized by both the 
liver and kidney before it achieves maximum effectiveness. Patients with re- 
nal disease may, therefore, suffer the extra burden of an inability to produce 
potent vitamin D metabolites. 

Investigators are currently testing the effects of synthetically produced vi- 
tamin D metabolites on a group of young children with renal failure in order to 
determine if the ravages of renal rickets can be ameliorated, permitting nor- 
mal development. The patients are brought in on total calcium balance, a pro- 
cedure only possible in the GCRC and, after proper trial periods, they are 



99 



I - 

i : <=" 

1 











treated with vitamin D metabolites. Initial studies on eight patients have 
been most promising. A return towards normal serum calcium and a trend towards 
positive calcium balance have been noted in all. 

Dietary Treatment of Renal Failure 

Approximately 30,000 patients die each year in the U.S.A. of renal failure. 
More than half of these patients could be helped by hemodialysis, an artifi- 
cial means of removing waste from the blood normally removed by the kidneys 
when they are functioning properly. There are between 10,000 and 15,000 pa- 
tients receiving hemodialysis. Any type of therapy that reduces the need for 
this costly form of treatment would represent a major contribution toward ef- 
fective treatment for all who are in need of it. 

Work supported by the Inpatient and Outpatient GCRC at one institution has 
shown that the provision of a dietary supplement in the form of keto acids, 
building blocks which the body can use to make needed protein, decreases the 
work required of the kidney. These substances can serve as building blocks 
for protein and under these conditions there is a marked reduction in the 
quantity of waste products from the diet requiring excretion by the kidney. 

Use of the treatment program in chronic uremic patients significantly prolong- 
ed the ability of their markedly diseased kidneys to get rid of the daily waste 
products, thereby prolonging the time before they require treatment by hemo- 
dialysis. 

Since this treatment markedly reduces the rate of waste material accumulation 
from dietary intake, it offers the potential for reducing the frequency of 
dialysis in patients who are already on dialysis. If this treatment regimen 
can be shown to be practically applicable to large numbers of patients on hemo- 
dialysis, it will thus permit existing dialysis facilities to treat a greater 
number of patients and will also improve the quality of life for the patient 
on dialysis since he will be required to spend less time on the hemodialysis 
machine. 

Premature Infants 

The seriously ill premature and neonate are in a very critical situation due 
to rapid and profound changes in basic physiological and biochemical parameters 
as they attempt to adapt to extrauterine life. Because of this, they must be 
closely monitored and repeated blood tests are frequently necessary. Despite 
the fact that only small quantities of blood are necessary for various tests, 
the infant requires frequent replenishment of its rapidly dwindling blood vol- 
ume. In the past, each time an infant required a small transfusion (10-30 ml), 
a complete 500 ml unit of whole blood was utilized, thereby contaminating the 
remaining 450+ ml and rendering it unsuitable for further use. Therefore, 
various methods of blood transfusions have been developed throughout the coun- 
try to make a more efficient use of donated blood. 



100 



One of the techniques utilized in the nurseries is to establish a walking do- 
nor blood program wherein hospital-based donors are used to donate small quan- 
tities of blood to needy infants. A "stable" of donors is screened periodi- 
cally to check blood type and antibody formation, to detect whether or not 
the donor has developed antigen for hepatitis virus, and antibodies to various 
viral illnesses and syphilis. These donors are then assigned on a randomized 
basis to neonates who need repeated transfusions. A GCRC was one of the first 
in the United States to develop such a program, and the only unit to evaluate 
the efficiency and potential dangers and complications of such a program. 

V. Future Objectives and Trends 

The President's Budget request for FY 1976 proposed $41.6 million for the GCRC 
Program. This compares with $42.2 million appropriated in FY 1972 and an ap- 
propriation level of $42.3 million for 1975. The history of appropriations, 
service patient credits, Council recommendations, and expenditures can be seen 
in Figure 1 (see page 90 ) . 

During the early 1970s, several factors combined to cushion the impact of the 
rapidly escalating cost on the GCRC Program budget. These included the phas- 
ing out of support to ten Centers in 1969. Also, in 1970, a policy of charg- 
ing "hospital sick" patients on the GCRCs was instituted, which was successful 
in reducing Program-wide costs by nearly 10%. Additional measures included a 
research out-patient policy implemented in 1970 which decreased hospitaliza- 
tion expenditures and has reduced the bed requirements and hospitalization 
costs in many Centers; and a discrete unit costing method by which the Pro- 
gram essentially rent3 hospital space for research. The latter has helped 
hold down facility costs and has resulted in a better management of ancillary 
services purchased by the unit. 

Between 1970 and 1973, the Program was able to accumulate a substantial poten- 
tial balance in various grant accounts. This is shown in Figure 1, where a- 
vailable funds appropriated plus service patient credits exceeded expenditures. 
It should be noted that these potential balances do not materialize until the 
grant account is closed, a process which is totally dependent on the availa- 
bility of finalized hospitalization rates. Moreover, these balances are cur- po 
rently being rapidly consumed by an expenditure level which exceeds available 
funds, a situation not unlike that occuring in 1969. It is projected that an 
estimated $3.5 million remaining in these accounts will become available during 
FY 1976, thus exhausting the savings accumulated between 1970 and 1973. 

Further substantial savings have been achieved by a 25% decrease in the number 
of personnel supported, from 2,297 positions in 1969 to a current level of 
1,722 positions. The number of supported beds has been similarly decreased 
from 1,051 in 1968 to 827 in 1975. During this same period, the cost per po- 
sition and cost per patient day have nearly doubled (see Table VI on page 89) 



CO 



It is now apparent that with the continuing cost escalation, without concomi- 
tant budget increases, further substantial reduction in GCRC resources must 
now be undertaken and further reductions in number of extramural dedicated 
research beds will occur. Efforts to recover third party payments for both 
research and nonresearch patients will be intensified. However, after all 
possible steps to conserve Program funds have been taken, it is estimated that 
support for 8 to 12 Centers will have to be phased out during FY 1976 and FY 
1977 to establish a balance between expenditures and available funds. 



102 






Fiscal Year 1975 

Annual Report 

General Research Support Branch 

Division of Research Resources 



The General Research Support Branch in FY 1975 administered the General 
Research Support Grant, the Biomedical Sciences Support Grant, the Health 
Sciences Advancement Award, and the Minority Biomedical Support programs. 

GENERAL RESEARCH SUPPORT GRANT 
AND 
BIOMEDICAL SCIENCES SUPPORT GRANT 
PROGRAMS 

T 6 Sf J esearch Support Grant (GRSG) program was authorized by Public 
Law 86-798 which was approved September 15, 1960, and the first awards were 
made in FY 1962. Recipients of GRSGs are medical and other health profes- 
sional schools, hospitals, and other non-academic research institutions. 
In 1966, the companion Biomedical Sciences Support Grant (BSSG) program was 
initiated. This program is conceptually identical to the GRSG program, but 
provides funds to academic institutions other than health professional 
schools. 

The general program objective is to strengthen, to balance, and to stabilize 
Public Health Service supported biomedical and behavioral research programs 
by providing flexible institutional funds on a formula basis to non-Federal 
public and non-profit private health professional schools, universities, 
hospitals, research organizations and other institutions actively engaged in 
biomedical and behavioral research. These funds are to complement and to 
enhance the effectiveness and efficiency of biomedical and behavioral research 
in those institutions. The most distinguishing feature of the program is the 
opportunity provided for grantee institutions to exercise on-site judgment 
regarding emphasis, specific direction and content of activities supported, 
thus enabling the institution to respond quickly and effectively to emerging 
opportunities and unpredictable requirements, to enhance creativity, to 
encourage innovation, to provide for pilot studies and to improve research 
resources, both physical and human. 

This program thus recognizes the need to share resources and to respond to 
opportunities that develop during the course of active, diverse biomedical 
and behavioral research programs and to contribute to the stability of the 
national research effort. 

Grants from this program are intended to support primarily those biomedical 

and behavioral research activities not readily or normally supported by 

PHS categorical research grant programs. Examples of areas of emphasis are: 

• Pilot projects 

• Initial investigations in new fields and in fields new to the 
investigator 

103 



• Unanticpated opportunities and requirements 

• New and more effective patterns of use of resources within and without 
the grantee institution 

» Central shared resources 

Enhancement of investigator's biomedical research skills 

• Expansion of research capabilities through improved research 
opportunities for minorities and women 

• Animal welfare improvement 

Fiscal and Administrative Considerations 

Tables I and II show how GRSG and BSSG funds were used in FY 1973. 



TABLE I 
FY 1973 Expenditure of General Research Support Grant Funds by Activity 

Number Dollars (in thousands ) % of Total Dollars 
RESEARCH PROJECTS 5,706 



New Pilot Proj . 1,118 

Cont. Pilot Proj. 1,244 

New Reg. Res. Proj. 824 

Cont. Reg. Res. Proj. 2,520 



$ 2,887 

3,005 

3,438 

10,050 



10.4 
10.9 
12.4 
36.3 



CENTRAL RESOURCES 

Animal Facilities 
Computer Facility 
General Use Equip . 
Instrument Shop 
Central Lab. Facility 
Photog. and Med. Arts 
Other 



1,461 
680 
990 
398 

1,265 
206 

1,260 



5.3 
2.5 
3.6 
1.4 
4.6 
0.7 
4.6 



RESEARCH TRAINING 



1,165 



4.2 



OTHER ACTIVITIES 
Total 



852 



$27,657 



3.1 



100.0 



104 



TABLE II 

FY 1973 Expenditure of Biomedical Sciences Support Grant Funds by Activity 

Number Dollars (in thousands ) % of Total Dollars 

RESEARCH PROJECTS 1,846 

New Pilot Proj. 425 

Cont. Pilot Proj. 404 

New Reg. Res. Proj. 393 

Cont. Reg. Res. Proj. 624 



$ 601 


13.5 


542 


.12.5 


779 


17.6 


1,102 


24.9 



CENTRAL RESOURCES 

Animal Facilities 
Computer Facility 
General Use Equip . 
Instrument Shop 
Central Lab. Facility 
Photog. and Med. Arts 
Other 



126 
38 

364 
11 

385 

6 

98 



2.9 
0.8 
8.2 
0.2 
8.7 
0.1 
2.2 



RESEARCH TRAINING 



217 



4.9 



OTHER ACTIVITIES 
Total 



154 



$4,423 



3.5 



100.0 



Tables III and IV show for the GRSG and BSSG programs respectively, (1) the 
trend in allowable research grants awarded by PHS to eligible GRSG or BSSG 
institutions (entitlement) since the initiation of the programs, (2) the 
trend in award funds, and (3) the relation between entitlement and awards. 

It can be seen from these data that there has been a steady upward trend in 
entitlement for the GRSG/BSSG programs. The GRSG entitlement base has 
increased seven fold since the start of the program in FY 1962, while the 
amount of money made available for the program in FY 1975 is less than twice 
the amount awarded in FY 1962. In FY 1962 GRSG grantees received 18.48c for 
each dollar of entitlement. This figure dropped to a new low of 4.91c in 
FY 1975. The same trends are reflected in the BSSG program data. In FY 1975 
a new low of 2.86c was paid for each dollar of BSSG entitlement. 



r* 



105 



TAB I.I''. I I I 

CKNKRA1, RESEARCH SUPPORT ( I RANT I'ROCRAM 

Trends in I'HS Research (Irani Awards 

(Entit lements) 1/ and in Ceneral Research Support (Irani Funds, FY 1962-1975 



Fiscal Year 



I'HS Awards 
(Kilt i t lement) 



1962 


$108 


2 34 


000 


1963 


192 


408 


000 


1964 


24 1 


426 


000 


1965 


286 


832 


935 


1966 


320 


415 


167 


1967 


354 


893 


188 


1968 


39 3 


366 


592 


1969 


44 1 


064 


040 


1970 


448 


080 


707 


1971 


430 


721 


426 


1972 


495 


806 


,184 


1973 


577 


966 


,843 


1974 


667 


165 


273 


1975 


756 


,111 


,529 



ORSC Funds 


Ratio (%) 


Awarded 


CRSC/F.nt i Llement 


$20,000,000 


18.487. 


30,000,000 


15.59 


35,000,000 


1 4 . 50 


4 3,985,365 


15.33 


39,200,000 


12.23 


41 ,700,000 


1 1.75 


48,174,445 


12.25 


48,200,000 


10.93 


45,802,000 


10.22 


43,423,000 


10.08 


44,298,000 


8.93 


46,277,000 


8.00 


38,242,000 


5.73 


37,116,205 


4.91 



1/ Previous fiscal year research grant awards received from the PUS by 
dRSd awardees. 



TABLE IV 



I', IOMF.DICAI. SCIENCES SUPPORT CRANT PKOCKAM 
Trends in PUS Research Crant Awards 
(Entitlements) and in BSSC Funds, FY 1966-1975 



1/ 



Fiscal Year 



PUS Awards 
(F.nt i t lement) 



1966 


$ 80,233,656 


1967 


87,564,767 


1968 


108,925,527 


1969 


1 19,007,903 


1970 


12 3,150,660 


1971 


122,385,049 


1972 


138, 129, 124 


1973 


160,949,957 


1974 


174,303,033 


1975 


199,865,5 57 



SSC Funds 


Ratio (7) 


Awarded 


BSSC/ En t i t lement 


5,000,000 


6.237. 


6,000,000 


6.85 


7,500,000 


6 . 8') 


1 ,500,000 


6.30 


7,125,000 


5.79 


6,7 7 7,000 


r . 54 


6,914 ,000 


j.01 


7,223,000 


4.49 


6,007,000 


3.45 


5,7 14,795 


2.86 



1/ Previous fiscal year research grant awards received from the 1*1 IS by 
BSSC awardees. 



106 



P.L. 86-798 states that up to 15 percent of the amount provided for research 
grants for any fiscal year to the National Institutes of Health may be used 
for the General Research Support program. Reports of appropriation hearings 
in both Houses of Congress have repeatedly affirmed the congressional intent 
that ultimately the 15 percent level be made available, but this goal has 
never been reached. As shown in Table V, a high of 8.3 percent was reached 
in FY 1969. Since then the level has declined to 3.7 percent in FY 1975. 



TABLE V 



GENERAL RESEARCH SUPPORT PROGRAM 
(Dollars in Thousands) 









If 


15% were made 


Amount made 




Percent of 


Funds 


Available for 


available for 


available for 


available GRS 


NIH Research 


Grants ±' 


GR£ 


> Program 


GRS Program 1/ 


funds to total 


1966 


$ 


604,377 




$ 90,657 


$45,200 




7.5 


1967 




681,197 




102,180 


51,700 




7.6 


1968 




727,366 




109,105 


59,700 




8.2 


1969 




729,230 




109,385 


60,700 




8.3 


1970 




744,061 




111,609 


57,677 




7.8 


1971 




765,510 




114,827 


54,200 




7.1 


1972 




901,119 




135,168 


55,212 




6.1 


1973 




820,913 1/ 




123,137 


60,700 


2/ 


7.3 


1974 


1 


,091,795 




163,769 


45,149 


3/ 


4.1 


1975 


1 


,142,782 




171,417 


42,957 




3.7 



1/ Thru 1972 includes NIMH 

2/ Includes 33.5 million impounded funds 

3/ Excludes Minority Biomedical Support program funds 






Tables VI, VII, and VIII summarize the distribution of GRSG and BSSG awards 
by categories of institution,' size of award, range and average size of 
award, and amounts of funds awarded each year for Fiscal Years 1968 through 
1975. The average size of awards has declined steadily over this period 
in parallel with a decline in the total amounts of funds awarded, and modest 
increase in number of grantees. 






107 



TABLE VI 
GENERAL RESEARCH SUPPORT GRANT PROGRAM 



Number of Grantees by Type for the General Research 
Support Grant Program FY 1968 - 1975 



Type of 














Revised 




Grantee 


I'Y 


FY 


FY 


FY 


FY 


FY 


FY 


FY 


Inst. 


1968 
95 


1969 


1970 


1971 


1972 


1973 


1974 


1975 


Medicine 


99 


100 


100 


101 


104 


104 


107 


Dentistry 


49 


49 


49 


33 


34 


34 


33 


34 


Osteopathy 


5 


5 


5 














1 


Pub. Health 


12 


12 


12 


12 


12 


12 


12 


12 


Pharmacy 


10 


12 


15 


15 


16 


14 


12 


17 


Ve t . Med . 


15 


17 


17 


17 


16 


15 


14 


15 


Nursing 











2 


4 


3 


4 


5 


Allied Health 

















1 


1 


1 


Hospitals 


71 


75 


79 


76 


79 


71 


66 


71 


Health Dept. 


3 


3 


3 


2 


2 


2 


2 


2 


Res. Inst. 


51 


58 


64 


69 


75 


71 


70 


75 



TOTAL 



311 



330 



344 



326 



339 



327 



318 



340 



108 



TABLE VII 



GENERAL RESEARCH SUPPORT GRANT PROGRAM 

Distribution of General Research Support Grants by Size of Awards 
and Funds Awarded for Fiscal Years 1968 Through 1975 

Number of Institutions 

Size of Grant FY FY FY FY FY FY FY '. FY 
(in thousands ) 1968 1969 1970 1971 1972 1973 1974 1975 

Under - $ 30.0 27 30 49 34 46 17 29 54 

$ 30 - 49.9 54 46 47 51 54 67 63 57 

50 - 99.9 74 80 85 77 78 69 71 73 

100 - 149.9 41 49 41 50 36 41 47 54 

150 - 199.9 40 36 34 36 45 .41. 48 45 

200 - 249.9 21 21 26 25 26 36 22 20 

250 - 299.9 19. 29 31 25 21 19 38 37 

300 - 349.9 13 12 8 8 10 12 

350 - 399.9 13 9 23 20 23 25 

400 - 449.9 9 18 

450 - 499.9 

500 - 599.9 



TOTAL 



311 



330 



344 



326 



339 



327 



318 



340 



Amounts (In Thousands) 



Grant Range 
(All Inst.) 


FY 
1968 


FY 
1969 


FY 
1970 


FY 
1971 


FY 
1972 


FY 
1973 


FY 
1974 


FY 
1975 


Low 

High 

Average 


13 
424 
155 


12 
429 
146 


5 
396 
133 


11 
383 
133 


12 
367 
130 


11 
359 
141 


16 
280 
120 


15 
255 
109 



Total General Research Support Grant Funds Awarded (In Millions) 



FY 
1968 



FY 
1969 



FY 
1970 



FY 
1971 



FY 
1972 



FY 
1973 



FY 
1974 



FY 
1975 



Total Funds 

Awarded $48.2 $48.2 $45.8 $43.4 $44.3 $46.2 $38.2 $37.2 



109 



TABLE VIII 

BIOMEDICAL SCIENCES SUPPORT GRANT PROGRAM 

Distribution of Biomedical Sciences Support Grants by Size of Awards 
and Funds Awarded for Fiscal Years 1968 Through 1975 



Number of Institutions 



A 



Grant Range 
(All Inst.) 

Low 

High 

Average 



Amounts (In Thousands) 



FY 
1968 



FY 
1969 



$36 $ 29 

219 220 

74 68 



FY 
1970 

$ 15 

199 

63 



FY 
1971 

$ 12 

210 

61 



FY 
1972 

$ 15 

212 

59 



FY 
1973 

$ 27 

221 

63 



FY 
1974 

$ 23 

187 

56 



Size of Grants 


FY 


FY 


FY 


FY 


FY 


FY 


FY 


FY 


(In thousands) 


1968 


1969 


1970 


1971 


1972 


1973 


1974 


1975 


Under - $ 30.0 





1 


8 


8 


14 


7 


16 


27 


$ 30 — 49.9 


27 


36 


35 


36 


36 


38 


42 


55 


50 - 99.9 


60 


59 


59 


57 


59 


53 


45 


34 


100 - 149.9 


11 


11 


9 


9 


5 


11 


1 


2 


150 - 199.9 


3 


2 


2 


1 


2 


2 


4 


3 


200 - 249.9 


1 


1 


— 


1 


1 


2 


— 


— 


Total No. of 


















Grants 


102 


110 


113 


112 


117 


113 


108 


121 



FY 
1975 

$ 19 

165 

47 



Total Biomedical Sciences Support Grant Funds Awarded (In Millions) 



FY 
1968 



FY 
1969 



FY 
1970 



FY 
1971 



FY 
1972 



FY 
1973 



FY 
1974 



FY 
1975 



Total Funds 
Awarded 



$7.5 $7.5 $7.1 $6.7 $6.9 $7.2 $6.0 $5.7 



110 



Program Funding 

The FY 1973 appropriation for the GRSG/BSSG programs was $53.5 million. Of 
this amount, $33,576 million was impounded, and then released in FY 1974. 
The President's budget for FY 1974 called for $9,500,000, but the final 
allocation was $44,232,000. The President's budget for FY 1975 requested 
no funds for the GRSG/BSSG program. However, $43,000,000 was appropriated 
for the programs in FY 1975. 

The FY 1975 DHEW Appropriation Bill allocated $43,000,000 to the GRSG/BSSG 
program. The administration proposed a deferral/rescission action for the 
entire $43,000,000, but the proposed rescission was not accepted by the 
Congress. FY 1975 GRSG awards were not made until March, three months later 
than usual, because it was necessary to know the outcome of the rescission 
request. The President's budget for FY 1976 again shows no funding for the 
GRSG/BSSG program. Grantee institutions have been unable to plan their 
research programs effectively in the face of these uncertainties. Expendi- 
tures of grant funds have been delayed and reduced because of reduced and 
delayed funding, and uncertainty of future funding. 

Program Plans 

The Subcommittee on Appropriations for Labor, and Health, Education and 
Welfare, of the House of Representatives, stated during the Fiscal Year 1975 
appropriations hearings, H. R. Report No. 93-1140, pages 45-46, that changed 
circumstances and the passage of time, while not diminishing the need for 
General Research Support, may have modified the program function and need, 
and therefore directed that NIH reconsider the General Research Support 
formulas and guidelines with a view to revising eligibility, and allocation 
and usage of the grants. The Senate Appropriations Subcommittee endorsed 
the request and asked that consideration be given also to support of small 
institutions (Senate Report No. 93-1146, page 67). 



In response to these congressional directives, extensive study was made of 
General Research Support program needs and desired changes by program staff 
and program advisory groups, and public comment was received on proposed 
changes. These actions culminated in recommendations for program modifica- 
tion that were forwarded through the echelons of DHEW to each congressional 
appropriations committee. The major changes that were recommended are: 

1. Merge the General Research Support Grant (GRSG) and Biomedical 
Sciences Support Grant (BSSG) programs into a single program, 
a Biomedical Research Support (BRS) Grant program. 

2. Establish a level of $200,000 in PHS research grants as the 
criterion of eligibility for each institution. Current 
regulations require $200,000 in NIH and NIMH research grants 
for BSSG awards and $100,000 for GRSG awards. 

3. Establish a new formula for the merged program with a maximum 
award of $300,000. 



Ill 



73 
CO 



4. Limit to $500,000 the credit permitted for any one allowable 
PHS grant to which the formula is applied. 

5. Support of research salaries of tenured faculty would be permitted 
only on a short-term basis provided it can be justified. 

6. Supplementation of ongoing PHS research project grants would be 
permitted only for unexpected or emergency needs. 

7. Alterations and renovations of research facilities could be charged 
to the grant not to exceed 20 percent of the BRSG award for the 
current year, or $40,000, whichever amount is smaller. 

8. Require each grantee to establish mechanisms acceptable to the 
NIH to assure: broadly-based review for advice on the use of the 
grant funds; wide dissemination within the grantee institution of 
information about the availability of grant funds and accomplishments 
of the grant; and policies and procedures for strong programmatic 
and fiscal accountability. 

9. Conduct periodic on-site evaluations to assess program performance, 
and to re-evaluate program goals. 

A Biomedical Research Development Grant (BRDG) program was also proposed as 
a companion program to the Biomedical Research Support Grant (BRSG) program 
to assist eligible institutions to establish specific capabilities for the 
conduct of biomedical and behavioral research. 

The purpose of the Biomedical Research Development Grant program would be 
to enhance the achievement of the Federal commitment to discovery of new 
knowledge necessary for better health through research contributions from a 
broader array of institutions. The program is intended for those institu- 
tions that currently have limited involvement in biomedical and behavioral 
research, but possess the necessary potential and can justify such research 
advancement in terms of the national interest and the NIH mission. 

Eligible institutions would be those which receive less than $200,000 of 
direct and indirect costs annually in PHS biomedical and behavioral research 
grant support as required for the proposed BRSG program. 

Biomedical Research Development Grants would be awarded on the basis of 
detailed applications that describe institutional objectives for development 
of biomedical and behavioral research capability, existing strengths and 
weaknesses, and plans to achieve the objectives. 

Up to 10 percent of the funds appropriated and apportioned each year for the 
Biomedical Research Support Grant program (formerly the General Research 
Support Grant and Biomedical Sciences Support Grant programs) , would be 
designated for support of the Biomedical Research Development Grant program. 

Although the Administration's FY 1976 budget message requested no funds for 
GRSG/BSSG, because other biomedical research programs were judged to have a 



112 



higher priority, it is prudent to continue work on issues that confront the 
GRSG/BSSG program because the details of the 1976 appropriation that 
ultimately will be enacted cannot be foreseen. If funding is forthcoming for 
FY 1976, it is planned to make program modifications as stated above. 

HEALTH SCIENCES ADVANCEMENT AWARD PROGRAM 

During FY 1975 the following grantees completed their Health Sciences 
Advancement Award program: 

University of Kansas 
Duke University 
Washington University 

The Health Sciences Advancement Award program is now terminated. A total of 
$26,250,000 was awarded to eleven institutions during the nine years that the 
program was in operation. The following is a summary of these awards: 



Institution Total Awarded 

University of Virginia $ 2,199,571 

Cornell University 1,780 233 

Purdue University 2 542 352 

University of Oregon 2,097,200 

Vanderbilt University 2,491 265 

University of Colorado 2,654,802 

Washington University 2,731,258 

Rice University 2,130 074 

University of Calif, at Davis 2,468,767 

University of Kansas 2,638,288 

Duke University 2,516 190 



Inclusive Dates 
of Support 

6/1/66-12/31/71 

6/1/66-12/31/71 

6/29/67-12/31/72 

6/29/67-12/31/73 

6/29/67-6/30/73 

6/29/67-12/31/72 

6/29/67-6/30/75 

6/19/68-5/31/74 

6/19/68-3/31/74 

6/1/69-5/31/75 

6/1/69-5/31/75 



Evaluation of this program is desirable; however, this cannot be undertaken 
with the present staffing. 






113 



MINORITY BIOMEDICAL SUPPORT PROGRAM 



A. Introduction 



Historical 



The Minority Biomedical Support (MBS) Program was deemed necessary 
in order that ethnic minorities may have equality of opportunity 
to participate in biomedical research. The Division of Research 
Resources launched this program in 1971 and made the first awards 
in June of 1972. Accordingly, the program is intended to encourage 
increased involvement of ethnic minority students and faculty in 
the biomedical sciences and in health professions so that the 
nation can benefit from this untapped resource. 

2. Goals of the Program 

The most important of all research resources are people. Minorities, 
a large segment of the talent in this country, have been an untapped 
resource for enhancing biomedical research. The NIH has elected 
to tap this resource through the MBS Program. 

The program goals are: to increase the numbers of ethnic minority 
faculty, students and investigators in the biomedical sciences 
and to broaden the opportunities for research and research partici- 
pation by ethnic minorities. The MBS Program is the NIH's major 
effort in providing opportunities for minorities to participate in 
biomedical research. This is a recognition that minority biomedical 
investigators can make a significant contribution to furthering the 
mission of the NIH and should be provided that opportunity. 

B. Program Highlights 

The MBS Program is an entirely new program to the NIH and thus has been 
experimental and changing in nature. It is unique in that it is 
centered in institutions that generally have not been NIH grantees and 
have had minimal biomedical research involvement. It is also unique 
in that one of the main elements of the program is undergraduate research 
participation. Undergraduate students are intimately involved in 
biomedical research with faculty at the grantee institutions and parti- 
cipate in all aspects of the projects including publishing and presenting 
papers at scientific meetings. 

1. Th e Xavier MBS Symposium 

Xavier University in New Orleans, through their MBS grant, conducts 
an annual symposium where MBS participants present papers on their 
research. There has been a tremendous increase in the number of 
participants attending and the number of papers presented since 
the first symposium was held in 197 3. The following table 
indicates the growth. 



114 



TABLE I 

1973 1974 1975 

Numbers attending 250 470 900 
Papers presented 76 165 280 

The quality of the papers has improved to a point that in 1975 
they were comparable to those presented at most other scientific 
meetings. (According to comments of NIH staff and members of the 
General Research Support Program Advisory Committee (GRSPAC) who 
were in attendance in 1975.) 

2. Funding of MBS Projects by NCI and NHLI 

During the latter part of FY 74 and FY 75, staff of the MBS Program 
and of the National Heart and Lung Institute (NHLI) met several 
times to negotiate an agreement whereby the Division of Lung 
Diseases would fund those MBS projects. that were deemed apprppriate 
for the mission of the Division of Lung Diseases, NHLI, and which 
had been reviewed and approved by the General Research Support 
Program Advisory Committee, National Advisory Research Resources 
Council, and the National Advisory Heart and Lung Council. The 
NHLI invited MBS program directors to come or send a representative 
to a meeting at NIH where the programs of the Division of Lung 
Diseases were described. Minority institutions were encouraged to 
submit projects through the MBS Program for funding by NHLI. Several 
were submitted but none were approved. However, the NHLI did identify 
two ongoing projects which they wished to fund. Subsequently, the 
other Divisions of NHLI agreed to follow the agreement between MBS 
and the Division of Lung Diseases. In summary, the NHLI has funded 
three MBS projects totaling about $113,696 in FY 75. A formal 
agreement was signed to the effect and the NHLI will continue its 
efforts to identify other projects and encourage MBS grantees to 
submit new projects for review. 

A second agreement was also made with the National Cancer Institute 
(NCI) whereby six cancer-related research projects were approved 
for funding by the National Cancer Board in their March 1975 
meeting. 



115 



o 









A list of the projects funded by each institute follows: 

TABLE II 

NHLI Funding Agreement 

FY 75 FY 76 FY 77 FY 78 

Charles R. Drew 

Post Graduate 

Medical School 

Dr. Niden 35,419 24,113.1/ 23,652 1/ 

New Mexico State 

University 

Dr. Bernstein 53,490 23,621 1/ 24,054 1/ 

Tuskegee Institute 

Dr. Dixon 24,787 26,341 1/ 26,612 1/ 10,997 1/ 



NCI Funding Agreement 

Texas Southern 

University 

Dr. Session 96,510 98,102 

Dr. Guilford 24,675 24,765 

Tennessee State 

University 

Dr. Hogg 62,886 

Norfolk State College 

Dr. Bempong 43,145 49,091 

Catholic University 

of Puerto Rico 

Dr. Correa 25,415 37,099 

Charles R. Drew 

Post Graduate 

Medical School 

Dr. Alfred 38,523 43,341 



1/ Indirect costs not included 



116 



3. Expansion of Eligibility 

On December 30, 1974, the proposed regulations for the MBS Program 
were published in the Federal Register. The regulations extended 
the eligibility to institutions other than the traditional minority- 
institutions. Eligibility was extended to: (1) four-year insti- 
tutions with significant but not necessarily over 50 percent minority 
enrollment, provided they have a history of encouragement and 
assistance to minorities, (2) two-year colleges with 50 percent 
minority enrollment, and (3) American Indian Tribal Councils ... 
(see regulations . ) 

These regulations were promulgated to provide opportunities to the 
numerous minority students who are not enrolled in the traditional 
minority institutions but are also in need of the same opportunities. 
This was deemed necessary to provide a program balance by geography 
and different ethnic minorities. Comments on the proposed regu- 
lations were received and final amended regulations were submitted 
for publication. 

4. Other Program Related Activity 

Several presentations about the MBS Program were presented at the 
request of outside groups. In September 1974, the University of 
Connecticut and Chicago State University requested that an MBS 
staff member be present at a meeting in which these two institutions 
would discuss a cooperative plan for minority research participation. 
MBS grantees are now involved with the University of Connecticut in 
research participation at Storrs, Connecticut. The effort is 
jointly financed by MBS grant funds at the MBS grantee institutions 
and by the University of Connecticut. An exchange of faculty has 
been planned. 

The American Biophysical Society invited the Acting Director, MBS 
Program, to participate in a symposium at their annual meeting in 
Philadelphia. The presentation described the MBS Program and its 
impact, in the minority institutions. A presentation was also made 
to a meeting of representatives from the American Association of 
State Colleges and Universities at their request. 

A request was received from Radio Station WGMS in Washington to 
discuss the MBS Program and the role of minorities in the sciences. 
A taped interview was prepared for broadcast in several local 
stations throughout the country. 

In April the MBS Program staff participated in planning and carrying 
out the NIH Minority and Women's Conference in Bethesda. 

C. Program Status 

1. Numbers of Minorities Participating in the MBS Program 



117 



As shown in Table III, there has been a marked increase in minority 
participation in biomedical research through the MBS Program. The 
increase is attributed to support of released time to faculty and 
financial support to students who collaborate with the faculty in 
biomedical research projects. Other support such as equipment, 
travel, supplies, and consultants has also made it possible for 
minority faculty and students at grantee institutions to carry out 
biomedical research. 



No. faculty 

No. undergraduates 

No. graduates 

No. postdoctorals 

Total participants 

Total support 

Total No. of grantees 





TABLE 


III 








1972 




1973 


1974 




1975 


199 




358 


499 




589 


288 




643 


906 




1,008 


44 




94 


143 




184 


1 




— 


2 




3 


532 




1,095 


1,550 




1,784 


2,000,000 


5,000,000 


8,000,000 


1/ 


7,662,964* 


s 38 




51 


66 




74 



1_/ Includes $1 million impounded FY 73 funds 



As was the case in FT 74, this year there were several supplemental 
applications received. Program balance and limited funds and 
disapprovals placed constraints on the number that would be funded. 

An indication of the types of applications funded is illustrated 
in Table IV. 



Type 1 
Type 2 
Type 3 
Type 5 

TOTAL 



TABLE IV 






S Awards FY 


1975 




No. 




Amount 


7 




$1,182,446 


5 




356,289 


56 




6,124,229 


68 




$7,662,964* 



* Includes $341,964 from NCI and NHLI for support of 
individual projects in those areas related to NCI and 
NHLI and $57,000 derived from reprogrammed funds 



118 



2. Policy and Procedural Changes 

In reviewing applications, experience dictated a change in require- 
ments for project descriptions. Staff revised the format for 
submitted research project protocols to conform to the format used 
by the Division of Research Grants. This resulted in better project 
descriptions that have been easier to review and consequently 
improved the track record of approved projects. 

A new policy in program management was instituted to deal with 
emerging problems where investigators were leaving the institution 
and the grantees were requesting approval for substituting new 
investigators. Any new project investigator must now submit a 
complete application for peer review through the MBS Program prior 
to becoming eligible to participate in an ongoing program where 
funds have become available through attrition or other means. 

Review procedures will involve rating of individual projects as to 
scientific merit and ability to meet MBS goals. This will be done 
during the site visit or by the primary reviewers prior to being 
considered by the GRSPAC. 

A revision of the MBS Policy and Information Statement was initiated 
and is being continued. Much of the revision will relate to the 
published regulations and the present considerations on evaluation 
and renewals by the GRSPAC. 

D. Program Evaluation 

During FY 1975 a concerted effort was made by staff to make detailed 
reviews of progress reports in order to set up a scheme for evaluating 
the program. In cooperation with MBS staff, the Program Analysis Branch 
developed data collection forms to reflect the information needs for 
an evaluation and the capturable data from progress reports. A trial 
run with a sample of grants was made as a test of the efficacy of the 
data collection sheets. The system is now being implemented for 
capture of data from FY 74 progress reports. 

Staff and members of the advisory committee developed a document listing 
data and information that would be useful in evaluating the program. 
These items were developed specifically to determine whether specific 
goals are being met by the program. A final document will be developed 
in early FY 76. The plan is to have it ready by the fall of 1976. 

E. Future Plans and Perspectives 

During the April meeting of the advisory committee, a discussion 
document on policies and criteria for renewal applications was considered 
and recommendations made. The committee recommended criteria to be used 
in evaluating the ongoing grants and in reviewing renewal applications. 
The recommendations included a need for continuing the program at some 



...-,_, 



119 



of the present institutions after the end of the present five-year 
project period. 

Criteria for the MBS Program evaluation will be developed early in 
FY 76. Policies and guidelines for renewal applications will be 
readied for anticipated applications in the fall of 1976. 

In the future the MBS applicants will be required to use the NIH 398 
forms for submitting applications. An addendum to the instructions 
for completing the NIH 398 form will be readied for next fall. A 
deadline of October has been specified by OMB. 

During FY 1976, a revised policy and information booklet will be 
completed. This will have to incorporate the published regulations, 
evaluation criteria, and criteria and policy on renewal applications. 

Expanded interfacing and cooperative agreements with other Institutes 
besides NCI and NHLI will be explored as well as increasing the 
activity with NCI and NHLI using a consultant slot from NCI for 
programming cancer-related projects. 

Expected increased interaction with other categorical institutes will 
require that MBS staff become acquainted with their programs and 
policies. Priority in training requests will be given to this aspect 
of staff enrichment. 

A major effort will be made to program applications from the new 
eligible institutions in order to achieve a better program balance. 

It is expected that budget constraints will limit the opportunities to 
expand the program to those institutions that have become eligible 
with the new regulations. The requested budget for FY 1976 is 
$7,165,000. This level will be just enough to fund our ongoing 
commitments. Unless the appropriation is larger than the requested 
amount, the only source of funds for the new eligibles would be from 
funds released as a result of projects funded by NCI and NHLI. 



120 



Fiscal Year 1975 Annual Report 

Program Analysis Branch 
Division of Research Resources 



The Program Analysis Branch is responsible for assessing the Division's data 
requirements and structuring an appropriate Division-wide data base to 
support decision making in the various program areas. This includes 
application of system analysis and design, maintenance of data in systems 
and employment of appropriate systems to produce reports, records, graphics 
and statistics for purposes of planning, developing and assessing programs. 
During the past year, PAB has expended a major effort to meet the Division's 
requirements for an integrated information management sytem as indicated 
by the following progress. 

1. A system for the expansion of data collection on the Minority 
Biomedical Support Program has been developed, tested, approved 
and implemented. Procedures have been established for capturing 
the scientific research projects, trainee and personnel-support 
data, and a fact sheet of useful items has been prepared. 

2. The Biotechnology Resources data system was expanded to collect 
the expenditures data from the Report of Expenditures instead of 
the Progress Report. 

3. The General Clinical Research Centers data items on the master 

, file were reviewed and revised to include newly identified items 
as well as to purge certain non-used data elements. Programs 
have been written to produce several reports previously prepared 
by hand, i.e., ROE worksheet, Budget worksheet. 

4. The Animal Resources Branch with PAB assistance has developed, 
reviewed and adopted a research project summary report for the 
Primate Centers as well as the Laboratory Animal Sciences Program, 
where appropriate and with modifications for various types of 
resources. Although the Primate Centers data is being received, 
procedures for editing have to be developed before collection 
begins. Also data collection from the Report of Expenditures have 
been implemented. 

Over a 3-4 month period, PAB worked closely with Program Staff and review 
committee members for the General Research Support (GRS) program to provide 
data for a number of revisions in the GRS procedure for determining awards. 
PAB adapted several computer programs and subroutines to produce experimental 
manipulation of the GRS and BSS data in order to analyze the effect of 
various alterations of the formula and the resulting impact on the GRS and 
BSS programs. The package of various analyses showing the possible effects 
of program changes was presented to the review committee and to the advisory 
council. 

The PAB continues to meet with the General Clinical Research Centers Branch 



121 






in developing criteria tor the acquisition of appropriate data to be used in 
assessing scientific programs. A great deal of data was provided and data 
programming changes made to assist the program in responding to the concerns 
of the House of Representatives Appropriation's Subcommittee in the occupancy 
rates for the program. 

This year PAB has worked on an entirely new and more compact version of data 
to be published as "Division of Research Resources Handbook." This will be 
a compendium of current and historical data on the awards of the Division 
and its five programs. It presents a brief description of the goals, 
objectives and general activities of the Division's programs with graphs and 
tables to reflect the magnitude, scientific and technical diversity, 
geographical coverage and general vitality of the offered programs. This 
publication constitutes a merger and revision of two previous publications — 
the "Research Resources Grants" booklet and the "Handbook for the National 
Advisory Research Resources Council." 

Other products derived from the computer based system includes the General 
Research Support Expenditures Booklet which shows the expenditures data 
over a six-year span as tabulated from the Annual Report of Expenditures 
filed by all recipients of General Research Support. The booklet includes 
summary tables for all types of institutions according to the type. A 
similar publication produced in PAB is the Biomedical Sciences Support 
Program Expenditures Booklet . 

For some time PAB staff has participated in the ECEA Subcommittee study of 
center grants and program projects. A sampling strategy and several study 
techniques were developed, described and incorporated into a final report 
submitted to the OAERT, OD, NIH. 

As DRR requirements for a mission evaluation study began to develop, PAB 
became involved in computer processing and analysis of sets of questions 
which described the general and specific objectives of the study. PAB 
developed a taxonomy for the questions and participated in the development 
of the RFP. 

Requests which come to DRR for information or support of large fields of 
research are usually handled centrally in PAB. This year a number of these 
were processed for such subject areas as genetics, nutrition, population 
research, heart and lung disease, digestive diseases, eye research, clinical 
research, and others. 

The Branch has responded to a large number of inquiries for data which are 
located and maintained by DRG. PAB has written queries to obtain on a 
regular basis such information as active NIH/ADAMHA research grant support 
at selected institutions, grants with $10,000 or more awarded for Hospital- 
ization, and NIH grant support in schools of veterinary medicine. The CRISP 
files were assessed to obtain information on grants using primates. Appli- 
cation and award data is obtained from DRG's IMP AC system and prepared in 
a booklet form for each round of the National Advisory Research Resources 
Council. 



The above exemplify some of the Program Analysis Branch's efforts to meet the 

122 



Division's requirements for data reporting and program evaluation as they fit 
into the decision making process. During the coming year PAB will continue 
to study the Branches' data needs in order to expand its data base for 
analysis and/or develop systems or revised procedures. Future plans include: 

1. Examining the specific output requirements of program and committee 
staff. 

2. Establishing a procedure to analyze and link DRR resource user's 
to other components of NIH. 

3. Educating staff as to what data is available, where and under what 
constraints. 

4. Reviewing and evaluating the PROPHET00 system as an element in the 
Division's Integrated Information Management System. 



123 



_ . 



Office of Science and Health Reports 

Operating in close cooperation with Xavier University of New Orleans which 
provided pictures and background, the Office produced a news story, with 
photos, on the 3d Annual Xavier Minority Biomedical Support Symposium These 
went to a representative minority press list throughout the United States. 

Earlier in the year, feature news stories on the Minority Biomedical Support 
program were written and placed in Lab Animal , Laboratory Management, 
Bioscience , and American Druggist . 

An Office-generated MBS feature also appeared in Vogue Magazine, and United 
Press International carried a MBS-related news story, headlined "Alligator 
Tongue Oil May Aid Arthritis Sufferers." This story was widely carried 
Placements included the Miami Herald ; the Camden Courier ; Cleveland Press ; 
Amarillo, Texas, Globe Times ; Science Digest ; the Providence Journal; and 'the 
New Orleans Times-Picayune . 

FASEB's Federation Proceedings ran an Office-written two-page spread on the 
2d Annual Symposium which dealt in-depth with its varied activities. 

During the year, a news release on new MBS grants appeared in the Birmingham 
Times. It proclaimed "Black Alabama Schools Get HEW Grants." Similar local 
angles based on an Office story appeared in the Harlingen, Texas, Valley Star, 
the McAllen, Texas, Valley Monitor , and the Miami, Fla., Times , plus numerou? 
other papers. 

The Message Magazine carried several references to the MBS program as part of 
a major article on "Outstanding Black Scientists." It was reprinted for 
distribution 

The Office arranged for the publication of a full -page treatment on the 
Minority Biomedical Support program in the "Letters" section of Science 
Magazine. This insertion included correspondence from Dr. Thomas G. Bowery 
and also Dr. Joe Johnson, MBS program director at Atlanta University. 

In the audiovisual arena, the Office produced approximately 200 slides for 
the Division's "interfacing" presentations with other institutes. The slides 
were carefully designed to convey maximum information about DRR's programs. 
Assistance with the structure, design, and delivery of the program presen- 
tations was provided. In addition, the Office produced color prints of the 
slides for the Director to present to the home Institute, and black and white 
(and color) prints for interested Institute viewers. As the year ended, the 
DRR "interfacing show" had been seen by the top staff of NHLI, NIAID, NICHD, 
NIDR, and NINDS. Plans were being made to continue the series in the fall. 

An editorial sparked by the Office in Lab Animal plugged DRR's "Cost Analysis 
and Rate Setting Manual for Animal Resource Facilities." The magazine wrote: 
"The problem is that (with few exceptions) cost accounting is a low priority 
item in most laboratory animal facilities. To its credit, the National 
Institutes of Health's Division of Research Resources has recognized this 






125 



fact. Even more to its credit, DRR has done something about it. . . Single 
copies of this manual may be obtained free of charge from Animal Resources 
Branch, Division of Research Resources. . . We strongly recommend that every 
laboratory animal facility director avail himself of this offer." 

The Office made arrangements for the placement and editing of an article in 
Lab Animal on the Primate Information Center at the Washington Primate 
Research Center. Authored by Maryeva Terry, the piece, titled "An Information 
Resource for the Biomedical Prima tologist," gave worldwide publicity to this 
unique resource. In addition, the Office wrote a Primate Information Center 
article for NIH News and Features and the NIH Record . 

A picture of a Japanese macaque standing erect on a pole at the Oregon Primate 
Center went out over the United Press Wire; it appeared on the front page of 
the Washington Star-News , in numerous other papers, and in Bioscience . 

A copy of the Office-produced "UCLA Health Sciences Computing Facility" book- 
let was sent to each of the 1,076 persons on the Association for Computing 
Machinery's SIGBIO mailing list, together with a letter. The Information 
Officer bylined an article in the Federation Proceedings on the facility, 
the NIH Record ran a center spread with 12 pictures; the NIH News and Features 
ran a UCLA Health Sciences Computing Facility story with pictures; the NIH 
Search for Health sent a four-part series on the UCLA Center to over 500 news- 
papers . 

A one-minute television spot on good laboratory animal care, which the Office 
or Science and Health Reports had helped to develop in conjunction with the 
American Association for Laboratory Animal Science, was given by AALAS members 
to 58 television stations across the United States. It appeared on KDKA-TV, 
Pittsburgh; KMBA-TV, Raleigh; WMBA-TV, Kansas City; WKBW, Buffalo; WCTV, 
Tallahassee; as well as other stations. It will be sent to another 125 
stations throughout the U.S. this summer. 

Requests for Division booklets continued to be strong, with the majority of 
requestors interested in our clinical research center booklets: "Research 
Advances in Human Transplantation" and "How Children Grow." Over 21,450 
publications were distributed by the Office during the fiscal year. They 
were mailed as a result of 4,875 individual requests. Among these were 43 
requests from Congressmen for almost 1,400 booklets. Bulk requests for "How 
Children Grow" included: 60 copies for in-service training of parent 
education staff members in the Sacramento School District; 25 copies for the 
Family Nurse Practitioner Program at the University of North Carolina; and 50 
copies to elementary and special education teachers at Illinois State 
University. About 4,000 copies of "How Children Grow" were distributed at 
the NIH Open House. 

An Office photo featuring Trick and Treat, a pair of baby orangutans cared 
for by the Wisconsin Primate Center, was carried over the United Press 
International wire; the duo also appeared in Lab Animal and were featured 
on the cover of the spring 1975 issue of RAR News. 



126 



A primate breeding story, datelined Fredrick, Md., quoted the Animal 
Resources Program Chief, Dr. Charles McPherson. The AP story said- 
"American scientists, facing a monkey shortage, have embarked on a pi an 
to make the U.S. self-sufficient in the production of non-human primates 
for laboratory experimentation." A domestic breeding contracts story was 
placed in Federation Proceedings , and the shortage of primates for biomedical 
research was front page material in the NSMR Bulletin . 

For the Animal Resources Program, the Office produced a beautiful new exhibit 
pegged to the "Laboratory Animal Care" educational series. Using a "LAC = 
Better Staff Skills" theme, the new exhibit featured a filmstrip projector 
and listening island" for interested professionals to view the series The 
new show was exhibited by the Office and Animal Resources staffers at the 
American Association for Laboratory Animal Sciences Convention in Cincinnati 
and the Federation meetings in Atlantic City. 

Additional promotion for the "Laboratory Animal Care" educational series 
included a cover article, written and photographed by the Office for Lab 
Animal Magazine. Featured on the cover was Dr. Joseph Spinelli, creator of 
the series, who was interviewed and photographed by the Office in California 
The long interview, titled "A New Audiovisual Program for Supervisor and 
Technician Training," was reprinted for distribution at the new exhibit. 
While on assignment, the Office staffers photographed animal caretakers at the 
California Primate Research Center. This photo, together with a promotional 
article, appeared in the Federation Proceedings , News and Features from NIH, 
and the NSMR Bulletin , among other publications. ' 

While on assignment in California, the Office photographed Dr. Joshua 
Lederberg, Nobel Laureate, and helped plan the dedication of the Stanford 
University Experimental Computer (SUMEX), funded by the Biotechnology 
Resources Program. The Office cooperated with the Stanford News Bureau on 
the dedication story. The photo of Lederberg and our news feature appeared 
in Medical Group News, Laboratory Management , NIH News and Features, and the 
NSMR Bulletin . 

An Office-created article together with photo of an infant with Menkes Kinky 
Hair Syndrome, told the story of the treatment of the boy's defect with 
copper at a clinical research center. It appeared in the Medical Tribune , 
the HIH Record , and News and Features from NIH . 

Late in the year, the Office worked with Dr. Charles McPherson in the develop- 
ment of a bylined article on laboratory animal diagnostic laboratories, 
exclusively for Lab Animal . The Office arranged for placement and supplied 
camera-ready art from the "Do We Care?" flyer to be used on the froit cover. 
Also appearing in this issue was an article promoted by the Office on sea hare 
mariculture by Dr. Michael G. Hadfield of the Kewalo Marine Laboratory in 
Hawa i i . 

The Office was responsible for radio interviews of DRR personnel on three 
occasions during the year. Dr. William Goodwin was interviewed by Fred Fiske 
on Station WWDC for his Empathy Program. (Washington Metropolitan Area). 
Both Dr. Thomas G. Bowery and Dr. Ciriaco Gonzales were separately interviewed 



127 



by June Carter Perry on WGMS for her Heritage Program. This program was aired 
in Washington D.C., New York, Chicago, Los Angeles, San Francisco, Fort 
Lauderdale, Boston, and Memphis. 

As the year drew to a close, the Office had made arrangements for the complete 
July issue of the Federation Proceedings to be devoted to research activities 
at Division-supported Primate Research Centers. The Information Officer and 
the Primate Centers Chief authored the introductory article. Along with the 
special issue, a press briefing will be held, a trade press story written on 
one article, and a news release completed on another paper. 

These various activities were selected to show the span of the Office's work 
during the year. This report does not address itself to the many other 
individual placements and projects, too numerous to mention, in which the 
Office was involved. 



^ 



128 



DIVISION OF RESEARCH SERVICES 

Report of Program Activities 
July 1, 1974 through June 30, 1975 

CONTENTS 

Page 
Division of Research Services 1 

Biomedical Engineering and Instrumentation 9 

Individual Project Reports 

1. Pharmacokinetics 23 

2. Implant Device Development 26 

3. Trace Element Analysis in Biological Materials 28 

4. The Role of Fluid Dynamics and Mass Transfer in 

Development of Atherosclerosis 30 

5. Mult i component Plastics in Biomedical Use 32 

6. Thermomi orography 33 

7. Investigation of Oxidative Metabolism and 

Potassium Kinetics in the Cat Brain 34 

8. Diagnostic Ultrasound 36 

9. Nuclear Magnetic Resonance Techniques for 

Biochemical Analysis 39 

10. Measurement of Low Level, Rapid Chemical Reaction Rates 
by Laser Jump, Temperature Jump, and Stopped Flow 

Techniques 41 

11. Electrical Safety Program for Clinical Center 

Patients and Patient Care Areas 43 

12. Atraumatic Electrical Sensing in the Human Brain 

Cortex 45 

13. In Vitro Muscle Studies /Hypertrophy 47 

14. Neural Trauma 49 

Environmental Health and Safety Program 51 

Environmental Services Branch 59 

Radiation Safety Program 67 

Safety Management Program ' 77 

Library Branch 83 

Medical Arts & Photography Branch 91 

Veterinary Resources Branch 95 

Individual Project Reports 

1. Genetic Analysis and Animal Model Development 115 

2. Development of Diets for Laboratory Animals 117 

3. Selection for 6-Week Weight in Inbred and Noninbred. . . . 119 

4. Tyzzer's Disease 121 

5. Suppression of Pseudolymphoma in NZB Mice with 

Syngenic Young Thymocytes 123 

6. Different Levels of Dietary Protein for Laboratory Rats. . 124 

7. Environmental Toxicosis of Rhesus Monkeys — 

Perrine Primate Facility 125 



1 



Page 

8. Neoplasia in the Nude Mouse 126 

9. Sodium Cyanate Neurotoxicity in Macaca Nemastrina 

Primates " \ \ ] vp7 

10. Erythrocebus Patas Monkey as an Animal Model for 
Cardiovascular Research 128 

11. Effect of Season on Pituitary and Gonadal 

Hormone Levels in Adult Male Macaques 130 

12. Hormone Level During the Postpartum Interval 

in Nursing and Non-Nursing Macaques 131 

13. Mycoplasma Induced Caprine Keratoconjunctivitis 132 

H. Evaluation of Efficacy of M. Bo vis PPD Teberculin'to 

Detect Tuberculosis in Wild Caught Indian Macaca Mulatta 133 
15. Defining the Nude Mouse Model 235 



NATIONAL INSTITUTES OF HEALTH 
DIVISION OF RESEARCH SERVICES — DR. JOE R. HELD,. DIRECTOR 



Report of Program Activities 
July 1, 1974, through, June 30, 1975 



A. Objectives 



The Division of Research Services supports, other. NIH components by providing 
centralized scientific, technical, and engineering services essential to 
biomedical research. Division programs function through a staff of pro- 
fessional and technical personnel organized into five functional areas: 
Biomedical Engineering and Instrumentation, Environmental Health and Safety, 
Library, Medical Arts and Photography, and Veterinary Resources. 

B. Current Programs 

A broad range of central research, support services and products are provided 
by the Division of Research Services. These currently include: 

1. The application of engineering principles and techniques to the 
solution of biomedical problems. 

2. The design, fabrication,' and maintenance of special research in- 
struments . 

3. Environmental surveillance to detect and eliminate conditions 
adverse to conducting high quality research or hazardous to 
patients, employees, or the community. 

4. Surveillance of biohazards, control of radioactive materials and 
maintenance of health and safety programs, 

5. Library and bibliographic services. 

6. Foreign language translation. 

7. Still photography and motion picture production. 

8. Graphics arts services and exhibits, design. 

9. Medical illustration and model making. 

10. Animal production, procurement, conditioning and holding.. 

11. Animal health services. 

12. Experimental surgery and related activities. 

13. The production of tissue cultures, microbiologic medias and ani- 
mal biologies. 

14- Central processing and sterile preparation of laboratory glassware. 

C. Program Progress and Accomplishments 

1. Biomedical Engineering and Instrumentation 

Fiscal Year 1975 emphasized the refinement and extension of techniques in- 
novated in previous years. Engineering design together with novel fabrica- 
tion processes provided NIH with instrumental methods of unprecedented ver- 
satility. The ability of the Branch to promptly respond to intramural re- 
search demands was hampered by staff curtailments and associated personnel 
constraints; the quality of BEIB contribution's, however, was not compromised. 

1 



Mathematically based systems modeling and prediction, verified for animals 
were successfully applied to human toxicology and therapy. Cytokinetic, 
pharmacokinetic, and pharmacodynamic bases for cancer chemotherapy were 
placed in quantitative perspective and used to explore alternative routes 
of drug administration, e.g., intrathecal and intraperitoneal, to seek 
optimal regimens. New methods for quantitative detection of trace metals 
in biological fluids were developed to better characterize environmental, 
diagnostic and therapeutic exposure of man to metallic ions. 

Significant advances were achieved in ultrasonic imaging of structure and 
function in the cardiovascular system together with improved techniques for 
non-invasive blood flow measurement of unprecedented accuracy and precision. 
Ultrasonic methods were extended to ophthalmological scanning for diagnos- 
tic and therapeutic purposes. Quantitative measurements of cortical metab- 
olism via televised fluoroscopy opened new avenues for the investigation 
of CNS physiology. 

An important breakthrough was achieved by the completion of a microelectrode 
positioner that enables long term stable recordings of action potentials 
from a single neuron in the exposed pulsating cortex of animals and humans. 
A comprehensive set of instruments for ophthalmological surgery, including 
remotely controlled surgical tools, syringes, fluid exchangers and retinal 
suturing devices were provided to extend the capabilities of the eye sur- 
geon and make his task easier. 

2. Environmental Health and Safety Program 

a. Office of the Associate Director for Environmental Health and Safety 

The transfer of the Radiation Safety Section, Department of Nuclear Medi- 
cine, Clinical Center, to the Division of Research Services as the Radia- 
tion Safety Program, took place on July 1, 1974. On the same date, the 
Safety Management Program transferred to DRS. On December 23, 1974, the 
Associate Director was appointed and given responsibility for the develop- 
ment of a well-integrated, comprehensive and centralized environmental 
health and safety program. Further progress toward centralization of func- 
tions was made on March 1, 1975, when the responsibilities for implementa- 
tion of the National Environmental Policy Act (NEPA) were assigned to the 
Associate Director. 

b. Environmental Services Branch 

Sixteen EPA effluent guidelines and several non-DHEW environmental impact 
statements were reviewed for the Office of the Assistant Secretary for 
Health, DHEW. Staff assistance was provided to the Division of Engineering 
Services in preparing the environmental assessment of the NIH Master Plan 
involving approximately sixteen construction projects. 

Staff assistance was provided to the Assistant Director for Administration, 
NIH, in the Generic Analysis of all NIH programs. Staff also served on a 
task force of the Assistant Secretary for Health, DHEW, to develop proposed 
Departmental regulations and procedures for implementation of NEPA. 



The national concern for employee health and safety was reflected in the ESB 
workload. Thirty- two employee requests were investigated concerning suspect- 
ed hazards in their work places and three extensive surveys were conducted 
for requested Environmental Differential Pay. Three formal OSHA complaints 
were also reviewed and 108 other laboratory surveillance visits directly 
related to employee health were made. 

c. Radiation Safety Program 

The Nuclear Regulatory Commission issued seven licenses to NIH for the use 
of radionuclides. Possession of these licenses has greatly reduced the de- 
tailed problems of isotope procurement, but carries strict responsibilities 
governing use and ultimate disposal. 

License renewals and amendments were obtained to permit the installation of 
two irradiators at the Clinical Center, one of 24-00 curie capacity, the other 
of 500 curie. 

Radioactive waste volume increased by 31% for the reporting period. Im- 
provements in the waste handling area consisted of equipping the waste com- 
pactor with a HEPA filter to prevent radioactive aerosols from escaping 
into the work environment, and of installing a ventilated hood for the stor- 
age of volatile radioactive wastes. 

Laboratory surveillance was maintained at a high level and carried out in 
the nearly 1500 areas where radioactive materials are being used. Strong 
emphasis was placed on the control of airborn radioactive substances. The 
number of air samples taken increased by 271% over the previous fiscal year. 
Investigation and remedial action took place where contamination was found. 

The Radiation Safety Program, continued to provide training in the safe hand- 
ling of radioactive materials. Over 850 individuals attended training cour- 
ses, most of them the one-day course entitled, "Radiation Safety in the 
Laboratory. " 

d. Safety Management Program 

Accident investigations were conducted on a continuing basis by safety spe- 
cialists. The NIH accident and injury reporting system continued during 
the reporting period to function on a recognized better level than most 
DHEW agencies. The close coordination of this activity with the Employee 
Health Service and other branches kept reporting close to 100%. Wherever 
necessary, remedial action was taken and recommendations were given. Fire 
prevention continued to be of major concern. A report, "NIH Fire Safety 
Posture", was completed. In it, each building on the NIH Bethesda location 
is described and discussed with regard to fire safety. The report provides 
a basis for eliminating fire hazards and for up-grading NIH facilities to 
prevent losses from fire. 

There was a wide range of training activities throughout the year. An im- 
portant part Is the new employee orientation for Clinical Center and ADA 
personnel. 

3 



'',. Library Brvinch 

The Library Advisory Committee met three times during the year. Dr. Philip 
McMaster, NIAID, was appointed Chairman in February replacing Dr. John S. 
Finlayson, BB, who had served in that capacity for several years. At the 
same time the Committee was enlarged to 17 members with representation from 
al] l/D's. 

On February 24, the Supreme Court, by a tie vote four to four, with Justice 
Blackmun disqualifying himself, affirmed without opinion the U.S. Court of 
Claims decision in the case of Williams and Wilkins vs. the U.S. that large- 
scale unauthorized photocopying and free distribution of copyrighted medical 
journal articles by NLM and the NIH Library are not copyright infringements. 

Effective November 1, the Technical Services Section was reorganized into 
two units, the Monographs Processing Unit and the Journals Processing Unit 
replacing the Acquisitions and the Cataloging Units. 

The Library became a member of the Ohio College Library Center's shared 
cataloging automated network system through the Federal Library Experiment 
in Cooperative Cataloging. 

A nonprint collection was organized. Current audiocassettes, tapes and 
slides were added to previous microform holdings and are available for use 
in the Library or for loan. Newly acquired nonprint items are included in 
the monthly memorandum of additions to the Library. 

4 . Medical Arts and Photography Branch 

Demands for MAPB services increased approximately 25 percent in FY 1975. 
Physical consolidation of the graphics activities has satisfied the need 
for complete unity in graphics and statistical art preparation. With new 
equipment and wider use of contract service, delivering finished work has 
accelerated. Delivery of scientific photography has been reduced from 15 
days to seven. Work has been done to establish graphic standards for 
statistical materials produced by the Branch. This is a forerunner of a 
continued drive to establish a unified visual communications system for 
the NIH. 

5. Veterinary Resources Branch 

VRB service functions continued to increase to meet demands of expanding 
intramural BID programs, although Branch personnel ceilings have been re- 
duced 18 percent over the last seven years. Increased service with de- 
creased personnel was accomplished by extensive use of overtime, improved 
animal production methods, automated processing of glassware and produc- 
tion of media, limited use of temporary positions, and contracting. 

The VRB rodent breeding colonies were designated as a World Health Organi- 
zation collaborating center in recognition of their importance as an in- 
ternational genetic repository. A committee of the National Research 
Council reviewed this effort and recommended that it be removed from the 
Service and Supply Fund and be given separate funding. More breeding nuclei 

4 



were provided this year to start new colonies outside NIH than have been re- 
quested in previous years. VRB colonies now serve as the genetic base for 
most NCI contract programs as well as the Frederick Cancer Research Center. 
The Catalogue of NIH Rodents was distributed internationally to over 1,000 
researchers and specialists in fields of laboratory animal science. Twelve 
new rodent strains were added to the collection. 

Open or complete disclosure formula rations for laboratory animal feeds de- 
veloped by VRB permit competitive bidding for feed contracts, thereby re- 
ducing prices. Savings this year from conversion to open formula rations 
are estimated to be over $100,000 compared to the estimated costs of closed 
formula rations purchased under noncompetitive contracts. 

Pathogen-free rabbit and guinea pig colonies were successfully initiated 
this year. Nucleus colonies of guinea pigs were hysterectomy derived and 
extablished in the barrier in a clean, conventional area. An autoclavable 
diet for guinea pigs was successfully tested. Hysterectomy derivations 
were completed to establish all VRB rabbit strains in a new nonbarrier fac- 
ility. They were foster nursed by SPF Edgewood Arsenal rabbits. 

The Perrine Primate Center, established by DRS in FY 1974, is now stocked 
with 350 rhesus breeders and 75 squirrel monkeys. Two contracts were award- 
ed in June 1974 for additional rhesus monkey breeding colonies. By FY 1978, 
these three DRS breeding operations are expected to supply 1,000 rhesus and 
100 squirrel monkeys annually for intramural research. 

Tissue culture and media production increased 7 percent. Blood agar plates 
were issued at a 7 percent increase also. Glassware issues increased slight- 
ly over last year, as did the use of disposable supplies. Surgical facilities 
were relocated from Building 28 to Building 14E, increasing capacity for 
surgical procedures. 

D. Division Management 

1. Personnel Appointments 

Mr. Levi C. Carter and Mrs. Rebecca Wilner were appointed during the year 
as the Division's Executive Officer and Personnel Officer, respectively. 

2. Equal Employment Opportunity 

The Division's EE0 Office and the Human Relations Committee (HRC) worked 
together to plan the second in a series of EE0 Seminars around the theme 
"Think People." The success of the two sessions demonstrated the need to 
increase awareness of all DRS employees to the problems and frustrations 
experienced by employees and management alike. 

The Division Human Relations Committee continued to keep the Director ad- 
vised and aware of employee concerns. A compilation of these efforts was 
issued in an HRC report to all employees detailing the more significant 
actions initiated by the committee. The HRC also began holding its meet- 
ings in the various Branches and areas of DRS to afford a greater number 
of employees an opportunity to communicate their concerns to the committee. 

5 



In this regard also, suggestion boxes were installed in each Branch so that 
employees could relate concerns and problems to the committee and the EEO 
Office. 

3. Employee Development 

The Division's Training Office held interviews with all employees, GS-9 and 
below (and equivalents), to gather necessary data for formulating career de- 
velopment plans. This activity was coordinated with the Guidance and Coun- 
seling Branch, Division of Personnel Management. 

Nineteen employees participated in the NIH Executive Development Program, 
coordinated by the Executive Management and Development Branch, DPM. These 
individuals, GS-12 and above (and their equivalents), completed individual 
development plans and remain active members in the program to develop man- 
agerial skills in executives. 

Employee training activities were designed to meet individual as well as 
Division needs. Several female employees participated in programs designed 
for women in or aspiring to administrative /managerial/supervisory positions. 

A well-balanced, incremental supervisors' training program was initiated 
within the Division. The DRS Supervisory Training Program, divided into 
modules, affords supervisors an opportunity to attend sessions to enhance 
their management skills and knowledge. More than 200 supervisors participa- 
ted and have indicated approval of the program. Their evaluations led to 
constructive revisions and additions to the overall program. 

4. Management Analysis Projects 

The Management Analysis staff conducted a work improvement study of the 
Glassware Unit, VRB, to increase efficiency of the glassware processing sys- 
tem. Final recommendations centered on the redistribution of current man- 
power, installation of new automated systems, and modifications of current 
processing procedures. A work measurement study project quantified the time 
required to perform all end-product tasks during glassware processing. The 
data will establish more equitable rates for glassware sold under the Ser- 
vice and Supply Fund. 

To increase effectiveness of the Small Animal and Glassware Billing Systems, 
the staff redesigned systems to include special reports for each group con- 
cerned with the sale of commodities from these activities. The new systems 
incorporate an improved distribution technique to automatically address each 
report system with the name and location of the individual receiving it. A 
variable message facility was also provided for the activity manager to 
communicate in written form with each customer of his service. 

The Management Analysis staff provided consultative services to the Library 
Branch in acquiring an Automatic Circulation Control System. Through the 
efforts of the Management Analysis Office, the Division of Computer Research 
and Technology agreed to play a major role in acquisition, modification, and 
installation of a computerized Circulation Control System currently being 
run by the University of South Carolina. 

6 



5. Contracting and Materiel Management 

More administrative time and attention were given to contracting operations 
because of the increased emphasis on securing outside services precipitated 
by the continued reduction in manpower over a period of years. For instance, 
operation of the NIH Perrine Primate Center was converted from an inhouse 
activity to contract because of staff shortages. Increased use of contracts 
for art and photography services has stimulated development of graphic stand- 
ards for use by contractors. The Division Director's role as Chairman of 
the Primate Steering Committee broadened the Division's responsibility for 
such matters as establishment . of a contract with the Pan American Health 
Organization for the development of New World monkey breeding stations in 
Latin America. Partial support for a international meeting on the primate 
resources also was provided to PAHO. 

Contract support was given to the National Academy of Sciences for estab- 
lishment of a committee on veterinary medicine. Increased emphasis was 
placed on the use of contracts for surveillance of laboratories, laboratory 
hoods and other equipment used in radiation, biohazard, and chemical carcin- 
ogenic activities. A new chemical waste disposal/recycling contract was 
awarded and attention was given to the possibility of contracting for total 
radioactive waste handling program. 

The Division Administrative and Management Analysis Offices were contacts 
with the NIH Materiel Management System study group, primarily because of the 
existing BEIB computerized inventory system. The proposed computerized 
ordering receiving and inventory system appears to have high potential for 
benefiting NIH, if properly coordinated with all users of the system. 

E. Visual Communications Projects 

The Visual Communications Project Officer provided consultation and advice 
on a wide variety of visual and editorial design projects. Included were 
scientific papers, slides and exhibits by investigators from DRS and other 
BID's, development of various training materials, and presentations on pro- 
gram and administrative matters. 

Consultation was provided regarding the sound and visual presentation capa- 
bilities of alterations to Jack Masur Auditorium in the Clinical Center. 

Continuing design and editorial assistance was provided the NCI in develop- 
ment of a series of slide/tape biohazard control and safety training pack- 
ages. An additional presentation titled, "Hazard Control in the Animal Lab- 
oratory", was completed and released through the National Audio-Visual Cen- 
ter. Two additional scripts and story boards were assessed and edited; 
"Safety Standards for Research in Cancer" and "Assessment of Risk in the 
Cancer Virus Lab." 

Editorial and format design assistance was provided for the "NIH Biohazards 
Safety Guide." It was released in loose leaf form for NIH laboratory use 
and in bound form for sale by the Superintendent of Documents, GPO. 

A series of carcinogen warning symbols was developed for review and possible 

7 




use in research labortories. 

More material was added to a centralized file of original slides of DRS sub- 
jects. Slides were made available to a number of BID's for use in lectures 
and publications. 

The Visual Communications Project Officer continued to lecture on effective 
communication techniques to NIH and NIH-related audiences. He served as 
Division contact for Freedom of Information Act affairs and also continued 
to coordinate and edit DRS scientific documents, reports, news stories, press 
releases, publications, and visual materials. Liaison was maintained with 
the NIH/OD, other BID's on reporting and informational matters, and repre- 
sentation was maintained with public interest groups such as the American 
Science Film Association and American Medical Writers Association. Ke also 
served on the science jury for CINE film awards and selection of U.S. motion 
pictures for use overseas. 

A project which began 26 years ago at the time of the PHS Donora (Pa. ) smog 
disaster study was completed as a visual comparison of conditions in pictures 
and sketches made from identical locations at Donora in 1949 and 1975 . It 
was presented at the annual American Industrial Hygiene Conference. 



DIVISION OF RESEARCH SERVICES 
Summary of Branch Activities July 1, 197-4, through June 30, 1975 

BIOMEDICAL ENGINEERING AND INSTRUMENTATION BRANCH Dr. Lester Goodman, Chief 

I. SUMMARY 

Fiscal Year 1975 emphasized the refinement and extension of techniques 
innovated in previous years. Engineering design together with novel 
fabrication processes provided NIH with instrumental methods of unpre- 
cedented versatility. The ability of the Branch to promptly respond to 
intramural research demands was hampered by staff curtailments and associated 
personnel constraints; the quality of BEIB contributions, however, was not 
compromised. 

Mathematically based systems modeling and prediction, verified for animals, 
were successfully applied to human toxicology and therapy. Cytokinetic, 
pharmacokinetic, and pharmacodynamic bases for cancer chemotherapy were 
placed in quantitative perspective and used to explore alternative routes 
of drug administration, e.g., intrathecal and intraperitoneal, to seek 
optimal regimens. New methods for quantitative detection of trace metals 
in biological fluids were developed to better characterize environmental, 
diagnostic and therapeutic exposure of man to metallic ions. More reliable 
quantification of the interaction of polymeric materials with intracorporeal 
media enabled improved implant devices. Fluid mechanic analysis and physical 
models were effective in better explicating atherogenesis. 

Significant advances were achieved in ultrasonic imaging of structure and 
function in the cardiovascular system together with improved techniques for 
non- invasive blood flow measurement of unprecedented accuracy and precision. 
Ultrasonic methods were extended to ophthalmologic al scanning for diagnostic 
and therapeutic purposes. Quantitative measurements of cortical metabolism 
via televised fluoroscopy opened new avenues for the investigation of CNS 
physiology. The patient electrical safety program was extended, better 
codified and advanced; versatile, new test apparatus was constructed and 
applied. NIH was provided with a variety of new systems for cell separation, 
biochemical analyses via NMR and calorimetry. Real-time physiological 
monitoring and display for surgery and patient care were improved signifi- 
cantly by innovative electronic and video methods. 

Mechanization and automation of routine procedures provided for more economic 
utilization of manpower, dollars and materials especially in the area of 
processing samples for physical and chemical analysis. Devices were 
introduced to better protect personnel from the hazards associated with 
radioisotope administration. Substantial progress was attained and fresh 
directions of investigation established via new concepts and instrumentation 
for defining the electrical, chemical and physical concomitants of muscle 
contraction and nerve conduction in normal and traumatized tissues. An 
important breakthrough was achieved by the completion of a microelectrode 
positioner that enables long term stable recordings of action potentials 



from a single neuron in the exposed pulsating cortex of animals and humans *■> 
A comprehensive set of instruments for ophthalmological surgery, includingtj 
remotely controlled surgical tools, syringes, fluid exchangers and retinal 
suturing devices were provided to extend the capabilities of the eye surgeon 
and make his task easier. 



The Scientific Equipment Rental Program continued to expand; it has been 
enthusiastically accepted and widely used by the NIH intramural research 
community as a reliable economic resource. 



( 






■ 




10 



II. BRANCH PROGRAMS 



A. Objectives 

To provide direct and consultative engineering support to clinical and 
biomedical research projects, including advice on systems analysis, 
experimental design, and synthesis of technical expedients. 

To design, develop, fabricate, and evaluate special-purpose devices and 
systems not commercially available. 

To maintain and repair scientific laboratory and clinical equipment. 

To obtain and disseminate information on developments and improved production 
methods in the biomedical engineering and instrumentation fields. 

B. Current Programs 

The primary purpose of the Branch is to provide service and support to the 
intramural program of the NIH. BEIB activities, therefore, are identified 
with many of the individual programs that constitute the intramural research 
effort. The overall Branch program is best described as the coordinated 
effort of its operating elements. 

1. Instrument Fabrication 

Production, modification, and design of biomedical equipment and instru- 
mentation systems requiring special tools and skills in the electronic, 
electrical, glass, mechanical, optical, rubber, plastics, welding, and 
sheet metal categories. 

2. Systems Maintenance 

Maintenance and repair of biomedical equipment and instrumentation systems 
and instruction of technicians and scientists in the proper use and operation 
of especially complex instruments and devices. 

3 . Supply 

Acquisition and disposition of materials, parts, and equipment required for 
branch operations and maintenance of controlled inventory stocks and records. 

<4- Engineering and Applied Science - 

Chemical, Electrical and Electronic, and Mechanical: 

a. Direct and consultative professional services for fundamental and applied 
projects relevant to biomedical research and health care at the NIH. 

b. Research, design, development, and evaluation related to new instrumenta- 
tion and equipment. 



11 



c. Communication between NIH and the scientific community on engineering ^ 
support to biomedical research and clinical practice. 

5. Satellites 

These technical support units, composed of selected engineers and technicians' 
with appropriate shop facilities, are located in certain areas where it is 
beneficial to make typical BEIB support and service immediately available 
via a controlled degree of decentralization. They are responsive to demand s^ 
of local programs and operate as integral parts of the resident team but arf 
administratively responsible to the central Branch. Each satellite is 
especially tailored to meet specific needs of the host institute or division, 
supplying it with advantages of a proprietary technical group while main- 
taining the chief benefits of centralized resources. 

C. Program Progress and Accomplishments 

1. Technical Services 

a. Instrument Fabrication Section 

Backlogs increased markedly over the year due to reductions in manpower. 
Although quality was maintained, delays in responding to typical requests 
for fabrication increased to more than two months; patient care related 
projects continued to receive first priority. Substantial overtime enabled 
the section to complete 3600 jobs valued at $900,000 compared with 3800 jobs 
valued at $850,000 in FY 1974. , 

b. Systems Maintenance Section 

First priority attention to patient care related requests and emergency 
demands, coupled with virtually complete elimination of preventive main- 
tenance due to a shortage of personnel, increased response time for typical 
demands to an excessive two weeks; two days is considered reasonable. 
Greater use of overtime and more direct production by supervisory technicians 
enabled the section to perform 10,200 jobs at a cost of $1,100,000 compared 
with 9,500 and $1,000,000 respectively in FY 1974. 

The Scientific Equipment Rental Program continued to expand over the year as 
summarized below: 





July 1, 1974 


July 1, 1975 


Percent 
Increase 


Number of pool items 


423 


550 


23 


Dollar value 


$478,000 


$700,000 


42 


Number of items on rental 


194 


240 


• 1 


Utilization rate 


46$ 


46$ 




FY 1974 
$65,000 


FY 1975 
$102,000 


Percent Increas 


Gross revenue 


57 


New equipment investment 


$17,500 


$ 43,000 


146 



Full realization of the potential value of this program to the NIH continues 
to be impeded by constraints on personnel and space. / 

12 



c. Supply Unit 

The effort was made, throughout the year, to achieve greater economy by 
consolidating inventories in terms of capital investment and number of items 
carried. A comparison with FY 1974 operations- shows a change in number of 
transactions processed from 21,000 to 22,000 with the value of goods sold 
increasing from $373,000 to $440,000 in FY 1975. 

2. Engineering and Applied Sciences 

a. Chemical Engineering 

Substantial progress was achieved in applying chemical reaction engineering 
to problems of drug, metabolic and environmental contaminant distribution in 
the body. Principles established in animals were demonstrated applicable to 
humans for both toxic effects and optimal therapeutic protocols. A pharma- 
cokinetic model, originally developed on the basis of extensive studies in 
mice, was used successfully to predict priming doses and infusion rates 
necessary to achieve arbitrary plasma concentrations of methotrexate in 
individual patients. The dynamics of plasma concentration following 
infusion was investigated to provide- safer and more reliable "rescue" therapy 
following large methotrexate dosage. Cytokinetic, pharmacokinetic, and 
pharmacodynamic bases of , resistance to anti-cancer drug therapy were 
explored, and several pharmacokinetic factors placed in quantitative 
perspective. Alternate routes of drug administration, e.g., intrathecal 
and intraperitoneal, were studied to exploit possible therapeutic advantage 
and avoid toxic consequences. 

Environmental, diagnostic and therapeutic exposure of humans to metallic ions 
and complexes requires more sensitive and reliable methodology for analysis 
and characterization. Flameless atomic absorption spectrophotometry was 
applied to quantitative trace analysis of platinum in biological fluids and 
tissues. Other elements measured in biological or biomedical materials by 
this technique include calcium, magnesium, silicon, copper, and iron; 
gallium is under investigation. An instrument was developed for electronic 
control of the furnace temperature program to enhance sensitivity and enable 
analysis of materials with different combustion characteristics. 

Both our understanding of biomaterials and ability to design prosthetic 
devices were advanced. A study to elucidate the kinetic and thermodynamic 
mechanisms associated with phthalate plasticizers from vinyl plastics 
revealed that desorption rate into a pseudoserum was independent of flow 
rate but strongly dependent upon lipid concentration in the serum. Studies 
which explored the effect of antineoplastic drugs on wound strength have 
significant potential bearing on the conduct of early chemotherapy following 
surgery. The application of segmented polyurethane to biomedicine, 
pioneered by one of our staff, was advanced by numerous applications at 
NIH and elsewhere to heart assist devices, cannulas, heart valves, and 
other devices. Of particular relevance are ventricular-aortic bypasses and 
composite heart valves developed at NIH which have been successful in animal 
studies. 



13 



Shear stress distributions in costs of canine aortas were studied by electro- 
chemical instrumentation in steady and pulsatile flow. Regions of high shear 
were shown to exist at flow divider tips and other sites of developing velo- 
city profiles especially in the presence of intricate three-dimensional 
geometry, flow branching, separation and reversal during pulsations. Regions 
of high shear and regions of disturbed flow correlate with anatomical locali- 
zation of atherosclerotic plaque. 

Extensive consultation was provided to a variety of intramural and collabora- 
tive programs. 

b. Electrical and Electronic Engineering 

BEIB completed a substantial number of new designs for electrical and 
electronic apparatus for the NIH research programs; projects deserving special 
mention are summarized as follows: 

Progress in clinical instrumentation was marked by further developments in 
two dimensional dynamic ultrasonic displays of physiological structures. 
Ultrasonic scanning was effectively extended to improve the quality of 
ophthalmological examinations and significant improvements were attained in 
measurements of blood flow rates. Others include: A new method for quantify- 
ing cortical metabolism as function of position via low light level TV 
fluoroscopy; a laser powered ophthalmological drill; electronic monitoring of 
culture growth; and several systems for multiplexing various modes of clinical 
information onto video displays. 

In the field of laboratory instrumentation, noteworthy advances were made in 
cell separation technology; rapid-scan Fourier transform NMR; dual thermistor 
differential micro-calorimetry. 

The patient electrical safety program was highlighted by the development of 
"second generation" test apparatus, new methods for scheduling and recording 
inspections, and more extensive consultation regarding equipment purchases. 

c. Mechanical Engineering 

Continued close collaboration with research and applications program princi- 
pals throughout the NIH resulted in substantial developments in several areas. 
Mechanization and automation of routine laboratory procedures were extended 
and improved; large-scale media preparation operations and glassware ' 
processing were made more economical in terms of manpower and costs thus 
permitting reallocation of resources to more productive and challenging 
assignments . 

Substantial advances were achieved in fundamental and applied research on 
concomitants of CNS trauma, particularly in examination of the relationship 
of electrical conduction in nerve fibers with mechanical shock; protection 
to clinical personnel handling radioactive material; new visual acuity tests; 
processing of electrophoretic preparations; combining the advantages of 
visual microscopy with those of electron microscopy; application of fluidic 
logic and control to the programming of reagent inputs to a rapid reaction 
stop-flow calorimeter. 

14 



A new family of instruments for use in eye surgery was generated. These 
include special surgical knives, a vitreous humor extractor, a unique foot 
control, a syringe drive, a sub-retinal fluid drainer, and new retinal 
suturing techniques. Two new devices for placement of electrodes in brain 
of man and of test animals are undergoing tests. Each of these advances 
the state of the art in specific areas. 

Extensive consultation was provided to intramural, collaborative, and 
extramural programs. 

d. Florence Agreement 

BEIB is responsible for implementing NIH commitments related to the 
"Florence Agreement." Duties involve review of applications for duty-free 
entry of foreign manufactured scientific apparatus acquired by domestic 
nonprofit institutions, assessment of the suitability of equipment cited for 
intended applications, investigation of availability of domestically pro- 
duced scientific equivalents, recommendations to the U.S. Department of 
Commerce for approval, disapproval, or resubmission; and providing pertinent 
technical advice to requesting agencies and the Department of Commerce. The 
Branch Chief serves as Chairman of the NIH Florence Agreement Committee which 
includes a number of NIH professionals who are expert in particular cate- 
gories of instrumentation. The Executive Secretary, who must be thoroughly 
knowledgeable in modern scientific equipment, has become recognized as a 
reliable source of expert guidance, especially in the areas of transmission 
and scanning electron microscopy. Activities for FY 1975 are summarized as 
follows : 

Number of applications received by NIH 610 

Referred to other agencies 100 

Processed by NIH 510 

Processed independently by the Executive Secretary. . 4-80 

Processed with help of other Committee members 30 

Recommendations for approval 340 

Recommendations for disapproval ^0 

Recommendations for resubmission 14-0 

3. Technical Advances 

A CHIN ACTUATED REMOTE CONTROLLER manipulates a viewing microscope in three 
axes to enable full use of a surgeon's hands for ophthalmological procedures. 

CONCOMITANTS OF NERVE TRAUMA are derived with a new apparatus that monitors 
compound action potential changes resulting from applied dynamic mechanical 
stresses. 

A FLUIDIC LOGIC CONTROLLED SYSTEM transfers precise volumes of reagents with- 
in a chemical analyzer to improve the quality of kinetic reaction studies. 

NMR SPECTROMETRY VIA RAPID SCAN FT TECHNIQUES is enhanced by automatic 
sequencing of fixed frequency pre-scan irradiation, homogeneity spoiling, 
and broad band rapid scan processes. 



15 






SCANNING ELECTRON MICROSCOPE VERSATILITY is substantially expanded with 
externally controlled accessories which provide three axis sample manipulation 
and direct optical viewing. 

BACTERIAL GROWTH IN BLOOD CULTURE bottles is monitored more accurately and 
conveniently by measuring minute electrical impedance changes. 

ELECTROPHORESIS GEL DESTAINING is accelerated by circulation of buffer 
through a charcoal bed. 

AORTIC BALL VALVE PROSTHESIS INTEGRITY is non-invasively assessed with a 
coordianted radioisotopic and microphonic signal detection and data 
processing system. 

RADIOACTIVE SERUM INFECTION with markedly improved safety is achieved with a 
novel tantalum-stainless steel syringe shield. 

SYNCHRONOUS VIDEO DISPLAY of images and temporal signals substantially 
expedites interpretation and evaluation of cardiodynamic phenomena. 

A VERSATILE TIME CODED DATA PLAYBACK TECHNIQUE using low speed magnetic tape 
recording is useful in epilepsy studies. 

LOCALIZED QUANTITATIVE MEASUREMENT OF CORTICAL FLUORESCENCE, flow rate and 
oxygenation of blood adds new dimensions to the understanding of central 
nervous system metabolism. 

A SYSTEM FOR IN VITRO STUDY OF CARDIAC MUSCLE HYPERTROPHY controls local 
ambient temperature and partial pressures of O2 and CO2, supplies periodic 
isometric clamping and electrical stimulation, and optically determines 
muscle growth rate. 

CONTAINERS UP TO ONE LITER ARE AUTOMATICALLY LABELED with pressure sensitive 
printed tags at a rate of 110 per minute in a mechanized glassware processing 
apparatus . 

A MULTIPLEXED VIDEO MONITOR AND TAPE RECORDING SYSTEM helps to define the 
relationship between evoked pupillary response and CNS disorders. 

.A PROGRAMMABLE EXTERNAL CARDIAC PACEMAKER changes heart rate in prescribed 
temporal patterns as an aid to therapy. 

AN INFANT HEAD MOTION MONITOR extends the versatility of a system used to 
study mother-infant behavior interactions. 

A SELF CONTAINED PORTABLE VISUAL ACUITY TESTER implements the "illiterate E" 
test randomly to eliminate the effect of patient anticipation. 

4-. Training 

An effective professional and technical program was essential in maintaining 
high quality support and service. Fifty-seven employees participated in 



16 



116 academic, administrative, and technical courses. Thirteen (123 man-days) 
undertook formal university education and training courses. Thirteen (52 
man-days) received specialized training on scientific equipment at manu- 
facturers' facilities and at the NIH. Thirty-eight (165 man-days) attended 
various administrative, clerical, technical and scientific courses and 
training seminars. One employee attended Basic Adult Education at NIH 
sponsored by the Montgomery County School System and three employees were 
enrolled in the Upward Mobility College taking a total of 25 quarters of 
college-level courses. 

D. Program Plans 

Fiscal 1975 was distinguished by the refinement and extension of concepts, 
methods and devices conceived in previous years. Several promising new 
avenues of investigation were opened in fundamental research and engineering 
applications. The expectation of constraints on personnel and materiel for 
the coming year requires careful consideration of priorities and utilization 
of available resources. Modified methods for maximally satisfying the 
needs of the NIH program including, perhaps, more extensive use of contractors 
is anticipated. Reorientation of duties and functions within the Branch 
must be explored. 

1. Considerable emphasis will be placed on innovating, improving and 
extending engineering applications for the benefit of research and clinical 
practice, especially in the areas of: 

a. Optimization of chemotherapeutic processes. 

b. Detection and analysis of trace elements and their role in toxicology, 
diagnosis, and treatment. 

c. Elucidation of the interaction between implanted artificial devices and 
the living environment. 

d. Improved non-invasive physiological measurements and anatomical imaging. 

e. Explication of the chemical, electrical and mechanical concomitants of 
physiological phenomena associated with muscle, nerve, and blood. 

f. Automated materiel and information processing systems. 

g. Apparatus and methods for protection of personnel from hazards in 
laboratories and clinics. 

2. Expansion of the Scientific Equipment Rental Program and increased 
operational efficiency. 

3. More extensive use of private sector capabilities for procurement of 
services via contract. 

4. Incorporation of Branch financial management functions within the 
forthcoming NIH Material Management and Common, Accounting Systems to 
improve responsiveness and economy of operations. 

17 



E. Publications and Patents 



1. Publications 



Bender, R.A. and Dedrick, R.L. : Cytokinetic aspects of clinical drug resis- 
tance. Cancer. Chemother. Rep . (In press) 

Berger, R.L., Friauf, W.S., Cascio, H.E.: A low-noise thermistor bridge for 
use in calorimetry. Clin. Chem . 20: 1009-1012, 1974. 

Bischoff, K.B. and Dedrick, R.L.: Addendum to "Critical evaluation of use of 
effective protein fractions in developing pharmacokinetic models for drug 
distribution." Shen, D. and Gibaldi, M. : J. Pharm. Sci . 63: 1702-1703, 197-4. 

Boretos, J.W. and Brown, J.W. : Materials and design considerations for 
improved apical aortic anastomosis. In Brighton, J. A. and Goldstein, S.R. 
(eds. ): Advances in Bioengineering , New York, NY, American Society of 
Mechanical Engineers, 1974, pp. 165-166. 

: Silicones. In Polymers in Medicine and Surgery, Proceedings of a 

Symposium, 1974, Morristown, New Jersey . Kronen thai, D. and Oser, Z. (eds. ) 
Plenum Polymer and Science Technology Series, Plenum Press. (In press) 

, Pierce, W.S., Baier, R.E., LeRoy, A.F., and Donachy, H.J.: Surface 



and bulk characteristics of a polyether urethane for artificial heart. 
J. Biomed. Mater. Res . ( In press ) 

Brighton, J.B. and Goldstein, S.R. (eds. ): Advances in Bioengineering , 
New York, NY, American Society of Mechanical Engineers, 1974, 190 pp. 

Cohen, J.S., Bradley, R.B. and Clem, T.R. : pH dependence of the 13 C spin- 
lattice relaxation rate of the carboxyl carbon of acetic acid. J. Am. Chem . 
Soc. 97: 908-909, 1975. 

Cohen, S.C., Gabelnick, H.L., Johnson, R.K. and Goldin, A.: Effects of 
cyclophosphamide and adriamycin on the healing of surgical wounds in mice. 
Cancer (in press) 

and : Effects of antineoplastic agents on 



wound healing in mice. Surgery ( In press' 

Dedrick, R.L.: Book Review: Transport Phenomena and Living Systems : 
Biomedical Applications of Momentum and Mass Transfer , by E.N. Lightfoot. 
Amer. Inst, of Chem. Engineers J . 20: 829, 1974. 

: Animal scale-up. In Teorell, T., Dedrick, R.L. and Condliffe, P.G. 

(eds. ) Pharmacology and Pharmacokinetics , Plenum Press, New York, NY, 1974, 
pp 117-144- 

Pharmacokinetic and pharmacodynamic considerations for chronic 



hemodialysis. Kidney International 7: S7-15, 1975, 



18 



Zaharko, D.S., Lutz, R.J. and Drake, J.C.: Device for controlled 



drug release-application to methotrexate infusion in mice. Biochem. Pharmacol . 
23: 2457-2461, 1974. 

, , Bender, R.A., Bleyer, W.A. and Lutz, R.J.: Pharmacokinetic 



considerations on resistance to anti-cancer drugs. Cancer Chemother. Rep . 
( In press ) 

Dvorak, J. A., Schuette, W.H. and Whitehouse, W.C.: A simple method for the 
quantification of geometric parameters of microscopic objects. J. Microsc . 
102: 71-78, 1974. 

Friauf, W.S.: Test equipment for hospital safety programs. In Proceedings of 
the 27th Annual Conference on Engineering in Medicine and Biology, 1974 , 
Philadelphia, Pennsylvania . Arlington, Va., The Alliance for Engineering in 
Medicine and Biology, 1974, Vol. 16, p. 496. 

Gennarelli, T.A. and Thibault, L.E.: Functional response of the central 
nervous system to controlled inertial loading. In Proceedings of the 27th 
Annual Conference on Engineering in Medicine and Biology, 1974, Philadelphia , 
Pennsylvania . Arlington, Va., The Alliance for Engineering in Medicine and 
Biology, 1974, Vol. 16, p. 175. 

Goldstein, S.R.: A servo-force balance isometric muscle force transducer. 
J. Appl. Physiol . 37: 134-137, 1974. 

, Schmidt, E.M., Bierley, F.L. and Bak, M. : Atraumatic electrical 

recording from the exposed pulsating human cerebral cortex — a new mechanism. 
In Proceedings of the 27th Annual Conference on Engineering in Medicine and 
Biology, 1974, Philadelphia, Pennsylvania . Arlington, Va., The Alliance for 
Engineering in Medicine and Biology, 1974, Vol. 16, p. 224. Also in ASME 
Advances in Bioengineering , 1974, pp. 52-54. 

, , , and : A gas bearing mechanism for stable 



electrical recording from individual neurons in pulsating human cerebral 
cortex. Trans. ASME, J. Dynamic Systems, Measurement, Control . (In press). 

Griffith, J.M. and Henry, W.L. : Switched gain: simplifies ultrasonic 
measurement of cardiac wall thickness. In Proceedings of the 27th Annual 
Conference on Engineering in Medicine and Biology, 1974, Philadelphia , 
Pennsylvania . Arlington, Va., The Alliance for Engineering in Medicine and 
Biology, 1974, Vol. 16, p. 264. 

and : A sector scanner for real-time, two-dimensional echo- 
cardiography^ Circulation XLIX: 1147-1152, 1974. 

and : Switched gain: a technique for simplifying ultrasonic 

measurement of cardiac wall thickness. IEEE Trans. BME (In press) 

Gross, J.F. and Dedrick, R.L.: Macroscopic pharmacokinetics and cancer 
chemotherapy. In Proceedings of Joint Meeting of Verfahrenstechmische 
Gesellschaft in Verein Duetscher Ingenieure and AIChE, 1974, Munich, Germany . 
Dusseldorf, West Germany, AIChE-GVC, 1974, paper F4-5. 

19 



Henry, W.L., Epstein, S.E., Griffith, J.M., Goldstein, R.E. and Redwood, D.R.: 
Effect of prolonged space flight on cardiac function and dimensions. In 
Proceedings of the Skylab Life Sciences Symposium, August 27-29, 1974 , 
Houston, Texas . The Lyndon B. Johnson Space Center, Houston, Texas, 1974, 
pp 711-721. 

, Griffith, J.M., Michaelis, L.L., Mcintosh, C.L., Morrow, A.G., and 

Epstein, S.E.: Measurement of mitral orifice area in patients with mitral 
valve disease by real-time, two-dimensional echocardiography. Circulation 51: 
827-831, 1975. 



Clark, C.E., Griffith, J.M. and Epstein, S.E.: Mechanism of left 



ventricular outflow obstruction in patients with obstructive asymmetric septal 
hypertrophy (idiopathic hypertrophic subaortic stenosis.) Am. J. Cardiol . 35: 
337-345, 1975. 



, Maron, B.J., Griffith, J.M., Redwood, D.R. and Epstein, S.E.: 

Differential diagnosis of anomalies of the great arteries by real-time 
two-dimensional echocardiography. Circulation 51: 283-291, 1975. 



Kump, W.R. and Dehn, W.R. : Fabrication techniques for multichannel micro- 
electrodes. Fusion , May 1975, pp 9-10. 

LeRoy, A.F.: Health consequences of environmental controls: Impact of mobile 
emissions control. Interactions of platinum-metals and their complexes in 
biological systems. Environ. Health Perspect. (In press) 



(ed. 



Trace contaminants in the environment. Chemical Engineering 



Progress Symposium Series ( In press 

Introduction. In LeRoy, A.F. (ed. 



Trace contaminants in the 



environment . Chemical Engineering Progress Symposium Series ( In press ) 

Levy, D.M., Metz, H.D., Friauf, W.S. and Johnson, R.K.: An automatic cell 
growth and biochemical analysis system. In Proceedings of the 27th Annual 
Conference on Engineering in Medicine and Biology, 1974, Philadelphia , 
Pennsylvania . Arlington, Va., The Alliance for Engineering in Medicine and 
Biology, 1974, Vol. 16, p. 476. 

Lewis, D.V. and Schuette, W.H. : NADH fluorescence and |kj o changes during 
hippocampal electrical stimulation. J. Neurophysiol . 38: 405-417, 1975. - 

, O'Connor, M.J. and Schuette, W.H. : Oxidative metabolism during 

recurrent seizures in the penicillin treated hippocampus. Electroencephalogr , 
Clin. Neurophysiol . 36: 347-356, 1974. 

Lutz, R.J., Cannon, J.N., Munroe, R.E. : Shear stress measurements in model 
arteries during steady and pulsatile flow. In Nerem, R.M. (ed.): Fluid 
Dynamic Aspects of Arterial Disease. Proceedings from a Specialists Meeting 



on Fluid Dynamic Aspects of Arterial Disease; 
Ohio, pp 5-8. 



September 19-20, 1974, Columbus, 



20 



> , Fletcher, J.E. and Fry, D.L.: The measurement of wall shear 

stress in model arteries by an electrochemical technique. In Proceedings of 
the 27th Annual Conference on Engineering in Medicine and Biology, 1974 , 
Philadelphia, Pennsylvania . Arlington, Va., The Alliance for Engineering in 
Medicine and Biology, 1974, Vol. 16, p. 279. 

, Dedrick, R.L., Straw, J. A., Hart, M.M., Klubes, P. and Zaharko, D.S.: 

The kinetics of methotrexate distribution in spontaneous canine lymphosarcoma. 
J . Pharmac okinet . Biopharm . (in press) 

Myerowitz, P.D., Griffith, J.M., Roberts, A.J., Harrison, L.H., Henry, W.L., 
and Mcintosh, C.L.: Long-term canine model for echocardiography. Am. J. 
Cardiol . 34: 72-7-4, 1974. 

Olson, H.M., Young, D.M., Prieur, D.J., LeRoy, A.F. and Reagan, R.L. : 
Electrolyte and morphological alterations of myocardium in adriamycin-treated 
rabbits. Am. J. Pathol . 77: 439-454, 1974. 

, Rosenoff, S.H., Reagan, R.L., Munroe, R.E., LeRoy, A.F., Young, R.C., 



Young, D.M. : Ultrastructural alterations of the myocardium and biochemical 
correlates in mice with adriamycin administration. Cancer Res , (in press) 

Peterson, J. I., Tipton, H. and Chrambach, A.: A gel slicer for transverse 
sectioning of polyacrylamide gels. Anal. Biochem . 62: 274-280, 1974. 

Redwood, D.R., Henry, W.L., Goldstein, S.R. and Smith, E.R.: Design and 
function of a mechanical assembly for recording echocardiograms during 
upright exercise. Cardiovasc. Res . 9: 145-149, 1975. 

Rhee, S.G., Greifner, M.I. and Chock, P.B.: ATP determination by stopped-flow 
method. Anal. Biochem . (in press) 

Schuette, W.H., Grauer, L.E., Whitehouse, W.C., Itscoitz, S.B. and Redwood, D.R. 
Measurement of ventricular ejection fraction in man utilizing roentgen video- 
densitometry. In Proceedings of the 27th Annual Conference on Engineering in 
Medicine and Biology, 1974, Philadelphia, Pennsylvania . Arlington, Va., The 
Alliance for Engineering in Medicine and Biology, 1974, Vol. 16, p. 438. 

, Whitehouse, W.C., Lewis, D.V., O'Connor, M. and Van Buren, J.M. : 

A television fluorometer for monitoring oxidative metabolism in intact tissue. 
Med. Instrum . 8: 331-333, 1974. 

Straw, J. A., Hart, M.M., Klubes, P., Zaharko, D.S. and Dedrick, R.L.: 
Distribution of anticancer agents in spontaneous animal tumors. I. Regional 
blood flow and methotrexate distribution in canine lymphosarcoma. J. Natl . 
Cancer Inst . 52: 1327-1331, 1974- 

Teorell, T., Dedrick, R.L. and Condliffe, R.G. (eds.): Pharmacology and 
Pharmacokinetics, Plenum Press, New York, NY, 1974, 388 pp. 

Thibault, L.E., Gennarelli, T.A., Tipton, H.W. and Carpenter, D.O.: The 
physiological response of isolated nerve tissue to dynamic mechanical loads. 

21 



In Proceedings of the 27th Annual Conference on Engineering in Medicine and 
Biology, 1974, Philadelphia, Pennsylvania . Arlington, Va., The Alliance for 
Engineering in Medicine and Biology, 1974, Vol. 16, p. 176. 

Thompson, E.J., Griffith, J.M., Sehoenberg, D.G. and Nirenberg, M.W. : An 
improved method for extracellular recording of action potentials from single 
cultured neuroblastoma cells. Med. Biol. Eng . 104-106, January 1975. 

Vurek, G.G., Warnock, D.G. and Corsey, R. : Measurement of picomole amounts of 
carbon dioxide by calorimetry. Anal. Chem . 47: 765-767, 1975. 

Wasylishen, R.E., Clem, T.R. and Becker, E.D.: Nuclear magnetic resonance 
chemical shifts of some monosubstituted isothiazoles. Can. J. Chem . 53: 
596-603, 1975. 

Zaharko, D.S. and Dedrick, R.L.: Pharmacokinetic models for antineoplastic 
agents. In Sartorelli, A.C. and Johns, D.G. (eds. ): Antineoplastic and 
Immunosuppression Agents I . Spring er-Verlag, Berlin, 1974, pp. 220-228. 

, , Peale, A.L., Drake, J.C. and Lutz, R.J.: Relative toxicity 

of methotrexate in several tissues of mice bearing lewis lung carcinoma. 
J. Pharmcol. Exp. Ther. 189: 585-592, 1974. 



2. Patents 

Boretos, J.W. : "Device for treating sub-ungual hematoma." U.S. Patent No. 
3,766,923 (October 23, 1973). 

Goldstein, S.R. : "Electrode insertion device for neuroelectrical recordings." 
U.S. Patent No. 3,841,310 (October 15, 1974). 

Knazek, R.A., Gullino, P.M., Dedrick, R.L. and Kidwell, W.R.: "Cell culture 
on semipermeable tubular membranes." U.S. Patent No. 3,821,087 (June 29, 1974) 

Peterson, J.I., Friauf, W.S. and Leighton, S.: "A high-precision fluorometer 
for measuring enzymatic substrates in tissues." U.S. Patent No. 3,854,050 
(December 10, 1970). 

Schuette, W.H. : "Modulated sine wave flowmeter." U.S. Patent No. 3,815,582 
(June 11, 1974). 



22 



Ill INDIVIDUAL PROJECT REPORTS 

Project No. Z01 RS 00001-07 BEI 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Chemical Engineering Section 

3 . Bethesda 

PHS-NIH 
Individual Project Report 
July 1, 1974 through June 30, 1975 

Project Title: Pharmacokinetics 
Previous Serial Number: DRS-BEIB-1 

Principal Investigator: Robert L. Dedrick 

Other Investigators: Daniel S. Zaharko, Richard A. Bender, Anthony M. Guarino, 
Robert J. Lutz, Andre F. LeRoy, Kenneth B. Bischoff, 
Marshall Anderson, Bruce Chabner, W. Archie Bleyer 

Cooperating Units: LCHPH-NCI, LT-NCI, PB-NIEHS, AK-CU Program NIAMDD, 
University of Washington, M-NCI 

Man Years: 

Total: 3.0 
Professional: 2.0 
Other: 1.0 

Project Description: 

Objectives : Improve and extend mathematical models for the distribution and 
disposition of drugs, environmental contaminants and endogenous metabolites 
in animals and man to: 

(1) Account for species differences in drug distribution. 

(2) Provide rational bases for extrapolation of toxicity from animals to man. 

(3) In conjunction with pharmacodynamics, provide a basis for optimization 
of cancer chemotherapy and chronic hemodialysis. 

(4) Enable rational transfer of in vitro thermodynamic and kinetic data to 
in vivo cases. 

(5) Predict effective dose schedules of anti-cancer drugs in individual 
patients. 

Methods Employed : Mathematical models are developed from physicochemical, 
physiological and anatomical information and the principles of chemical 
reaction engineering. Resulting differential equations sets are solved 
analytically or numerically and compared with experimental data. Uncer- 
tainties are clarified by additional experiments and model modification. 

23 



Major Findings : 

(1) Methotrexate distribution in spontaneous canine lymphosarcoma has been 
modeled as a saturable transport process with strong intracellular binding to 
dihydrofolate reductase and weak binding to cell membranes or extracellular 
tumor components . 

(2) A pharmacokinetic model, originally developed on the basis of extensive 
studies in mice, has been used successfully to predict methotrexate priming 
doses and infusion rates required to achieve selected plasma concentrations 
in individual patients. 

(3) Tumor perfusion, membrane transport, intracellular enzyme levels and 
enzyme synthesis rate have been illustrated and placed in quantitative per- 
spective by a discussion of the pharmacokinetics and pharmacodynamics of 
methotrexate. This provides an operational basis for examination of drug 
resistance. 

(4) Filterability of platinum administered as cis-dichlorodiammine platinum 
(II) decreases during incubation with dog plasma in vitro . This appears to 
correlate with a decrease in kidney clearance in vivo and suggests that one 

or more chemical reactions occur which may influence distribution, disposition, 
and biological effect. 

Significance : Drugs and other chemicals are tested for effect in animals, and 
the extrapolation to man is a subject of serious concern. At issue are both 
the risk associated with environmental contaminants and optimization of 
therapy . 

Proposed Course : Continued pharmacokinetic modeling with particular attention 
to pharmacodynamic and cytokinetic events. Increased clinical emphasis 
. through support of high-dose methotrexate protocols and other attempts to 
overcome drug resistance. 

Keyword Descriptors : Pharmacokinetics, methotrexate, polychlorinated 
biphenyls, mathematical modeling, drug resistance, cancer chemotherapy, 
cis-dichlorodiammine platinum (II). 

Honors and Awards : Food, Pharmaceutical and Bioengineering Division Award of 
American Institute of Chemical Engineers to R.L. Dedrick. 

Publications : 

Teorell, T., Dedrick, R.L. and Condliff, P.G. (Eds.): Pharmacology and 
Pharmacokinetics . New York, Plenum Press, 1974, 388 pp. 

Dedrick, R.L. : Animal Scale-Up. In Teorell, T., Dedrick, R.L. and 
Condliffe, P.G. (Eds. ): Pharmacology and Pharmacokinetics , New York, Plenum 
Press, 1974, pp. 117-144. 

, Zaharko, D.S., Lutz, R.J. and Drake, J.C.: Device for Controlled 

Drug Release: Application to Methotrexate Infusion in Mice. Biochem . 
Pharmacol . 23: 2457-2461, 1974. 

24 



• 



Straw, J. A., Hart, M.M. , Klubes, P., Zaharko, D.S. and Dedrick, R.L. : 
Distribution of Anticancer Agents in Spontaneous Animal Tumors. I. Regional 
Blood Flow and Methotrexate distribution in Canine Lymphosarcoma. J. Nat . 
Cancer Inst . 52, 1327-1331, 1974. 

Zaharko, D.S. and Dedrick, R.L. : Pharmacokinetic Models: Application to 
Antineoplastic Agents. In Sartorelli, A.C. and Johns, D.G.(Eds.): 
Handbook of Experimental Pharmacology XXXVII I/I, Berlin, Springer Verlag, 
1974, pp. 220-228. 

, , Peale, A.L., Drake, J.C. and Lutz, R.J.: Relative Toxicity 



of Methotrexate in Several Tissues of Mice Bearing Lewis Lung Carcinoma. 
J. Pharmacol. Exp. Therap . 189: 585-592, 1974. 

Gross, J.F. and Dedrick, R.L.: Macroscopic Pharmacokinetics and Cancer 
Chemotherapy. Proc . Joint Meeting Gesellschaf t Verf ahrenstechnik und 
Chemieingenieurwesen (GVC) and American Institute of Chemical Engineers 
(AIChE), Munich, Germany, 1974, Paper F4-5, 10 pp. 

Bischoff, K.B. and Dedrick, R.L.: Addendum to Shen, D. and Gibaldi, M. : 
Critical Evaluation of Use of Effective Protein Fractions in Developing 
Pharmacokinetic Models for Drug Distribution. J. Pharm. Sci . 63: 1702-1703, 
1974. 

Dedrick, R.L.: Pharmacokinetic and Pharmacodynamic Considerations for Chronic 
Hemodialysis. Kidney International 7 (Suppl. 2), S-7-15, 1975. 

, Zaharko, D.S., Bender, R.A., Bleyer, W.A. and Lutz, R.J.: Pharmaco- 
kinetic Considerations on Resistance to Anti-Cancer Drugs. Cancer Chemo- 
therapy Rep . (In Press). 

Bender, R.A. and Dedrick, R.L.: Cytokinetic Aspects of Clinical Drug 
Resistance. Cancer Chemotherapy Rep , (in Press) 

Lutz, R.J., Dedrick, R.L., Straw, J. A., Hart, M.M., Klubes, P. and Zaharko, 
D.S.: The Kinetics of Methotrexate Distribution in Spontaneous Canine 
Lymphosarcoma. J. Pharmacokinet. Biopharm . (in Press). 

Bischoff, K.B.: Pharmacokinetics and Cancer Chemotherapy. In Teorell, T., 
Dedrick, R.L. and Condliffe, P.G. (Eds.): Pharmacology and Pharmacokinetics , 
New York, Plenum Press, 1974, pp. 351-366. 

: Some Fundamental Considerations in Applications of Pharmacokinetics 
to Cancer Chemotherapy. Cancer Chemotherapy Rep. (In Press). 



25 



Project No. Z01 RS 00002-10 BEI 

1 



Biomedical Engineering and 
Instrumentation Branch 
Chemical Engineering Section 
Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974- through June 30, 1975 

Project Title: Implant Device Development 

Previous Serial Number: DRS-BEIB-4 

Principal Investigator: John W. Boretos 

Other Investigators: William S. Pierce, Robert Poirier, James W. Prescott, 

C. Kollarits, M. Fisherman, John W. Brown, Robert Baier, 
Robert L. Dedrick, Robert J. Lutz 

Cooperating Units: SB-NHLI, GD-NICHD, Pennsylvania State University, CB-NEI, 
Calspan Corp. 



Man Years: 



Total : 

Professional: 
Others : 



1.8 

1.5 
0.3 



Project Description: 

Objectives : Elucidate the interaction of polymers used for specific implants 
with the physiological environment; explore specially prepared polymers and 
design features with respect to their suitability and performance in a variety 
of contexts. 

Methods Employed : Basic polymer composition is carefully controlled and 
modification of cross-linking systems is employed. Rheological properties 
are studied as a function of cross-linking. Implants are examined after 
removal for lipid absorption, protein deposition, changes in surface-free 
energy, and alteration of physical properties. Observations include SEM, 
infrared spectroscopy, contact angle measurements, energy dispersive x-ray 
analysis and atomic absorption spectroscopy. Flow characteristics and pres- 
sure gradients across heart valve implants are studied in vitro in test 
apparatus. 

Major Findings : Ten heart assist devices with segmented polyurethane blood 
contacting surfaces were implanted in calves for up to 35 weeks. No lipid 
absorption was observed; physical strength remained stable; surfaces 
developed a biocompatible layer of protein. Six additional assist devices 
have been implanted with similar results; two total heart implants have been 
achieved. 



26 



' 



A series of ventricular-aortic by-pass devices functioned satisfactorily for 
periods up to 17 weeks in dogs with negligible blood damage. Clinical trials 
are now being planned. 

Six segmented polyurethane covered polypropylene poppets housed in standard 
"Starr-Edwards 3M" cages have been implanted in calves. One was electively 
removed after one year; no obvious physical or chemical changes occurred and 
there was no evidence of injury to the animal. 

Significance : Physiologically compatible polymers with enduring strength are 
needed for such applications as heart valves, heart assist devices, vascular 
implants, and subcutaneous uses. 

Proposed Course : (l) Extend experimental studies to further characterize 
the surface and bulk properties of polyether urethanes and more specifically 
determine its interactions with blood and subcutaneous tissue. 

(2) Study new designs of tricuspid heart valves for acute and chronic use. 

(3) Study new designs of drains to be used in the eye to treat glaucoma. 

Keyword Descriptors : Polymers, implants, heart valves, heart pumps, glaucoma 
drains. 

Honors and Awards : None 

Publications : 

Boretos, J.W., Pierce, W.S., Baier, R.E., LeRoy, A.F., and Donachy, H.J.: 
Surface and Bulk Characteristics of a Polyether Urethane for Artificial Heart. 
J. Biomed. Mater. Res , (in press). 

Boretos, J.W. and Brown, J.W. : Materials and Design Characteristics for 
Improved Apical Aortic Anastomosis. In 197 4 ASME Advances in Bioengineering . 
Brighton, J. A. and Goldstein, S.R. (eds. ) American Society of Mechanical 
Engineers . / 

Boretos, J.W. : Silicones. In Polymers in Medicine and Surgery, Proceedings 
of a Symposium, 197 4-, Morristown, New Jersey . Kronenthal, D. and Oser, Z. 
(eds. ), Plenum Polymer and Science Technology Series, Plenum Press (in press). 

Boretos, J.W. : Polymer Considerations for Electronic Implants. In Ray, CD. 
(ed. ) Medical Engineering , Year Book Medical Publishers, Inc., Chicago, IL, 
1974, pp 1120-1123. 

Boretos, J.W. : Machining of Plastics. In Ray, CD. (ed.), Medical Engineering , 
Year Book Medical Publishers, Inc., Chicago, IL, 1974, pp. 1173-1181. 



27 



Project No. Z01 RS 00003-03 BEI 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Chemical Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: Trace Element Analysis in Biological Materials 

Previous Serial Number: DRS-BEIB-2 

Principal Investigators: Andre F. LeRoy 

Other Investigators: H.M. Olson, A.M. Guarino, R.L. Dedrick, C. Litterst, 
T.E. Gram, G.P. Canellos 

Cooperating Units: LT-NCI, M-NCI 

Man Years: 



Total: 


2.0 


Professional: 


1.6 


Others : 


0.4 



Project Description: 

Objectives : Enhance analysis and identification of metal complexes in bio- 
logical materials. Improve analytical methods with detection limits on ^ the 
order of nanograms to picograms in milligram samples. Emphasize analysis of ^ 
platinum, gallium, calcium and magnesium compounds as they relate to diagnosis 
and chemotherapy. 

Methods Employed : Flameless atomic absorption spectrophotometry for analysis 
of specific elements. Chemical agents are used to promote release of elements 
from the biological matrix more smoothly and completely. Solvent extraction 
may be very useful for many applications. Electronic control of the tempera- 
ture program for combustion allows materials with different combustion 
characteristics to be analyzed. 

Electrophoresis to fractionate proteins with subsequent determination of 
metal species among fractions. In some cases, ultrafiltration is required to 
concentrate proteins enough to permit detection of metals. 

Major Findings : Sensitivity of platinum determination is approximately one 
nanogram. Urine and plasma samples from dogs treated with cis-dichlorodiam- 
mine platinum have been directly analyzed as a function of time. More than 
half of platinum administered appears in the urine within about two hours; 
the remainder is released in the urine much more slowly. Samples of various 
tissues from treated dogs have been analyzed after acid digestion. The 
results indicate that loss of platinum taken up in tissue is very slow. 

28 



* 



Direct analysis of gallium has given erratic results to date. 

Significance : Quantitation, identification and characterization of metal 
species at trace levels in biological tissue is important in biochemical 
research and environmental toxicology. Characterization of such compounds 
in tissues and body fluids can help identify drug action and suggest other 
potentially useful compounds. Methods under development offer an alternative 
to administering radiolabeled substances to human subjects. 

Proposed Course : Extend applicability of direct combustion techniques to more 
tissue types by use of suitable time-timperature relationships; try to mini- 
mize need for pretreatment . Complete analyses required for pharmacokinetic 
modeling. Perform referee analyses for metals using neutron activation 
analysis where applicable. Improve analysis for gallium. 

Keyword Descriptors : Trace-element analysis, biological tissues and fluids, 
atomic absorption spectrophotometry. 

Honors and Awards : None 

Publications : 

LeRoy, A.F.: Interactions of Platinum-Metals and Their Complexes in Biologi- 
cal Systems. Environ. Health Perspect . (in press. ) 

Olson, H.M. , Rosenoff, S.H., Reagan, R.L., Munroe, B., LeRoy, A.F., Young, R.C. 
Young, D.M. : Ultrastructural Alterations of the Myocardium and Biochemical 
Correlates in Mice with Adriamycin Administration. Cancer Res , (in press. ) 

Olson, H.M., Young, D.M. , Prieur, D.J., LeRoy, A.J., Reagan, R.L.: Electro- 
lyte and Morphologic Alterations of Myocardium in Adriamycin- Treated Rabbits. 
Am. J. Pathol. 77: 439-450, 1974. : . 



29 



Project No. Z01 RS 00004-05 BEI 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Chemical Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: The Role of Fluid Dynamics and Mass Transfer in Development 
of Atherosclerosis 

Previous Serial Number: DRS-BEIB-3 

Principal Investigators: Robert J. Lutz, Joseph N. Cannon 

Other Investigators: Donald L. Fry, Robert L. Dedrick, Kenneth B. Bischoff 

Cooperating Units: 0D-IR-NHLI, Howard University 

Man Years: 

Total: 1.2 
Professional: 0.8 
Other: 0.4 

Project Description: 

Objectives : Measure shear stress on the inner wall of simulated arteries 
during steady and pulsatile flow and correlate data with localization of 
atherosclerosis as found in experimental animals. Visualize flow patterns 
In the three-dimensional geometry of arterial branches. Measure the effects 
of shear on the transport rate of macromolecules through simulated and real 
arterial endothelium. 

Methods Employed : An electrochemical technique is used, based on an oxidation- 
reduction reaction at electrodes implanted at a fluid-solid interface, which 
determines mass transfer rates of redox ions. Velocity gradients at the wall 
(shear rate) are calculated from mass transfer rates with suitable boundary 
layer equations. 

Flow visualization can be achieved in a transparent cast of a canine artery 
using dye injection techniques and/or cinematography of latex microspheres. 

Major Findings : In the arterial model, sharp shear peaks exist near the flow 
divider tips of branches; shear rate rises as flow enters smaller branches 
where velocity profiles are redeveloping. Shear drops suddenly just distal 
to the flow divider tips resulting in flow separation and flow reversal during 
pulsations. The intricate three-dimensional geometry of the arterial tree 
and branching of the flow from the main channel are responsible for flow 
pattern characteristics. Regions of high shear and regions of disturbed flow 
patterns correlate with areas of increased plaque localization. 

30 



I 



Significance : Elucidation of the role of hemodynamics and mass transfer in 
the onset and development of atherosclerotic plaques is fundamental in the 
study of vascular disease 

Proposed Course : Verify electrochemical techniques experimentally and by 
computer simulation for measuring pulsatile shear stresses. Fabricate more 
realistic arterial models which include wall distensibility, and determine 
shear rate patterns. Devise mechanical models of the phospholipid membrane 
of arterial endothelial cells and determine the effect of shear on transport 
of macromolecules across these artificial membranes. 

Keyword Descriptors : Atherosclerosis, electrochemical shear measurement, 
arterial models, arterial fluid dynamics 

Honors and Awards : None 

Publications : 

Lutz, R.J., Cannon, J.N., Fletcher, J.E., and Fry, D.L.: The Measurement of 
Wall Shear Stress in Model Arteries by an Electrochemical Technique. In 
Proceedings of the 27th Annual Conference on Engineering in Medicine and 
Biology, 1974? Philadelphia, Pennsylvania . Arlington, Va., The Alliance for 
Engineering in Medicine and Biology, 197 4-, Vol. 16, p. 27. 

Lutz, R.J., Cannon, J.N., Munroe, R.E. : Shear Stress Measurements in Model 
Arteries During Steady and Pulsatile Flow. In Nerem, R.M. (Ed.): Fluid 
Dynamic Aspects of Arterial Disease. Proceedings From a Specialists Meeting 
on Fluid Dynamic Aspects of Art erial Disease , Columbus, Ohio, September 19-20, 
1974, pp. 5-B. 



31 



Project No. Z01 RS 00006-03 BEI 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Chemical Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974- through June 30, 1975 

Project Title: Multicomponent Plastics in Biomedical Use 

Previous Serial Number: DRS-BEIB-5 

Principal Investigator: Henry L. Gabelnick 

Other Investigator: Margaret L. Wehling 

Cooperating Units: None 

Man Years: 

Total: 0.6 
Professional: 0.3 
Other: 0.3 

Project Description: 

Objectives: Extend definition of the interaction of plastic systems with the 
Sologlcal environment, emphasizing the kinetics of addxtive elutxon from 
polymers and absorption of body constituents. 

Methods Employed: Determination of elution rate of migrating species via 
quantitative anal ytical techniques. Parameters under investigation include 
fluid composition and flow conditions. 

Major Findings : Refined analytical techniques enable evaluation of the 
di-2-ethylhexyl phthalate-polyvinyl chloride system exposed to a soybean 
emulsion "pseudo-serum." 

Desorption of phthalate from surgical grade polyvinyl tubing ( 3/16" I.D.-) was 
independent of flow rate over the range 100 to 300 ml/mm Howe, er the rate 
S uptake of phthalate by the pseudo-serum increased by a factor of two when 
the lipid concentration was increased from 100 to 300 mg%. 

Proposed Course : Project terminated in December 1974 due to departure of the 
principal investigator. 

Keyword Descriptors : Phthalates, plasticizes elution, vinyl tubing, desorp- 
tion kinetics 

Honors and Awards : None 

Publications: None 32 



Project No. Z01 RS 00005-03 BEI 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Chemical Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: Thermomi orography 

Previous Serial Number: None 

Principal Investigators: John I. Peterson 

Other Investigators: Robert L. Bowman 

Cooperating Units: LTD-NHLI 

Man Years: 

Total: 1.3 
Professional: 0.8 
Other: 0.5 

Project Description: 

Objectives : Develop a method for microscopic observation of biological cells 
by their thermal effects. 

Methods Employed : Investigation of the possible use of the optical-thermal 
properties of the cholesteric mesophase ("liquid crystals"). 

Major Findings : The well-known and previously investigated properties of 
cholesteric esters have been based on materials of undocumented and probably 
low purity. The accepted theoretical model for their behavior is untenable 
from the chemical point of view. The investigation of highly purified 
material shows behavior which is different and possibly more useful than 
previously observed, as well as being divergent from that expected. 

Significance : A technic of microthermography would be useful for cell 
calorimetry and other energy studies on an individual cell basis, and could 
provide a possible route to facilitation of screening studies involving 
various kinds of cellular reactions. 

Proposed Course : Verification of conclusions derived to date and extension 
through continued investigation. 

Keyword Descriptors : Thermography, liquid crystals, purification, cholesteric 
esters. 

Honors and Awards : None 

Publications : None -*-* 



Project No. Z01 RS 00007-01 BEI 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Electrical and Electronic 
Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: Investigation of Oxidative Metabolism and Potassium Kinetics 
in the Cat Brain 

Previous Serial Number: DRS-BEIB-7 

Principal Investigators: William H. Schuette, DarrellV. Lewis 

Cooperating Units: EEG-NINDS 

Man Yi'.-if::: 

Total: 2.0 
Professional: 1.5 
Others: 0.5 

Project Description: 

Objectives: (l) Develop and apply new and improved techniques for analyzing 
oxidative metabolism of the cat brain and correlating these results to simul- 
taneous extracellular potassium kinetic measurements. 

(2) Determine the Qio of potassium kinetics in the cat hippocampus. 

(3) Validate oxidative metabolism measurements obtained by NADH fluorescence 
techniques with direct measurement of cortical oxygen consumption. 

Methods Employed : NADH fluorescence measurements are made with a unique 
two-channel fluorometer. 

Q 10 measurements are made by cooling the brain with an "Elliott's B" solution 
drip while measuring local temperature with a thermistor. Potassium kinetics 
are measured with a potassium sensitive microelectrode following electrical 
stimulation. 

: 4 

Cortical oxygen consumption is determined from the combination of oximetry and 1 
flow of blood drained from the sagittal sinus of cats. 

Major Findings : (l) Clearance of potassium following stimulation of the 
brain is an exponential process. 



34 



(2) The Q-]_q for this clearance is approximately 2.1. 

(3) A linear relationship exists between the amount of potassium released 
following a stimulus to the brain and the time integral of the NADH fluores- 
cence signal. 

(4) NADH fluorescence signals appear to be related to direct oxygen 
consumption measurements. 

Significance : Evidence for potassium clearance being an active process has 
been reinforced. 

The utility of NADH fluorescence as an indicator of oxidative metabolism has 
been demonstrated. 

Proposed Course : Refinement and extension of work done to date. 

Keyword Descriptors : NADH, fluorescence, potassium, kinetics, oximetry 

Honors and Awards : None 

Publications : 

1. Lewis, D.V., O'Connor, M.J. and Schuette, W.H. : Oxidative Metabolism 
During Recurrent Seizures in the Penicillin-Treated Hippocampus. 
Electroencephalogr . Clin Neurophysiol . 36: 3-47-356, 1974-. 

2. Schuette, W.H., Whitehouse, W.C., Lewis, D.V., O'Connor, M.J. and 

Van Buren, J.M. : A Television Fluorometer for Monitoring Oxidative Metabolism 
in Intact Tissue. Med . Instrum . 8: 331-333, 197/4. 

3. Lewis, D.V. and Schuette, W.H. : NADH Fluorescence and \K J Changes During 
Hippocampal Electrical Stimulation. J. Neurophysiol. 38: -405-417, 1975. 



35 



Project No. Z01 RS 00008-03 BEI 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Electrical and Electronic 
Engineering Section 

3- Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: Diagnostic Ultrasound 

Previous Serial Number: DRS-BEIB-8 

Principal Investigators: James M. Griffith, Walter L. Henry, William R. Brody, 

Steven Charles 

Other Investigators: David Myerowitz, Barry J. Maron, Stephen E. Epstein 

Cooperating Units: CB-IR-NHLI, SU-IR-NHLI, IR-NEI 

Man Years : 

Total: 3.5 
Professional: 2.0 
Others: 1.5 

Project Description: 

Objectives : ( 1 ) Noninvasively obtain dynamic images and measurements of 
cardiac structure and function and assess for diagnostic and therapeutic 
purposes. 

(2) Noninvasively obtain images and measurements of ophthalmic structure and 
assess for diagnostic and therapeutic purposes. 

(3) Noninvasively obtain dynamic measurements of blood flow in circulatory 
vessels. 

Methods Employed : A previously reported real-time, two-dimensional sector 
scanner was refined and used effectively in several new research applications. 

The sector scanner technique was extended to ophthalmological applications. 

Principles of high resolution radar and communication theory are being applied 
to doppler flowmeter design for improved resolution. 

A moving-trace monitor system was developed which allows two seconds of EKG 
to be recorded on each frame of real-time two-dimensional echogram. 



36 



Major Findings : 

(1) Mitral valve orifice area can be accurately measured by real-time 
two-dimensional echocardiography. 

(2) Two-dimensional echocardiography is a significant new tool for the 
differential diagnosis of anomalies of the great arteries. 

(3) Mechanical sector scanning in real time is applicable to ophthalmic 
scanning; this considerably reduces examination time. 

Significance : Safe noninvasive methods for making quantitative and qualitative 
physiologic measurements are of substantial value for research and diagnostic 
purposes. 

Proposed Course : The doppler flowmeter design will be improved so that 
useful velocity and range resolution are obtained. Then it may be possible 
to combine a flowmeter and a sector scanner so that real-time two-dimensional 
imaging is available simultaneously with flow measurement. 

Keyword Descriptors : Ultrasound, Pulse Echo, doppler 

Honors and Awards : None 

Publications : 

1. Griffith, J.M. and Henry, W.L. A Sector Scanner for Real Time Two- 
Dimensional Echocardiography. Circulation , XLIX: 114-7-1152, 1974. 

2. Myerowitz, P.D., Griffith, J.M., Roberts, A. J., Harrison, L.H., Henry, 
W.L., and Mcintosh, C.L. Long-Term Canine Model for Echocardiography. 
Am. J. Cardiol . 34: 72-74, 1974- 

3. Griffith, J.M. and Henry, W.L. Switched Gain: Simplifies Ultrasonic 
Measurement of Cardiac Wall Thickness. In Proceedings of the 27th Annual 
on Engineering in Medicine and Biology 1974, Philadelphia, Pennsylvania, 
Arlington, Va., The Alliance for Engineering in Medicine and Biology, 1974, 
Vol. 16, p. 264-. 

4. Myerowitz, P.D., Brown, J.W., Harrison, L.H., Griffith, J.M., Henry, W.L. 
and Mcintosh, C.L. A Comparison of Simultaneous Echocardiographic and 
Electromagnetic Flowmeter Determination of Stroke Volume. Supplement III to 
Circulation , Vols. 49 and 50, October 1974. 

5. Henry, W.L., Griffith, J.M., Michaelis, L.L., Mcintosh, C.L., Morrow, A.G., 
and Epstein, S.E. Quantitation of the Mitral Orifice Area by Real-Time 
Two-Dimensional Echocardiography. Supplement III to Circulation , Vols. 49 

and 50, October 1974. 

6. , Epstein, S.E., Griffith, J.M. , Goldstein, R.E., Redwood, D.R. 

Effect of Prolonged Space Flight on Cardiac Function and Dimensions. Am. J. 
Cardiol. 35: 143, 1975. 



37 



7. Griffith, J.M. and Henry, W.L. A Moving-Trace Monitor for Video 
Systems. Med. Instrum . 9: 73, 1975. 

8. Henry, W.L., Maron, B.J., Griffith, J.M., Redwood, D.R., and Epstein, S.E. 
Differential Diagnosis of Anomalies of the Great Arteries by Real-Time 
Two-Dimensional Echocardiography. Circulation 51: 283-291, 1975. 

9. , Clark, C.E., Griffith, J.M., and Epstein, S.E. Mechanism of 
Left Ventricular Outflow Obstruction in Patients with Obstructive Asymmetric 
Septal Hypertrophy (Idiopathic Hypertrophic Subaortic Stenosis). Am. J. 
Cardiol. 35: 337-345, 1975. 



38 



Project No. Z01 RS 00009-05 BEI 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Electrical and Electronic 
Engineering Section 

3 . Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: Nuclear Magnetic Resonance Techniques for Biochemical Analysis 

Previous Serial Number: DRS-BEIB-6 

Principal Investigators: Thomas R. Clem, Walter S. Friauf, Edwin D. Becker 

Other Investigator: James A. Ferretti 

Cooperating Units: LCP-NIAMDD, PSL-DCRT 

Man Years: 

Total: 2.0 
Professional: 1.5 
Other : . 5 

Project Description: 

Objectives : Innovate and implement improved methods for structural elucida- 
tion of organic molecules by means of muclear magnetic resonance with empha- 
sis on flexibility and convenience in selecting specific nuclei for study and 
the particular type of test performed. 

Methods Employed : Develop and evaluate techniques for improving sensitivity 
and versatility, including use of a superconducting magnet, pulse train exci- 
tation with digital programming of the sequences, heteronuclear decoupling, 
real-time computerized data acquisition, digital averaging, phase correction, 
matched filtering, Fourier Transformation, and printout of spectra. Develop 
and evaluate Rapid Scan Fourier Transform NMR techniques as an intermediate 
alternative to CW and pulsed FT methods. Develop and evaluate improved 
methods of RF generation for greater reliability and flexibility. 

Major Findings : NMR techniques can be used to routinely obtain parameters of 
organic molecules beyond those previously available including nuclei other 
than iH and 13 C. 

Significance : Technique offers unprecedented capability for elucidation of 
organic molecule structure and, in particular, the location of ^C, et al, 
atoms. The high field strength of the superconducting magnet enables finer 
resolution than is obtainable with most other 1 ^C NMR apparatus. 



39 



Proposed Course ; Modifications with a second superconducting magnet to 
enable experiments with full-time application to 13c and related atoms. 

Keyword Descriptors: Nuclear Magnetic Resonance, Fourier Transform NMR. 



Honors and Awards : None 

Publications : 

Cohen, J.S., Bradley, R.B., Clem, T.R.: pH Dependence of the l^C Spin-Lattice 
Relaxation Rate of the Carboxyl Carbon of Acetic Acid. J. Am. Chem Soc . 97: 
908-909, 1975. 

Wasylishen, R.W., Clem, T.R., Becker, E.D. Nuclear Magnetic Resonance 
Chemical Shifts of Some Monosubstituted Isothiazoles. Can. J. Chem . 53: 
596-603, 1975. 



40 



Project No. Z01 RS 00010-04 BEI 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Electrical and Electronic 
Engineering Section 

3 . Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: Measurement of Low Level, Rapid Chemical Reaction Rates by 
Laser Jump, Temperature Jump, and Stopped Flow Techniques 

Previous Serial Number: DRS-BEIB-9 

Principal Investigators: Michael Greifner, P. Boon Chock 

Other Investigators: None 

Cooperating Units: LC-IR-NHLI 

Man Years: 



Total: 


1.0 


Professional: 


.75 


Other : 


.25 



Project Description: 

Objectives : Measure incremental parameter changes corresponding to important 
biochemical reactions over a wide dynamic range. Develop a system capable of 
detecting and displaying chemical reaction rise times of less than 100 
nanoseconds. 

Methods Employed : Light absorption and fluorescence are monitored with 
photomultipliers . Dynode switching provides wide dynamic range without 
impairment of frequency response, linearity or accuracy. High intensity 
pulsed light sources improve the singal to noise ratio of nanosecond absorp- 
tion measurements. Signal averaging techniques recover low level signals 
otherwise obliterated by noise. Improved data processing reduces investigator 
evaluation time for a typical experiment from weeks to days. 

Major Findings : Development of new stopped flow cell reduces dead time from 
milliseconds to microseconds. Allows researchers to record reaction rates 
previously masked in mixing time of two chemicals. Stopped flowmeter with 
increased sensitivity provides an order of magnitude improvement in absorption 
level detection over commercially available instruments. High sensitivity is 
required to detect especially low level enzyme reactions. 



41 



Significance: Improved system sensitivity and frequency response enable new 
exploratory investigations into the complex mechanisms of various enzyme 
functions. State-of-the-art instrumentation for temperature jump apparatus 
and stopped flowmeters can provide information on the incremental, fast 
interactions between antibiotics with enzymes or proteins. 

Proposed Course : Complete evaluation of stopped flowmeter reaction times . 
Patent new stopped flow cell. Design and develop multi-mix stopped flow 
apparatus. Design and develop pulse unit for high intensity lamps. Test 
and evaluate temperature jump apparatus. Design and develop instrumentation 
for detection of fluorescence and absorption time constants of laser 
temperature jump. 

Keyword Descriptors : Laser temperature jump, stopped flow. 

Honors and Awards : None 

Publications : Rhee, S.G., Greifner, M.I., and Chock, P.B. ATP Determination 
by Stopped-Flow Method. Journal of Analytical Biochemistry (in press). 



42 



Project No. Z01 RS 00011-02 BEI 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Electrical and Electronic 
Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: Electrical Safety Program for Clinical Center Patients and 
Patient Care Areas. 

Previous Serial Number: None 

Principal Investigator: Roland Corsey 

Other Investigators: Corwin Strong, Anthony Vita, Walter S. Friauf 

Cooperating Units: ADM-CC, SMS-BEIB 

Man Years : 

Total: 1.0 
Professional: 1.0 
Other: 

Project Description: 

Objectives : Establish a patient environment free of shock hazards and assure 
Clinical Center compliance with accreditation requirements regarding electri- 
cal safety. 

Methods Employed : Establish NIH standards for the evaluation of commercial 
and non- commercial medical equipment; establish a testing program for all 
patient-contact electrical equipment; train nursing staff on the fundamentals 
of electricity and electrical safety; investigate and report on electrical 
accidents; conduct surveys of patient care areas to correct electrical 
hazards in grounding and power distribution; advise medical and nursing 
staff on new equipment purchases; participate in shaping of national, 
electrical safety standards. 

Major Findings : The test program for medical equipment has uncovered 
instances of high electrical leakage current and poor grounding. Surveys of 
patient care areas have established the need for improved grounding and 
power distribution systems in critical care areas. 

Significance : In critical care areas such as catheter laboratories, operating 
rooms and intensive care areas, the likelihood of accidental electricution 
has been reduced. 



43 



Proposed Course : 

1. Train additional personnel on the fundamentals of electrical safety. 

2. Extend the patient care area surveys to non-critical areas. 

3. Extend the equipment testing program to test all new equipment before it 
is put into service. 

Keyword Descriptors : Medical equipment, electrical safety standards, 
critical care areas. 

Honors and Awards : None 

Publications: 



Friauf, W.S.: Test Equipment for Hospital Safety Programs, In Proceedings 
of the 27th Annual Conference on Engineering in Medicine and Biology, 1974 , 
Philadelphia, Pennsylvania . Arlington, Va., The Alliance for Engineering in 
Medicine and Biology, 1974, Vol. 16, p. 496. 



-s 



44 



Project No. Z01 RS 00012-04 BEI 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Mechanical Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 197-4 through June 30, 1975 

Project Title: Atraumatic Electrical Sensing in the Human Brain Cortex 

Previous Serial Number: DRS-BEIB-12 

Principal Investigators: Seth Goldstein 

Other Investigators: Edward M. Schmidt, John Van Buren, John Oakley 

Cooperating Units: LNLC-NINCDS, SN-NINCDS 

Man Years: 



Total: 


1.5 


Professional: 


1.0 


Others : 


.5 



Project Description: 

Objectives : (l) Achieve stable electrode location with respect to an active 
neuron for reliable actue extracellular recording of human brain cell 
acitivity within the pulsating cortex at prescribed depths up to 0.5 cm with 
minimum tissue damage. 

(2) Extend this technique to achieve intracellular recording from the 
pulsating cortex. 

Methods Employed : A microelectrode is supported by a gas bearing assembly and 
held within the cortex at the desired insertion angle. A fine lead screw is 
actuated by gas thrust bearings to retain the "floating" action during 
electrode depth adjustment. An electrocortigram is simultaneously obtained 
from the adjacent area of cortex. 

Major Findings : The device has been successfully used to obtain high quality 
extracellular human recordings for prolonged durations. Intracellular 
recordings using glass micropipette electrodes have been obtained from 
pulsating monkey brain cortex. 

Significance : Single-cell electrical recording from cerebral cortex in humans 
has been limited because of difficulty in atraumatically eliminating the 
effects of cortical motion. This new method is expected to markedly improve 
the acquisition of valid information necessary to enhance anderstanding of 
brain function and epilepsy. 



45 



Proposed Course : Extension of the technique to intracellular studies in 
human brain cortex; refinement of technique and apparatus, if necessary; 
clinical applications; extension of device family for related types of 
measurement requirements . 

Keyword Descriptors : Single-cell electrical recording, extracellular 
electrical recording, intracellular electrical recording, neuroelectric 
recordings. 

Honors and Awards : Goldstein, S.R. : Electrode Insertion Device for 
Neuroelectric Recordings. U.S. Patent No. 3,341,310 (October 15, 1974). 

Publications : 

Goldstein, S.R., Schmidt, E.M., Bierley, F.L., and Bak, M. : A Gas Bearing 
Mechanism for Atraumatic Electrical Recording from Individual Neurons in 
Human Cerebral Cortex. Transactions of the American Society of Mechanial 
Engineers, Journal of Dynamic Systems, Measurements and Control (in press). 



i 



46 



• 



Project No. Z01 RS 00013-01 BEI 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Mechanical Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: In Vitro Muscle Studies/Hypertrophy 

Previous Serial Number: None 

Principal Investigators: Edward Lebowitz, Lawrence Thibault 

Other Investigators: None 

Cooperating Units: CB-NHLI 

Man Years : 

Total: 1.0 
Professional: 1.0 
Other: 

Project Description: 

Objectives : ( 1 ) To explicate the mechanism of cardiac hypertrophy in vitro 
using cat papillary muscle preparations. 

( 2 ) To investigate phosphorylation of papillary muscle in vitro ( organ 
culture ). 

Methods Employed : Experimental apparatus has been developed in which cat 
papillary muscle is suspended in a constant temperature recirculating medium. 
PO2 and PCO2 of the medium are monitored as electrical stimuli are applied 
to the preparation. 

Forces of contraction are measured concomitantly with gas tensions. Tissue 
growth is detected optically. 

Major Findings : The preparations can be maintained viable for several days. 
This enables both phosphorylation and hypertrophy for adequate periods to 
reliably analyze both of these phenomena in vitro . 

Significance : More detailed knowledge of hypertrophic mechanisms in cardiac 
muscle bears directly upon clinical diagnosis and therapy. Quantification of 
phosphorylation in cardiac muscle should contribute to the fundamental under- 
standing of cardiac contractility. 

Proposed Course: Improve and extend experimentation and analysis. 



47 



Keyword Descriptors : Hypertrophy, phosphorylation, organ culture, 
papillary muscle. 

Honors and Awards; None 



I 



Publications: None 



A8 



Project No. Z01 RS 0001/4-01 BEI 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Mechanical Engineering Section 

3. Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

Project Title: Neural Trauma 

Previous Serial Number: None 

Principal Investigators: Lawrence Thiabult, Thomas Gennarelli 

Other Investigators: None 

Cooperating Units: Georgetown University 

Man Years: 



Total : 


1.0 


Professional: 


1.0 


Other : 


.0 



Project Description: 

Objectives : To determine the effects of mechanical strain on nerve tissue 
function. To investigate the role of mechanical strain on nerve tissue mem- 
brane transport regulations. 

Methods Employed : Equipment has been developed which permits controlled loads 
to be applied to isolated neural tissue. Mechanical stress and strain are 
measured concomitantly with electrophysiological parameters and associated 
biochemical changes. 

Major Findings : Mechanical strain affects neural function. Compound action 
potentials are modulated by strain, both fully reversibly and irreversibly 
depending upon the level of strain. Biochemical changes, e.g. potassium 
movement, occur simultaneously, suggesting membrane permeability changes. 

Significance: Elucidation of the effects of membrane strain on chemical 
transport processes contributes substantially to the basic understanding of 
fundamental physiological mechanisms. 

Proposed Course : Refine and extend experimental and analytical techniques for 
nerve cells and other tissues. 

Keyword Descriptors : Nerve tissue, neural trauma, membrane transport, 
mechanical strains. 



49 



Honors and Awards: None 



Publications: 



Gennarelli, T.A. and Thibault, L.E.: Functional response of the central 
nervous system to controlled inertial loading. In Proceedings of the 27th 
Annual Conference on Engineering in Medicine and Biology, 1974, Philadelphia , 
Pennsylvania . Arlington, Va., The Alliance for Engineering in Medicine and 
Biology, 197-4, Vol. 16, p. 175. 

Thibault, L.E., Gennarelli, T.A., Tipton, H.W. and Carpenter, D.O.: The 
physiologic response of isolated nerve tissue to dynamic mechanical loads. 
In Proceedings of the 27th Annual Conference on Engineering in Medicine and 
Biology, 1974, Philadelphia, Pennsylvania . Arlington, Va., The Alliance for 
Engineering in Medicine and Biology, 1974, Vol. 16, p. 176. 



. 



"*! 



50 



I 



DIVISION OF RESEARCH SERVICES 

Summary of Program Activities July 1, 1974 through June 30, 1975 

ENVIRONMENTAL HEALTH AND SAFETY PROGRAM Dr. Rudolf G. Wanner 

Associate Director 

I. SUMMARY 

1. Office of the Associate Director for Environmental Health and Safety 

The transfer of the Radiation Safety Section, Department of Nuclear 
Medicine, Clinical Center, to the Division of Research Services as the 
Radiation Safety Program, took place on July 1, 1974. On the same date, 
the Safety Management Program transferred to DRS. On December 23, 1974, the 
Associate Director was appointed and given responsibility for the development 
of a well-integrated, comprehensive and centralized environmental health 
and safety program. Further progress toward centralization of functions was 
made on March 1, 1975, when the responsibilities for implementation of the 
National Environmental Policy Act (NEPA) were assigned to the Associate 
Director. 

2. Environmental Services Branch 

Two major program events caused a complete reorientation of activities in 
the Office of the Chief which, in turn, added to the workload of the Branch's 
two Sections. The first event was the organization of the Environmental 
Health and Safety Program within DRS. 

The second event was the sudden increase of activities generated by the 
National Environmental Policy Act which escalated beyond predicted levels. 
Sixteen EPA effluent guidelines and several non-DHEW environmental impact 
statements were reviewed for the Office of the Assistant Secretary for 
Health, DHEW. Staff assistance was provided to the Division of Engineering 
Services in preparing the environmental assessment of the NIH Master Plan 
involving approximately sixteen construction projects. 

Staff assistance was provided to the Assistant Director for Administration, 
NIH, in the Generic Analysis of all NIH programs. Staff also served on a 
task force of the Assistant Secretary for Health, DHEW, to develop proposed 
Departmental regulations and procedures for implementation of NEPA. 

The national concern for employee health and safety was reflected in the ESB 
workload. Thirty- two employee requests were investigated concerning 
suspected hazards in their work places and three extensive surveys were 
conducted for requested Environmental Differential Pay. Three formal OSHA 
complaints were also reviewed and 108 other laboratory surveillance visits 
directly related to employee health were made. 

The Branch concern for environmentally safe and sound facilities and equip- 

51 



ment continued. The major equipment problem remains procurement of Laminar 
Flow Biological Safety Cabinets. Two pathways were simultaneously pursued; 
one the continued development of a Qualified Products List and the other a 
proposal to the National Sanitation Foundation to develop a joint industry 
and public health supported standard and certification procedure. The 
Branch expended 80 mandays in the field performing acceptance tests in _ 
order to "speed up" the process. Staff worked cooperatively with individual 
investigators and other DRS staff in designing new or modified equipment in 
24 instances. In addition, 66 Laminar Flow Biological Safety Cabinets were 
modified by an ESB contractor, and 118 chemical fume hoods are being up- 
graded cooperatively with the Division of Engineering Services. Fourteen 
major construction projects were reviewed continually to assure proper 
environmental safeguards. 

Investigator requested consultation on procedures, equipment and basic 
information remains high. Approximately one manyear was spent in providing 
this information on a person-to-person basis. Eighty percent of the 
requests are from the intramural programs. In addition to the person-to- 
person consultations, mail requests for environmental health and safety 
information are mounting. This is reflected in the 300 plus mailings of 
the "Biological Laboratory Hazards" memorandum and provision of over 4-00 
copies of the Biohazards Safety Guide to non-NIH investigators. 

3. Radiation Safety Program 

On July 1, 1974, the Radiation Safety Section, Department of Nuclear 
Medicine, Clinical Center, was transferred to DRS and designated the 
Radiation Safety Program. As a part of the consolidated environmental 
health and safety program and in an effort to improve current operations, 
an Acting Deputy Head of the Radiation Safety Program was appointed. 

■Major program efforts consisted of assurance of compliance with the^ 
regulations of the Nuclear Regulatory Commission, formerly the Atomic 
Energy Commission. The NRC issued seven licenses to NIH for the use of 
radionuclides. Possession of these licenses has greatly reduced the 
detailed problems of isotope procurement, but carries strict responsibilities 
governing use and ultimate disposal. 

License renewals and amendments were obtained to permit the installation of 
two irradiators at the Clinical Center, one of 2400 curie capacity, the other 
of 500 curie. Physical and radiation problems encountered during and after 
the initial installation were satisfactorily solved. 

The use of radionuclides for diagnostic, therapeutic, and research purposes 
is rapidly increasing at NIH. Although users of radioactive material are 
required, as part of the NRC regulations, to show proof of training in the 
safe handling of such substances, radiation incidents continue to occur. 
These incidents were in their majority due to human errors, thus preventable. 
Whenever physical factors were the cause, the Radiation Safety Program took 
prompt remedial action. 



52 



All authorized users of radioactive iodine were notified of an additional 
safety requirement. As of October 1974, no iodinations are permitted in 
hoods without charcoal filters. This requirement was met by being able to 
accommodate investigators in doing their iodinations in Building 21, which 
has a sufficient number of hoods with charcoal filters. 

Under NRC requirements, the Radiation Safety Program is responsible for 
receiving, shipping and disposal of radioactive materials. An increase 
of 17% in the number of shipments received reflects the increased use by 
NIH investigators. To this workload were further added new regulations for 
receiving and opening packages, checking for contamination at the time of 
arrival. Consequently, manpower had to be provided on weekends and holidays. 

Radioactive waste volume increased by 31% for the reporting period. Im- 
provements in the waste handling area consisted of equipping the waste 
compactor with a HEPA filter to prevent radioactive aerosols from escaping 
into the work environment, and of installing a ventilated hood for the 
storage of volatile radioactive wastes . 

Laboratory surveillance was maintained at a high level and carried out in 
the nearly 1500 areas where radioactive materials are being used. Strong 
emphasis was placed on the control of airborn radioactive substances. The 
number of air samples taken increased by 271% over the previous fiscal year. 
Investigation and remedial action took place where contamination was found. 

Surveys of diagnostic, therapeutic and research x-ray units were made 
routinely and by request. In only one instance, a significant radiation 
hazard was found, an x-ray diffraction unit had to be shut until corrective 
action was taken. Shielding and other protective recommendations were made 
for other units where a hazard potential existed. In addition, 50 electron 
microscopes were surveyed for x-ray leakage. 

Personnel monitoring for exposure continued as a routine activity. The 
number of users of film badges, or external radiation personnel dosimeters 
increased by 9% over the last fiscal year. An important improvement was 
the replacement of ring badges by thermoluminescent dosimeters. 

The new dosimeters do not have to be worn on the hand, which makes them 
more acceptable to the user and less prone to water damage. 

Investigators and workers working with certain levels of radioactive materials 
and specified substances are required to submit urine specimens for radio- 
assay. The number of specimens assayed increased by 6% during the reporting 
period. The number of whole body counts, required by NRC of users of gamma 
emitting radionuclides, increased by 17%. 

The Radiation Safety Program continued to provide training in the safe 
handling of radioactive materials. Over 850 individuals attended training 
courses, most of them the one-day course entitled, "Radiation Safety in the 
Laboratory." 



53 



4. Safety Management Program 

Accident reports processing has been improved substantially by using a 
computer-based system. This system allows for a better data analysis and 
makes it possible to identify more precisely areas and activities with high 
accident rates. Consequently, preventive and corrective measures can be 
more accurately applied. 

Accident investigations were conducted on a continuing basis by safety 
specialists. The NIH accident and injury reporting system continued during 
the reporting period to function on a recognized better level than most 
DHEW agencies. The close coordination of this activity with the Employee 
Health Service and other branches kept reporting close to 100$. Wherever 
necessary, remedial action was taken and recommendations were given. Fire 
prevention continued to be of major concern. A report, "NIH Fire Safety 
Posture", was completed. In it, each building on the NIH Bethesda location 
is described and discussed with regard to fire safety. The report provides 
a basis for eliminating fire hazards and for up-grading NIH facilities to 
prevent losses from fire. 

In other accident prevention activities, efforts continued to survey the 
NIH work environment for compliance with Safety Standards and to examine 
potential accident producing situations. A concentrated effort was made 
to clear the corridors and elevator lobbies of the Clinical Center from 
excess storage of items. The photographic survey made to document unsafe 
conditions was made available to those responsible for and using the areas 
in question. Subsequent surveys showed some improvement, but not to the 
extent desired. 

Following a request from the Division of Engineering Services, an "Industrial 
Safety Guide" was under development through the reporting period. It is one 
of a series of guide books issued by the Safety Management Program. The 
"Supervisor's Guide to OSHA" was prepared and distributed as a publication 
which identifies workplace safety standards set by the Occupational Safety 
and Health Act as they are applicable to the NIH environment. A "Safety 
Guide for Contract and Project Officers" is being reviewed and should be 
available by mid-FY 76. It will enable the Division of Contracts and 
Grants, 0D, to include an up-to-date safety and health clause on contracts 
where applicable and required. 

There was a wide range of training activities throughout the year. An 
important part is the new employee orientation for Clinical Center and ADA 
personnel. Safety specialists contributed with presentations and material 
to a variety of NIH training courses. In addition, three slide/cassette 
programs on Research Laboratory Safety, Safe Driving and Workmen's Compen- 
sation were completed. A new training course on Biohazards Safety is under 
development. This course may become a requirement for laboratory workers 
handling hazardous biological agents. 



54 



II. PROGRAMS 



A. Objectives 

To function as the central manager, coordinator and regulative authority 
over the Environmental Services Branch, the Radiation Safety Program and 
the Safety Management Program in support of the Director, DRS, to achieve 
Division objectives pertaining to environmental health and safety. 

To administer a comprehensive environmental health and safety program for 

NIH. 

To establish, interpret and monitor compliance with policies and standards 
which serve to maintain and protect health, safe working conditions and 
environmental quality for the NIH community. 

To provide related technical, surveillance and training services. 

B. Current Programs 

The Associate Director supervises and coordinates the current programs of 
the component units. These include: 

1. The establishment of standards, policies and guidelines for environmental 
health and safety, and their application. 

2. Analysis of data and interpretation of regulations to develop solutions 
for the elimination of environmental, radiation and other safety hazards. 

3. Implementation of the requirements of federal, departmental and agency 
regulations at NIH. 

<4. Laboratory support services for the NIH environmental health and safety 
program. 

5. Training services as required by federal regulations. 

6. Training development as specific needs at NIH are recognized and 
identified. 

7. Surveillance for environmental, radiation and other safety hazards by 
a monitoring system. 

8. Maintenance of registries of biological agents, radioactive materials, 
chemical carcinogens and other substances of known or suspected hazardous 
potential. 

9. Review of Technical Reports on environmental health and safety from or 
for NIH, PHS, DHEW and other sources. 



55 



10. Maintenance of a reporting and information system on environmental 
health and safety at NIH. 

C. Program Progress and Accomplishments 

1. Office of the Associate Director for Environmental Health and Safety 

The transfer of the Radiation Safety Section, Department of Nuclear Medicine, 
Clinical Center, to the Division of Research Services as the Radiation 
Safety Program, took place on July 1, 1975. On the same date, the Safety 
Management Program transferred to DRS. These were major steps of progress 
towards a consolidation of NIH environmental protection programs, with 
the Environmental Services Branch already in the Division. 

On December 23, 1974, the Associate Director was appointed and given 
responsibility for the development of a well-integrated, comprehensive and 
centralized environmental health and safety program. Consequently, a 
considerable amount of time and effort was spent in the second half of 
FY 75 on the identification of existing problems and their solution within 
the newly established program. At the same time, continuity of services 
by the component units was maintained. 

Further progress toward centralization of functions was made on March 1, 
1975, when the responsibilities for implementation of the National Environ- 
mental Policy Act (NEPA) were assigned to the Associate Director. As 
Agency Environmental Officer, he is responsible for assuring NIH compliance 
with the Act. This includes preparing NIH policy and procedures, the 
receipt and processing of all technical review requests, and NEPA training 
activities. The transfer of NEPA responsibilities was another major step 
towards achievement of FY 75 objectives. It made it possible to coordinate 
and administer a comprehensive program, since the responsibilities for 
implementation of the other major requirements, the Occupational Safety 
and Health Act (OSHA) and the Nuclear Regulatory Commission (NRC), were 
already inherent in the program. 

The Associate Director and selected staff are members of NIH committees 
relating to environmental health and safety, such as the Biohazards Committee, 
Radiation Committee, Infections Control Committee and their various sub- 
committees to provide technical advice to NIH research and service functions, 
to identify problem areas, to make recommendations of their solution and to 
review and recommend procedures and technical information for risk assessment 
and reduction of hazards . 

A close working relationship was established with the Office of Research 
Safety, NCI, resulting in coordination of activities, such as the maintenance 
of a chemical carcinogen registry, inspection of biological safety cabinets 
and evaluation of laboratory containment facilities. 

Past experience and repeated incidents of the same nature have demonstrated 
that the NIH research population is not always aware of special investigations 
carried out, remedial action taken and preventive recommendations made. The 
issuance and distribution of Environmental Health and Safety Special Invest- 



56 



igations Reports (EHSSI) was introduced. These reports will be prepared 
whenever a particular incident study of interest to the scientific 
community has been completed. The Environmental Health and Safety Program, 
through its component units, as a whole accomplished its objectives for 
FY 75. 






I 



57 



ENVIRONMENTAL SERVICES BRANCH Vinson R. Oviatt, Chief 

BRANCH PROGRAMS 

A Objectives 

The Environmental Services Branch objectives at NIH, Bethesda, Maryland, and 
field station facilities are: 

1. To locate and solve environmental problems. 

2. To assure a safe, compatible environment for patients, staff, and 
the surrounding community. 

3. To promote an environment conducive to a quality research program. 

B. Current Programs 

The Branch objectives were attained through the following closely co- 
ordinated program areas: 

1. Biohazards and Contamination Control 

The biohazards and contamination control program is designed to promote 
■ a safe environment for personnel and to protect research work at all NIH 
facilities in Bethesda and in the field. There is a regular surveillance 
of potentially hazardous laboratory and animal room areas, control equip- 
ment and facilities. Consultation is provided on a case-by-case basis for 
laboratory arrangements needed to protect the investigator and the public. 

2. Industrial Hygiene 

The industrial hygiene program recognizes, evaluates, and controls environ- 
mental factors and stresses which may cause illness or significant discomfort 
among workers or citizens of the community. Gaseous and particulate air 
contamination potentially or actually generated at NIH and laboratory use 
of chemical carcinogens are major surveillance activities. Problems of 
noise, temperature extremes, and non-ionizing radiation are also investigated 
and resolved. 

3. Hospital Environmental Control 

The hospital environmental control program in the Clinical Center is designed 
to protect patients, employees, and visitors from environmental influences 
which may be unsafe, unhealthful, or uncomfortable. 

59 



4. 



General Sanitation and Sanitary Engineering 



The general sanitation and sanitary engineering program is concerned with 
basic environmental factors affecting the health of NIH employees, visitors 
and the quality of the research environment. These factors include food 
sanitation, water supply, solid and liquid waste disposal, housekeeping 
practices, pesticides, and water pollution control. 

5. Environmental Studies for Support of Research and Patient Care 

Continuing environmental studies are conducted as a necessary adjunct to 
surveillance and consultation activities. Studies are oriented to 
environmental systems and problems; evaluation of new equipment and methods; 
quality glassware, animals, and water; environmental stresses related to 
light, heat, noise, food, water, and waste; and the identification of 
environmental contaminants . 



• 



6. Training 

Training to promote job effectiveness is provided for ESB personnel and 
staff members at NIH. This training is particularly related to environmental 
control devices and practices in the general research environment which 
require special training for proper operation and handling. 

C. Program Progress and Accomplishments 

1. Biological Control 

The NIH Biohazards Safety Guide was developed and printed in two formats. 
A looseleaf edition permitting continuous updating as new biological safety 
developments occur has been distributed to NIH laboratory investigators. A 
perfect bind edition is available for investigators outside NIH, either as 
single copies furnished upon written request or in quantity from the Govern- 
ment Printing Office, Superintendent of Documents. The Guide will be 
published in Spanish by the Pan American Health Organization, Washington, 

D. C. 

A new questionnaire for registration of microbial agents, tissue cultures 
and animals was developed and distributed to laboratory workers. Included 
in the questionnaire were requests for information on serum samples, their 
storage, concentration of agents, and volumes of fluids handled. The 
information obtained has been placed in a computer data bank. Readouts on 
microfiche cards are broken down into several categories; lists of individuals 
by name alphabetically and by social security number, listing by building and 
room number and listing of employees by item (microbial agent, tissue 
culture or animal). Q 

A chamber for the decontamination of equipment has been constructed in 
Building 13. It will serve to sterilize equipment shipped to Surplus 
Property, Materiel Management, ODA; to instrument repair in the Biomedical 
Engineering and Instrumentation Branch, DRS; or to companies outside NIH, 
as necessary, to reduce any biohazards. 



60 



ESB assisted the Procurement Branch, Materiel Management, in making seven 
site visits to manufacturers of Class II Laminar Flow Biological Safety- 
Cabinets for field testing and evaluation of cabinets for compliance with 
the NIH Specification. Test data and drawings were reviewed by staff 
personnel before each visit. Approximately eighty mandays were involved. 

ESB initiated a request to the National Sanitation Foundation, Ann Arbor, 
Michigan, to develop performance standards for the Class II Laminar Flow 
Biological Safety Cabinet. As a result, members of the Biological Control 
Section are serving on a committee to develop the standards. Under this 
standard, the NSF would be responsible for carrying out necessary tests, 
publishing a list of approved models by manufacturer and controlling the 
quality of the equipment. Such a standard would reduce the commitment of 
ESB to Materiel Management, ODA, and shorten the delivery time of the 
cabinets. 

Fourteen plan reviews of major building renovations at different stages of 
design were made. These included the renovation of Building 376, Fort 
Detrick, Maryland, to house the NINCDS slow virus program; the open bay 
area in Building 41; and Building 14D to house infected primates. 
Approximately fifteen draft reviews of such items as the Clinical Center 
Biological Disaster Plan, the National Sanitation Foundation's Standard 
for Biohazard Cabinetry and the Design Criteria for Viral Oncology Research 
Facilities were performed. Programs of Requirements for a large number of 
laboratories in Buildings 36 and 41 were also reviewed. 

The number and subject of consultations with individuals at NIH and outside 
NIH are shown in the following table (each consultation averaged four hours: 

Outside 
NIH NIH 

(a) Selection of Equipment 70 14 

(b) Proper Use of Equipment 11 1 

( c ) Safety Devices and 

Biohazards Control 81 38 

Modification of equipment included the development of a safety cabinet for 
handling biological agents and radionuclides; the modification of a 
Laminar Flow Biological Safety Cabinet to permit the handling of nude mice^ 
under sterile conditions; and in conjunction with the Biomedical Engineering 
and Instrumentation Branch, DRS, development of a ventilated containment hood 
for a freeze fractionator unit that will be used for work with scrapie virus. 

Investigations were made in response to employee requests for evaluation of 
their work environment for hazardous conditions. These included microbiological 
assessment of air quality at the incinerator; review of laboratory procedures 
related to a possible laboratory-acquired serum hepatitis case; micro- 
biological aerosol of NIHAC Waste Treatment Plant; and the NIHAC Primate 
Quarantine Facility. 



61 



An ESB contractor conducted a survey to analyze facility and systems 
adequacy of selected biological laboratories performing hazardous work. 

Sixty-six Laminar Flow Biological Safety Cabinets were modified under contract 
to provide more air velocity in-flow at the work access opening, thus pro- 
viding greater protection to the investigator. 

A "re-certification" of the containment capabilities of the secondary barrier 
systems in the Building 36 Virology Suite was completed. 

Seven thousand six hundred and thirty-eight (7,638) bacteriological tests 
were performed in the analysis of patient food and milk, potable water and 
waste water, and other environmental samples. 

2. Industrial Hygiene 

The Occupational Safety and Health Act of 1970 and subsequent Presidential 
Directives and Regulations published in the Federal Register generated a 
major workload for the industrial hygiene program. In one instance, a 
complaint was filed with OSHA via the Congress which required a special 
survey of working conditions in the NIH Power Plant. 

Compliance with OSHA Regulations for control of chemical carcinogens in the 
NIH research environment continued to provide a major workload. A special 
in-depth survey of select animal rooms, laboratories, and other spaces 
reporting the use of chemical carcinogens was completed by an ESB contractor. 
This survey indicated that facilities and work practices require improvement 
to assure a safe and healthful work environment. 

ESB reviewed and commented on proposed DHEW regulations to control chemical 
carcinogens in the research environment. This issuance should clarify the 
responsibilities of management, the worker, and safety personnel. 

An ESB contractor completely surveyed and labeled 761 NIH chemical fume hoods. 
A large number of hoods (118) did not meet minimum standards. A cooperative 
project with the Division of Engineering Services to upgrade these hoods is 
being undertaken. 

An independent evaluation was made of the recently designed NCI Laminar Flow 
Biological Safety Cabinet under contract to determine if its performance as 
a chemical fume hood is acceptable. Several potential problems and limitations 
on its usage were identified. 

ESB, in cooperation with BEIB and the Radiation Safety Program, developed and 
tested a small hood for use within a standard chemical fume hood to remove 
gaseous radioactive iodine from the air before it is discharged to outside 
air via the existing exhaust system. The hood has a top mounted charcoal 
filter and blower. Its use should greatly reduce the number of reportable 
radioisotope release episodes. 



62 



Increasing concern about noise, both as a health hazard and as an inter- 
ference in the work environment, resulted in a continued large workload in 
making the various evaluations and determining the required corrective 
measures . 

An improved system for disposal of chemical waste at NIH was implemented 
this year. The NIH Fire Department carefully packages waste chemicals 
for disposal or recycling by a contractor. Remaining acids, bases, and a 
few special chemicals not disposed of by this means are disposed of at NIH 
in its special facility. Plans for upgrading the chemical packaging and 
disposal facility have been completed. 

3. Hospital Environmental Control 

This program continued on a low priority basis due to reduced staffing. A 
member of the Biological Control Section was assigned on a part-time basis 
to provide requested surveillance and monitoring services. The Operating 
Room Surveillance Protocol was reestablished in cooperation with the 
Surgical Nursing Service and the Infections Control Committee. 

A. General Sanitation and Sanitary Engineering 

Semiannual surveys were made of all GSI Cafeterias and Blind Industries and 
Services of Maryland snack bar facilities, both on and off the main NIH 
reservation. Brief visits were regularly made between surveys to assure 
continued high quality food service sanitation. 

Continued monitoring of general NIH outside "grounds" sanitation, including 
loading docks, showed some improvement this year. 

A new NCI animal care program is expected to improve animal room sanitation 
in the coming year. 

Routine analyses of NIH and NIHAC central distilled water systems for specific 
resistance, and potable water systems for chlorine content and microbial 
quality were continued. In addition, copper analyses of the various distilled 
water systems were made quarterly and special analyses for selected high 
purity systems were provided as needed. 

The Branch completed sixteen EPA Environmental Impact document reviews in 
support of the NIH Agency Environmental Officer. 

Solid waste at NIH presented a major workload ranging from individual 
sanitation problems of improper waste disposal to reviews of building 
system plans. A major effort was mounted in terms of trials of paper bag 
and paper board box systems which will replace "G.I." cans when the Mont- 
gomery County Pathological Incinerator and the new NIH Back-up Pathological 
Incinerator are put into use in FY 76 and FY 77. 

Monthly visits were made to the NIHAC to conduct sampling at the Sewage 
Treatment Plant, Broad Run and Lagoon #2. At the same time, waste water 
samples were also taken from the NIH storm drains and analyzed. Samples 

63 



were taken from NIH sewers for mercury analyses. The Branch was involved 
with the EPA in a special study of waste water effluent from the Clinical 
Center. Assistance was provided DES in selection of an engineering con- 
sultant who will develop plans to upgrade the NIHAC Waste Water Treatment 
Plant. 

Air quality data from the Maryland monitoring trailer located on the NIH 
grounds was obtained from computer tapes supplied by the state and a 
program prepared to extract and report the pertinent NIH data. 



5. 



Environmental Studies 



An extended study of mold spores in the Clinical Center was initiated in 
collaboration with the Clinical Mycology Section, Laboratory of Clinical 
Investigation, NIAID. Of special concern is the relationship of aspergillus 
found in the air supply and aspergillus infections which have been seen 
in increasing numbers of immunosuppressed patients. 

A study was completed of the biota of Broad Run at the NIHAC. The study 
involved an extended survey of "bottom life" of the stream above and below 
the Waste Treatment Plant. ESB staff was assisted by a professional marine 
biologist under contract with ESB. 

An improved all-glass water still was developed to meet the high purity water 
demands of several investigators . The still has the unique capability of 
maintaining long "shelf life" sterility of the distilled water. 

A study of the sterility, shelf life and various methods for packaging 
and sterilizing materials used in nursing units was conducted for the 
Pharmacy Department, Clinical Center. 

'6. Training 

ESB continued participation with other NIH safety groups in developing 
laboratory safety posters which are displayed throughout the campus and 
are printed in the NIH Record. This is an effort to raise the safety 
awareness level of NIH employees. 

The Quarterly Memorandum, "Biological Laboratory Hazards," is apparently 
meeting a need at NIH and in collaborative laboratories . The mailing list 
now exceeds 300 laboratories, including several overseas institutions. 
The Laboratory Infection Bibliography , developed under contract, will 
supplement the memorandum. 

Nine presentations were made to separate intramural laboratories on proper 
laboratory practice. In addition, staff attended five Institute Laboratory 
Chiefs' Meetings to discuss the "Biohazard Safety Manual" and related matters. 
The sixteen-hour laboratory practice course was again presented to summer 
student employees . Four hundred NIH employees attended a series of training 
sessions on noise hazards and hearing conservation presented by the Branch. 



64 



Demand for Branch personnel as lecturers and speakers in all facets of 
environmental health and safety remained high. Of particular interest was 
participation in hearing conservation programs presented to two sixth 
grade Elementary School classes. Technical presentations were given to the 
Metropolitan Area Construction Safety Association, The American Industrial 
Hygiene Association, National College Health Association, 17th Annual 
Biological Safety Conference, Michigan Environmental Health Association, 
National Metropolitan Area Environmental Health Association, American 
Association of Laboratory Animal Sciences, Kentucky Hospital Association, 
American Society for Microbiology and the Tissue Culture Association. 
Staff also lectured at the NIOSH course, "Safety In The Laboratory." 

ESB personnel received 913 hours of training at designated short courses 
or in classroom experience at colleges and universities. Two COSTEP 
trainees received on-the-job experience in the Branch. 

D. Problems 

The unplanned changing scope and direction of ESB's program is creating 
an adverse impact on allocation of resources. New laws and directives 
concerning the environment unpredictably superimpose a workload on ESB's 
basic service effort. Special studies and document reviews for OSHA and 
NEPA have deadlines precluding work planning that ensures NIH investigators 
receive the personal services that ESB is supposed to provide. Contracting 
with private firms has helped remove some of the routine workload; however, 
contracts require ESB staff time for preparation, to monitor the contractor, 
to evaluate the results of the contractor's efforts and to see that NIH 
acts on contractor recommendations. Hopefully, program plans of the NIH 
Environmental Health and Safety Program will solve this problem. 

The procurement of Class II Laminar Flow Biological Safety Cabinets to 
.meet the needs of NIH scientists is continually faced with long delivery 
schedules of one year or more. This hampers planning for biological 
research that require this equipment. In an effort to improve delivery 
schedules, ESB has provided review of test data, drawings and made site 
visits to manufacturers of this equipment to help eliminate problems with 
compliance to the NIH specification. Technical advice is being provided to 
the National Sanitation Foundation in their development of a performance 
standard for the manufacture of this equipment. 

E. Program Plans 

The Branch programs will be integrated into the overall scheme of the DRS 
Environmental Health and Safety Programs. A realignment of ESB staff > into 
functional work units based on program demands and objectives in keeping 
with professional backgrounds is planned. A major decision must be made 
concerning manpower utilization considering the following factors: 
Technical assistance demands from NIH intramural and extramural investi- 
gators and programs, necessary surveillance and outside legal directives 
concerning environmental health and safety. Assistance is anticipated ^ in 
training activities with consolidation of this activity into the Associate 
Director's office. Decisions regarding programming will be developed 

65 



jointly with the other DRS Environmental Health and Safety components to 
present a balanced program. 

Contracting for services in FY 75 will continue at approximately the same 
level as in FY 75. It is expected that some analytical work will have to 
be contracted out for those materials of environmental concern that we 
cannot analyze in our own laboratory. 



F. 



Publications and Patents 



Herman, L.G. : Disinfectants and Environmental Monitoring. In Proceedings 
of a Seminar Presented at the 23rd Annual Session of the American Association ; 
for Laboratory Animal Science , Joliet, Illinois, Pub. 74-5, pp. 38-44, 
1974. 

Herman, L.G. : Environmental Microbiology and Infection Control Programs in 
Health Care Facilities: Introductory Remarks. He lath Laboratory Science 
11: No. 2:6970, 1974. 

Waters, P.F., Hadermann, A.F., and Karamian, N.A.: Aseptic Aerosols From 
Cold Vapour Humidifiers. Lancet 739-740, 1974. 

Herman, L.G. : The Hospital Environment. Professional Sanitation Manage- 
ment . Issue 6:11-14, Issue 7:20-23, 1974. 

Irwin, J. : A Trap and Filtration Apparatus for Vacuum Lines. Health 
Laboratory Science 11: no. 3:195-196, 1974. 

Wilkinson, T.K: Ultraviolet Radiation as a Disinfectant. In Proceedings 

of a Seminar Presented at the 23rd Annual Session of the American Association 

for Laboratory Animal Science , Joliet, Illinois, 1974. 

McCoy, Z. and Irwin, J.: The Effect of Disinfectants on Bacteriophage 
0X 174 1,2. Lab. Anim. Sci . 24:no. 4:630-632, 1974. 

DeRoos, R.L., Oviatt, V.R. , DuChene, A.G. and Vick, N.J.: Water Use in 
Biomedical Research and Helath Care Facilities — A Presentation of Article 
Summaries" ! Div. of Env. Health, School of Public Health, Univ. of Minn. , 
Minn., Minn., pp. 163, 1974. 

Farmer, J. J., Ill, Herman, L.G. : Pyocin Typing of Pseudomonas aeruginosa. 
J. Infect. Pis . Vol. 130, Supplement: S43-46, 1974. 

Voxakis, A.C., Lamy, P.P., Herman, L.G.: Sterility Assurance Through 
Environmental Monitoring. Hosp. Form. Mgt. pp. 14-19, 1974. 

Dunsmore, D.J.: Wylbur 'Talks" to DRS. INTERFACE pp. 17-19, No. 53, 
December 25, 1974. 

Karamian, N.A. : Separatory Funnel, U.S. Patent #3,836,334, Issued 
September 17, 1974. 



RADIATION SAFETY PROGRAM 



Michael B. Musachio, Head 



BRANCH PROGRAMS 



A. Objectives 

The objective of the Radiation Safety Program is to assure compliance 
with Part 10, Code of Federal Regulations, Chapters 19 and 20, conditions 
of licenses granted by the Nuclear Regulatory Commission (NRC), other 
applicable Federal regulations, and all policies established by DHEW and 
NIH in regard to the safe use of ionizing radiation so as to assist the 
NIH researcher in obtaining the maximum benefit from ionizing radiation 
while maintaining personnel exposure and the release of radioactive 
materials to unrestricted areas at the lowest practicable levels. 



B. 



Current Programs 



The program objectives were achieved through the following closely 
coordinated program areas. 

1. License Activities 

License activities include a continual review of the seven licenses issued 
to NIH by the Nuclear Regulatory Commission which permit the receipt, 
storage, use and disposal of radioactive materials in accordance with 
Nuclear Regulatory Commission regulations and standards. License appli- 
cations, renewals, or amendments are prepared and submitted to NRC as 
necessary. A semiannual inventory of all radioactive materials is 
conducted to ensure that possession limits prescribed by the NRC are not 
being approached. New or proposed legislation or regulatory guidelines are ' 
thoroughly reviewed for impact on the Program. The administrative aspects 
of license activities are conducted in close coordination with the Radiation 
Committee and NIH Management. 

2. Radionuclide Shipping and Receiving 

The radionuclide shipping and receiving program covers all radioactive 
materials coming to or leaving the NIH reservation. All incoming shipments 
are checked for contamination, proper labeling and packaging, damage, and 
correct compound, isotope and activity. A check is made as to whether the 
individual ordering the material is authorized by the Radiation Committee 
to work with radioactive materials. 

3. Radioactive Waste Disposal 

The radioactive waste disposal program includes supervision and coordination 



67 



of the waste disposal program, including the waste disposal records. These 
activities are conducted under the conditions of License No. 19-00296-11, 
issued by the NRC. 



4. 



Patient Therapies and Diagnostic Studies 



Health physics support is provided to patients receiving therapeutic doses 
of radioactive materials and in some diagnostic studies to ensure that: 
they receive the dose prescribed, personnel exposures are as far below 
permissible levels as practical, and there is compliance with all applicable 
regulations and policies. 

5 . ' Radiation Safety Surveillance 

The surveillance program consists of routine surveys in all laboratories 
where radioactive materials or other equipment capable of producing 
ionizing radiation are used. The areas are checked for compliance with 
the provisions of 10 CFR 19, 10 CFR 20, Occupational Safety and Health 
Act, and other policies and standards approved or promulgated by the 
Radiation Committee. Appropriate followups are made to secure compliance 
and in the case of repeated or highly hazardous conditions, the matter is 
.referred to the Radiation Committee for appropriate corrective action. 

6. Personnel Monitoring 

The personnel monitoring program monitors radiation workers to determine 
radiation dose from external sources and internally deposited materials. 
This generally consists of film and thermoluminescent dosimetry, whole 
body counts and radioassays of urine samples. It involves record keeping 
of lifetime exposure histories, review and distribution of the results, 
and if necessary, appropriate remedial action. 



7. 



Training 



The training program goal and activities are aimed at making all radiation 
workers fully aware of the regulations and policies governing the safe 
use of ionizing radiation, to be cognizant of the hazards associated 
with its use, and to inform and motivate radiation workers with regard to 
use procedures and equipment which will minimize personnel exposures. 
The provision of such training is mandatory under the requirements of 
10 CFR 19 and the Occupational Safety and Health Act. 

8. Technical Assistance and Other Radiation Safety Services 

The technical assistance program includes consulting services to personnel 
at all levels on all aspects of radiation protection. Space is available 
in Building 21 for handling high levels of activity. Shielding materials 
are provided, and portable survey meters are issued to laboratories. The 
survey meters are calibrated semiannually and repaired as needed. In 
addition, technical assistance is given to the researcher to effectively 
use ionizing radiation in the conduct of biomedical research. Supervision 
and assistance is also provided in contaminating accidents. Increasingly, 



requests for technical assistance are received from NIH field stations, 
other components of DHEW, other federal agencies, state and local govern- 
ments, universities, business organizations and concerned citizens 
regarding radiation safety. 

c - Program Progress and Accomplishments 
1. License Administration 

License No. 19-00296-17 was amended to permit the installation of a 2,400 
Curie Cs-137 irradiator in Building 10 for irradiating mice and conducting 
other in vitro studies. The unit is similar in size and design to the 
existing blood product irradiator in Building 10, Rm. 3B11. A survey was 
conducted at the time of installation. There was a question regarding 
structural stability of the legs. This was corrected and the matter was 
referred to the NRC for further investigation. 

License No. 19-00296-12 was renewed and was also amended to permit re- 
location of the 500 Curie Co-60 irradiator from Building 10, Rm. B1-B52 to 
Room B2-B52, and after renovation it will be permanently installed in 
Room B2-B54. A radiation survey conducted after the initial move, 
required by a license condition, indicated radiation leakage. Additional 
shielding satisfactorily corrected the problem. 

License No. SUB-985, which permits use of depleted uranium as beam 
defining devices in two linear accelerators, was renewed by the NRC. 

On November 21-22, 1974, an NRC representative Division of Regulatory 
Operations, Region I, conducted an inspection of License No. 19-00296-10. 
The results indicated satisfactory progress in the areas of personnel 
training and the control of releases of radioiodine to the lowest 
practicable level. Occasional failure of investigators to collect breathing 
zone air samples during iodinations was noted. A reply was prepared 
outlining the administrative controls established to assure compliance 
with this requirement. Copies of the inspection report and the NIH reply 
were posted on bulletin boards in all buildings where radioactive materials 
are used as required by 10 CFR 19. 

Semiannual accountability reports for the special nuclear material contained 
in the plutonium-powered pacemakers (License No. SNM-279) were submitted on 
a timely basis to the NRC. 

Approximately 200 sealed sources were checked for leakage on a semiannual 
basis as required by License No. 19-00296-10. 

There were several radiation incidents requiring NRC notification. The 
most significant were a 600 rem body badge exposure to a physician with the 
Metabolism Branch, NCI. The individual definitely did not receive this 
high a dose, however, no plausible explanation of this exposure could be 
determined. Similarly, a physician in the Nuclear Medicine Department, 
Clinical Center, was reported as having a 600 rem exposure to his finger 
badge. An explanation of this exposure could not be clearly determined and 

69 



it is speculated that the film was light struck. 

An investigation was conducted as a result of an 86.4 nCi thyroid burden 
of 1-125 in a Guest Worker, Clinical Endocrinology Branch, NIAMDD. The 
individual performed an iodination without adequate control of airborne 
radioactive materials and was exposed to an estimated 1-125 concentration. 
The NRC was notified in accordance with the provisions of 10 CFR 20.4-05. 

On October 22, 1974, a report was submitted to the NRC as required by 
10 CFR 20.405. It resulted from an 84 nCi thyroid burden of 1-131 reported 
in a Radiopharmacy Technician NM, CC. Breathing zone air samples were 
not available and there was a possibility that the maximum permissible air 
concentration may have been exceeded. A thorough investigation indicated 
that the most probable cause of the uptake was the result of an undetected 
contamination incident, the result of inadequate personnel monitoring. The 
calculated exposure to the individual was 943 mrem to the thyroid and 2 mrem, 
whole body exposure. The circumstances leading to the incident were care- . 
fully reviewed and appropriate steps have been taken to prevent a recurrence. 

Routine air sampling indicated that a Research Associate, Laboratory of 
Immunology, NIAID, was exposed to an air concentration of 1-125, twice 
the time modified maximum permissible concentration listed in Appendix B, 
Table I, 10 CFR 20, resulting from improper use of the iodine containment 
facilities. It was reported to the NRC in accordance with 10 CFR 20.405. 

Quarterly Radiation Committee meetings were attended. Major considerations 
were: review and reaffirmation of existing policy on use of prophylactic 
thyroid blocking agents for radioiodine users; approval of new maximum 
permissible activity guidelines establishing maximum levels of various 
radionuclides which can be safely handled in the typical NIH research 
laboratory; review of experimental protocols for ionizing radiation; 
review of applicants for authorized use; review of radiation incidents; 
discussion of non-compliant areas; and general discussions of finding and 
requirements of the NRC. 

2. Radionuclide Receiving and Shipping 

In fiscal year 1975, a total of 9,163 incoming shipments of radioactive 
materials totalling 122.3 Curies was received. The total cost of such 
materials was $1,316,185.38. This represents a 11% increase in shipments 
over the previous fiscal year. 

New procedures for receiving and opening packages, were instigated in 
response to new Nuclear Regulatory Commission regulations. The new 
procedures require checking and recording of contamination data on incoming 
packages and coverage for checking incoming packages for contamination on 
weekends and holidays. 

3. Radioactive Waste Disposal 

Again, the volume of liquid and solid radioactive waste continued to 
increase significantly. Six hundred and forty, 55-gallon drums and 10 

70 



boxes of radioactive waste were shipped out for burial by Hittman Nuclear 
Corp. under the terms of an agreement with the Department of Defense. This 
is an increase of 31$ over last fiscal year. 

Liquid scintillation vials are picked up weekly for disposal by burial 
under NIH contract 75-C-18 CC. During the fiscal year, 42,507 trays 
containing 100 vials each were disposed of, an increase of over 31$ above 
the previous fiscal year. 

A ventilated hood was installed in the waste handling area to be used for 
the storage and assay of volatile radioactive wastes. 

The waste compactor was equipped with a HEPA filter to minimize the 
possible release of infectious or radioactive aerosols to the atmosphere 
or work environment. 

4. Patient Therapies and Diagnostic Studies 

Health physics support was given to the Clinical Center in administering 
therapeutic doses of radiation to 21 patients receiving up to 250 millicuries 
of 1-131. This included radiopharmaceutical assays, assistance in admin- 
istration of the material, instructions of patient and nursing personnel, 
contamination control, daily pickup and assay of urine, removal of con- 
taminated linens and other materials, survey and decontamination of room 
on patient discharge, and records required by the NRC. 

5. Laboratory Surveillance 

Continued emphasis was given to laboratory and x-ray surveys during FY '75 
to assure compliance with NRC regulations, OSHA requirements and NIH 
policies and procedures governing the safe use of ionizing radiation. 

Laboratory compliance and contamination surveys were conducted by Radiation 
Safety Section staff and by Contract (NIH-75C-217-CC ). The contractor 
conducted 1,4-89 laboratory surveys. Another 1,44-8 surveys were conducted by 
Radiation Safety Program personnel. The total figure is down by about 48$ 
from FY- 74 and is attributed to delays in awarding the laboratory survey 
contract, reduced manpower levels, increased use of radioactive materials, 
and increased NRC regulatory demands. 

As a result of increased emphasis by NRC on the control of airborne radio- 
active materials, 2,226 air samples were taken from the work area and 
building exhaust systems, an increase of 271$ over the previous fiscal 
year. 

57 diagnostic therapeutic or research x-ray surveys were conducted by Applied 
Health Physics Inc. (Contract No. 74-C-4H1-CC ) and 30 surveys or followups 
were conducted by Radiation Safety Program personnel. In addition, 50 
electron microscopes were surveyed for x-ray leakage by RSP personnel. One 
x-ray diffraction unit was found to constitute a significant radiation 
hazard and operations were curtailed until appropriate corrective action was 
taken. 

71 



6. Personnel Monitoring 

Film badge processing ( external radiation personnel dosimeters ) has been 
under contract to the Radiation Detection Company since May 1973. Con- 
tractor performance has generally been satisfactory and excellent response 
has been received on requests for immediate film readings. 

Individuals on film badges increased from 1778 to 1945, a 9% increase over 
the previous fiscal year. In addition, 43 employees of the Rocky Mountain 
Laboratory and two Arizona field stations are also covered on the service. 

Thermoluminescent dosimeters were substituted for the film type dosimeter 
previously used in ring badges. The new dosimeters are more comfortable to 
the user and there are less difficulties with unidentified or water-damaged 
dosimeters . 

The number of radioassays of urine specimens increased from 1190 last fiscal 
year to 1260 in fiscal year 1975, an increase of approximately 6%. Specimens 
were requested of individuals involved in radiation incidents and of those 
working with certain levels of radioactive materials in compliance with 
criteria established in the license applicaton and license conditons. 

429 investigators and their staff working with greater than established 
levels of gamma emitting radionuclides were requested to receive whole 
body counts, a 17$ increase over the previous fiscal year. 

7. Radiation Safety Training 

Continued emphasis was placed on Radiation Safety Training. A special 
effort was made to identify individuals working with radioactive materials 
not formally trained in the safe handling of these materials . A one-day 
course, "Radiation Safety in the Laboratory" was presented monthly with 
502 NIH employees and 18 guests in attendance. 

A two-week course, "Radiological Health for Radionuclide Users" was con- 
ducted twice with 119 persons in attendance. 

Short one to two hour specialized training sessions were presented to 
several groups of NIH employees . One-hour presentations were made to 
Clinical Center nurses as part of their orientation program with 118 in 
attendance. A two-day training course, "Liquid Scintillation Counting 
Methodology", conducted by an equipment manufacturer was attended by 36 
persons. A similar one-day training course was presented to 23 persons 
at the Rocky Mountain Laboratory, NIAID. Two separate presentations were 
made to five physicians and six nuclear medicine technologists of the 
Nuclear Medicine Department, Clinical Center, to emphasize the importance 
of using syringe shields and controlling personnel contamination. A one- 
hour session was presented to 11 members of the nursing staff of the 
Employee Health Service. A special training session was conducted for the 
medical and nursing personnel of the Health Catheterization laboratories 
in the Clinical Center regarding the hazards of x-rays and radioactive 
materials to which they may be exposed. 



72 



Three high school and college students working part-time were given basic 
radiation safety training in an hour session. 

12 nurses on 9 West and eight nurses on 13 West received special in- 
struction on handling patients who received diagnostic levels of radioactive 
materials. 

8. Technical Assistance 

The calculated exposures of Nuclear Medicine technologists to selected 
radionuclides in dosing syringes was verified using calibrated solutions 
and film dosimetry. Dry samples of the same radionuclides were also 
measured on an extrapolation chamber to simulate skin contamination. The 
data was necessary to clarify differences in theoretical calculations 
presented in the literature. The dose rate at the surface of a syringe 
loaded with 20 mCi of Tc-99m was found to be around 800 mrem per minute. 

Problems with the commercially available syringe shields discouraged 
routine use by Nuclear Medicine technologists. To overcome these 
difficulties, several meetings were held with the personnel of the Nuclear 
Medicine Department, manufacturers, and staff of BEIB, DRS. As a result, 
a prototype tantalum syringe shield was designed and is in current use. 
An industrial firm has requested drawings and it is expected to be in 
commercial production shortly. 

A prototype iodine containment facility and adsorption unit was designed 
by RSP personnel and fabricated by BEIB, DRS. Tests under actual operating 
conditions indicated it was effective in reducing the concentration of 
radioiodine released to the environment by 99.8%. 

Several meetings were held with personnel from the Bureau of Biologies, 
'FDA and representatives of ESB, DRS, in regard to the location and design 
requirements of a central iodination facility to serve Building 29. The 
final plans for this facility, which is to be located in Room 301, were 
completed and approved. 

Final plans for the renovation of the wing of Building 10 (W.R. #34-2836) 
were reviewed by this office and were discussed with the Office of Licensing, 
NRC. Assistance will be provided in inspecting and testing the shielding. 
The 2,000 Curie Co-60 source will be moved under the supervision cf Radiation 
Safety personnel. 

The shielding requirements for Ga-67 and the hazards associated with 
Xe-127 were evaluated for the Nuclear Medicine Department. 

The NRC referred a local hospital for assistance in performing dese calcu- 
lations for a patient who inadvertently received an overdose of radioactive 
material. 

Radiation Safety in the Physician's Handbook was reviewed for the Clinical 
Center . 



73 



Technical assistance was provided to several researchers with counting 
problems particularly with double and triple radioisotope labeling 
experiments; to several local hospitals, university, federal Government, 
commercial, and NCI contract Radiation Safety Officers on 1-125 air sampling 
and control measures; and to the NHLI, Surgery Branch, in developing a 
counting method for four different radioisotopes to determine blood flow 
in three areas of the heart and the cardiac muscle. 

Approximately 250 G-M portable survey meters were calibrated, batteries 
replaced and repaired, if necessary, semiannually by the Institute of 
Resource Management Inc. under contract NIH 74--C-1140-CC. 



D. 



Problems 




The most critical problem facing the Radiation Safety Program is the 
wide disparity between the available manpower resources and the workload 
required to provide essential services and to assure compliance with the 
provisions of 10 CFR 19, 10 CFR 20 and the requirements of the Occupational 
Safety and Health Act. 

The imposed manpower ceiling of 18 full-time positions is exactly the 
same level deemed inadequate by the Chairman of the Radiation Committee in 
1968 in his report to the Director of NIH. Since this time, it is conser- 
vatively estimated that the workload has increased by greater than 200%. The 
Radiation Safety Program is a captive of the increased use of radioactive 
materials as an essential research tool and increasingly more stringent 
regulations and guidelines of the Nuclear Regulatory Commission. 

In. 1972, NIH was requested to attend a meeting at the Regional Office of 
the Nuclear Regulatory Commission to discuss radiation safety program 
deficiencies and to provide assurances that corrective action would be 
taken. As a result of a much greater use of contracting, increased use of 
part-time personnel, increased use of compensated and uncompensated overtime, 
reorganization and reassignment of program personnel, improved work 
procedures, increased responsibility on authorized users, a realignment of 
program priorities, strong support of the Radiation Committee, and the 
personal sacrifice and dedication of Radiation Safety Program staff, there 
was a significant increase in the level of Radiation Safety compliance at 
NIH. 

However, the early gains made in lessening the disparity between manpower 
resources and workload have been negated by program growth and the increasing 
requirements by the Nuclear Regulatory Commission. Unless there is strong 
administrative commitment to the principles of the Radiation Safety Guide 
and the necessary manpower is provided for the Radiation Safety Program to 
effectively accomplish its mission, the number of radiation incidents and 
the number of citations issued by the Nuclear Regulatory Commission can be 
expected to increase. Any significant license restrictions or the possi- 
bility of license revocation could be a source of considerable embarassment 
to the NIH and NRC. A commitment of unusually high levels of manpower might 
be required to cope with added restrictions, and the restrictions could 
seriously jeopardize the effectiveness of the intramural research program. 



74 



E. Program Plans 

Further use of contract services will be explored. The feasibility and 
estimated cost of contracting the total radioactive waste handling program 
is under current review. Improvement in existing contracts as they expire 
is planned to assure high quality service. 

High priority will be given to improved work procedures and more effective 
utilization of existing manpower resources. 

Continued high priority will be given to radiation safety training, sur- 
veillance and compliance. 

Employee development will be encouraged particularly Adult Education, 
Upward Mobility College, In-service training and continuing education 
programs . 

Technical assistance will be sought to assure that data processing is fully 
and effectively used in program management. 

High priority will be given to employee morale and the work of the DRS 
Human Relations Committee. 

F. Publications and Patents 

A paper entitled, "Radiation Safety in Nuclear Medicine" was presented at 
the Society of Nuclear Medicine in San Diego, California, June 11-14, 1974, 
and an exhibit by the same title won a bronze medal in the Technologists' 
Section exhibits. 



75 



SAFETY MANAGEMENT PROGRAM John R. Leach, Head 



BRANCH PROGRAMS 



A. Objectives 

The primary objective of the Safety Management Program is to develop 
and implement a continuing and comprehensive effort toward creating and 
maintaining safe conditions, procedures, and attitudes as they relate 
to prevention of all types of accidental injuries, illnesses, or fires. 

B. Current Programs 

1. Accident Reporting, Investigation, and Analysis 

In coordination with the Employee Health Service, CC, and other functional 
areas, the activity is designed to ensure prompt, accurate reporting of 
accidents; selected investigation of accidents to better define or identify 
contributing factors and/or to initiate corrective action to prevent a 
recurrence; and to apply analytical techniques to the accident experience 
to establish work priorities and to measure relative performance. 

2. Accident Prevention 

In addition to prevention activities resulting from accident investigation, 
this function specifically applies accident prevention principles, codes, 
or standards to the work environment. In addition to individual and 
corporate efforts of SMP staff, coordination is effected with other 
functional responsibilities, i.e. engineering design, construction, pro- 
curement, personnel, policy, transportation, etc. 

3. Training and Promotion 

A function of accident prevention, these activities represent a significant 
portion of total SMP effort. Primary direction is toward integration of 
safety needs with other training activities conducted throughout NIH. 
Promotional activities include distribution of general and specific 
material on hazards and their control to employees. 

4. Compensation Officer 

Not typically considered a responsibility of Safety Management, a 
valuable service is rendered to injured employees applying for compensation 
benefits. Additionally, the Compensation Officer serves as the focal point 
at NIH for information and advice on requirements of the Federal Employees' 
Compensation Act, and for education of administrative and supervisory 

77 



personnel in requirements and responsibilities under the Act. 
C. Program Progress and Accomplishments 

1. Accident Reporting, Investigation, and Analysis 

Accident data was transferred from a manual to a computer system. Problems 
initially encountered in implementing the system, because more data was 
captured than in the present DHEW system, essentially have been resolved. 
DHEW machine-readable data can now be provided rather than source documents. 
More importantly, the SMP system provides a more comprehensive analysis 
on a timely basis. Such data will be passed on to the management and 
supervision of high accident producing activities to intensify prevention 
activities. The change to a computer system necessitated a change of 
reporting forms. Modification of a DHEW form was developed, approved, and 
put into service. After several months use, indicated changes were incor- 
porated in a pending revision. 

During the early part of the year, staffing permitted a significant 
expansion of accident investigation activities; however, personnel changes 
and losses among Safety Specialists have had a serious impact on this 
activity, although inspections of the major NIH field stations were completed. 
In spite of restrictions, staff effectively responded on accident reports. 
Subsequent actions have eliminated serious potential hazards. In light of 
continuing restrictions on employment, it will be necessary to increase the 
ability of certain supervisory personnel to adequately investigate a broader 
range of accidents. 

2. Accident Prevention ' 

A comprehensive report, "NIH Fire Safety Posture" was completed and forwarded. 
It covered all strengths and weaknesses of Bethesda campus buildings re- 
lated to fire safety. It is anticipated that the report will serve as a 
basic guide to short and long-range upgrading NIH facilities against 
extensive loss due to fire. SMP continued to review and analyze Federal 
and other standards for applicability at NIH and continued to examine the 
work environment to identify specific instances of non-compliance with 
existing standards or potential accident-producing conditions. The examin- 
ation effort was not as extensive as had been planned due to limited resources, 
although all major field activities were inspected during this year. 

A request from the Plant Engineering Branch, later modified to include all 
of the Division of Engineering Services, directed considerable staff time 
toward development of an "Industrial Safety Guide." Much material has been 
developed to date, but there is a major problem of acceptable format. 
Construction/alteration review and approval continued. J 

Work was initiated, in conjunction with the Division of Contracts and 
Grants, CD, to develop an effective and acceptable "safety and health" 
clause appropriate in certain classes of contracts. DHEW policies requiring 
such a clause were originally issued in 1968 and changes such as the 
Occupational Safety and Health Act of 1970 have made certain of the pro- 
visions obsolete. Unofficially, the Director of Safety, DHEW, indicated 

78 



a willingness to consider any material developed at NIH as a Department- 
wide substitute for the existing policy. Although originally felt to have 
limited application, it now appears a broadly coordinated undertaking will 
result. 

3- Training and Promotion 

SMP representation was regularly included in all basic Supervisory Training 
conducted at NIH including routine new employee orientation for Clinical 
Center and ADA personnel. An eight-hour review of fire prevention codes 
was presented to approximately 40 DES engineering staff. In conjunction 
with the Training and Development Branch, Division of Personnel Management, 
safety material was provided for inclusion in secretarial training. 

Changes in provisions of the Federal Employees' Compensation Act necessitated 
a major training and orientation effort for supervisory personnel in ADA 
and DES, as well as timekeepers in several areas. 

Several releases of "Spot Hazards" were prepared and distributed. 

The Supervisor's Guide to OSHA was prepared and distributed. It identifies 
workplace standards promulgated under the Occupational Safety and Health 
Act considered applicable to the NIH environment and outlines basic 
supervisory roles. This simplified description of complex standards will 
measurably aid efforts toward more complete compliance. 

A "Safety Guide for Contract and Project Officers" was prepared in draft 
and reviewed by interested or affected staff. Work was temporarily halted 
when some questions associated with the basic provisions needed further 
development by the Division of Contracts and Grants. This project will 
be completed by mid-FY 1976. 

Three slide/cassette programs were completed: Research Laboratory Safety, 
Safe Driving , and Workman's Compensation . Copies were provided to all major 
field locations and DHEW. The original artwork for the Research Laboratory 
Safety series was released to the National Safety Council for production and 
distribution through their facilities. This is the first time a cooperative 
undertaking with the Council has been brought to a satisfactory conclusion. 

Training was provided to other government personnel for qualification as 
road test examiners on request by the Civil Service Commission. 

Developing and establishing training needs identified by the NIH Biohazard 
Committee was initiated. 

In addition to approximately 4-0 mandays of career training, the staff 
participated in presentations to personnel and/or students of the University 
of Maryland, Georgetown Medical School, University of Minnesota, and local 
research organizations. 



79 



4. 



Compensation Officer 



The total claims for compensation filed during CY-1974 did not vary 
significantly from the previous year, but there was an atypical up-swing 
during the last quarter of FY-1974. This is largely due to the changes 
in the Federal Employees' Compensation Act which now permits continuing 
an employee in a pay status up to 45 days for loss from work as a result 
of a traumatic injury. Previously, "lost time" injuries involving less 
than 21 days, required a three-day waiting period in a non-pay status. 
Participation with the Division of Personnel Management in the "Hire the 
Handicapped Program" resulted in reassignment of several employees who 
otherwise would have been retired on compensation disability as a result 
of work-associated injuries or illnesses. 



D. 



Problems 



Many of the attempts to achieve compliance with applicable standards were 
thwarted by the lack of adequate research space. It is nearly impossible 
to provide the needed ventilation or building renovations without signifi- 
cantly disrupting ongoing research. While one may argue the corridor must 
be "clean," there is clearly a problem of diminishing returns if already 
congested laboratories are expected to absorb even more equipment. This 
problem is certainly not new to NIH and is subject to decision controls 
external to NIH. SMP will continue to seek alternatives which will provide 
improvement. Some of the larger, semiroutine labs may lend themselves to 
industrial work-flow techniques which typically have not been considered in 
the research environment. 

A complete report of crowded and cluttered conditions in Building 10 was 
completed and forwarded. While some areas subsequently showed improvement, 
the overall impact of this project was not as effective as was hoped. 
Continued space shortages coupled with restricted manpower in the central 
services, seriously affects quick resolutions of this long-stand problem. 

The present size of the staff does not permit adequate performance in the 
wide range of the responsibilities associated with the program. Staff 
shortages require a critical evaluation of priorities. 

E. Program Plans 

Computer-based accident data will be used as a more timely management 
information system than was possible under the manual procedure. Data 
analysis will also improve techniques for determining program priorities or 
areas of concentration. 

A comprehensive analysis of safety education and promotion needs will be 
completed and translated into a coordinated program. A safety awareness 
program, "Life is Fragile" will be implemented. 



In conjunction with the Supervisor's Guide to OSHA , a self-inspection 
program will be initiated as one means of extending compliance efforts, 
addition, methods for possibly utilizing other personnel for certain 



In 



classes of inspection and reporting will be investigated. 

Although Program objectives will be performed, the order of priorities and 
staff assignment will depend on the nature of the organization of the 
Environmental Health and Safety Program. 



81 



DIVISION OF RESEARCH SERVICES 
Summary of Branch Activities July 1, 1974, through June 30, 1975 

LIBRARY BRANCH Ruth C. Smith, Chief 

I. SUMMARY 

The Library Advisory Committee met three times during the year. 

Dr. Philip McMaster, NIAID, was appointed Chairman in February replacing 

Dr. John S. Finlayson, BB, who had served in that capacity for several years. 

At the same time the Committee was enlarged to 17 members with representation 

from all I/D's. 

On February 2-4, the Supreme Court, by a tie vote four to four, with Justice 
Blackmun disqualifying himself, affirmed without opinion the U.S. Court of 
Claims decision in the case of Williams and Wilkins vs. the U.S. that large- 
scale unauthorized photocopying and free distribution of copyrighted medical 
journal articles by NLM and the NIH Library are not copyright infringements. 

A memorial for Dr. Henry W. Scherp was presented to the Library in the form 
of monies to be applied for the purchase of books and journals for the 
Library collection in subject areas of interest to NIDR. 

A duplicate Library catalog was established on the Lower Level for use in 
proximity to the book collection. 

Effective November 1, the Technical Services Section was reorganized into 
two units, the Monographs Processing Unit and the Journals Processing Unit 
replacing the Acquisitions and the Cataloging Units. Functions and duties 
were realigned to eliminate much duplication of procedures. 

The Library became a member of the Ohio College Library Center's shared 
cataloging automated network system through the Federal Library Experiment 
in Cooperative Cataloging. On-line access to the cataloging data-base in 
Columbus will significantly contribute to more effective performance of 
technical services. 

After inspection and analysis of major automated library circulation systems, 
the decision was made to adopt the University of South Carolina Library 
system. The designer of the system visited the Library as consultant to 
advise with the Library, DRS Management Analysis Office and the DCRT repre- 
sentative. The PDP 11/40 minicomputer to be used in the Library underwent 
tests in DCRT. The project is in progress to convert the Library's biblio- 
graphic records for books in the collection into machine readable form. 

A nonprint collection was organized. Current audiocassettes, tapes and 
slides were added to previous microform holdings and are available for use 
in the Library or for loan. Newly acquired nonprint items are included in 
the monthly memorandum of additions to the Library. 



83 



The Branch Chief was named the Division of Research Services Chairman of the 
1975 Combined Federal Campaign. The Assistant Chief served as DRS Coordinator 
of the Drive. 

The Library prepared exhibits in connection with each NIH minority cultural 
week celebration for display in the outside corridor. The Branch Chief 
continued as a member of the NIH Minority Cultural Program Committee. 

The Branch Training Program provided training for individual employee develop- 
ment and more effective use of the employee in the Library. 

At the request of the National Cancer Institute, the Frederick Cancer Research 
Center at Ft. Detrick was visited five times during the year in relation to 
monitoring the library services provided by the contractor. 






8A 



II. BRANCH PROGRAMS 

A. Objectives 

The primary mission of the Library Branch is to operate an efficient, compre- 
hensive library in support of NIH scientific, medical, and administrative 
programs. Activities of the Library include selection, acquisition, organi- 
zation, maintenance, and circulation of literature pertinent to the programs; 
operation of a photocopy service; provision of interlibrary loan service; 
provision of informational, reference, and bibliographical services; pro- 
vision of Library services advisory assistance; and provision of a translating 
service for foreign scientific and medical literature. To fulfill its mis- 
sion, the Library is responsive to changing literature needs of the NIH 
investigators, is knowledgeable of current developments in manual and machine 
methods of communication and information retrieval, and is alert to adjust- 
ment of procedures for improved Library services. 

B. Current Programs 

Technical Services 

The Journals Processing staff procures journals by purchase, gift and 
exchange which have been selected as pertinent to the scope of the Library. 
The staff organizes and processes the journals for inclusion in the collec- 
tion and maintains accession records using manual and automated systems. 
It also prepares completed volumes for commercial binding. 

The Monographs Processing staff procures monographs and similar literature 
which have been selected as pertinent to the scope of the Library. The 
staff catalogs, analyzes for subject representation and processes these 
accessions for inclusion in the collection using manual and automated systems. 
It. also maintains the Library's catalogs and prepares listings for the 
monthly memorandum of additions to the Library. 

Readers Services 

The Circulation staff provides a charging system, making available books and 
journals. The staff issues Library Identification Cards; operates the 
Library's security system; provides an overdue recall system; and makes 
assignments to locked study carrels. 

The Stacks and Copy Service staff maintains the stacks, carrels, reference 
and Reading Room areas and shelves books and journals to facilitate access 
by the Library clientele. A copy service is provided which allows greater 
use of the Library's journal collection. 

The Interlibrary Loan staff obtains from other libraries literature required 
by NIH investigators which is not included in the collection. 

The Readers Services Section is responsible for developing, maintaining, and 
servicing a collection of library material in nonprint media pertinent to 
the scope of the Library and for providing equipment for its use. 

85 



Reference and Bibliographic Services 

The Library Services Adviser Program provides an integrated response to the 
information needs of the NIH scientific community. This may consist of 
utilization of external resources in addition to the resources and services 
available in the NIH Library, such as specialized information centers, 
computerized information retrieval systems, and clearinghouses. The Refer- 
ence staff supplies ready response to questions, verifies citations, and 
compiles short reference lists upon request. Its staff receives inquiries 
at the Reference Desks in the Upper and Lower Level Reading Rooms and by 
telephone. Reference Librarians answer difficult reference questions and 
compile literature searches as requested and maintain the collection of 
basic Reference Books. Professional staff provides bibliographic assistance 
with experienced searchers to conduct requested medical, chemical and bio- 
logical computer searches through National Library of Medicine's MEDLINE, 
Chemical Abstract's Chemical and Biological Activities (CBAC) and Biological 
Abstract's BioSciences Information Service (BIOSIS). Professional staff 
also selects books, journals and other literature for the Library collection 
by continually searching for literature pertinent to the scope of the Library. 

Translating Service 

The Translation staff provides oral, recorded and written translations as 
requested. Oral translations are emphasized in-house. Written translation 
service is provided through contractual firms with quality control maintained 
by the Library. 

C. Program Progress and Accomplishments 

Technical Services 

A reorganization of the Technical Services Section was effective November 1, 
197^. The Journals Processing Unit and the Monographs Processing Unit 
replaced the former Acquisitions Unit and the Cataloging Unit in order to 
eliminate duplication of procedures. Reorganization of functions and duties 
necessitated the rewriting of all position descriptions, posting of six 
realigned positions according to the Merit Promotion Plan and an intensive 
on-the-job training program for all Section employees. 

The Library became a participant in the Ohio College Library Center's shared 
cataloging automated system through the Federal Library Experiment in 
Cooperative Cataloging. The Library's staff has access and makes input to 
cataloging and acquisition data in the computer in Columbus contributed by 
700 or more libraries. Catalog cards for monographs are obtained through 
this system. 

A duplicate Library catalog was established on the Lower Level near the 
monograph collection to provide needed information on location. Duplication 
of the cards was performed by a contractual firm. 



86 



The second edition of Current and Noncurrent Journals in the NIH Library was 
issued in 197-4 (for administrative use). Arranged alphabetically by title, 
it includes for the first time complete holdings for all journals in the 
Library's collection. Due to the increased size of the second edition, the 
subject section of the first edition was eliminated. 

Readers Services 

Plans were completed for the implementation of an automated circulation 
system which will provide a more efficient service to the NIH community 
and better control of the Library's collection. Major automated library 
systems around the country were inspected and studied and after discussions 
with DRS Management Analysis Office staff and DCRT, it was concluded that 
the circulation system used by the University of South Carolina met the 
needs of the NIH Library. A PDP 11/40 minicomputer delivered the last of 
April was tested in DCRT prior to placement in the Circulation Unit. 
Mr. Kenneth Simons, designer of the system, visited the Library and made 
valuable suggestions especially relating to layout and system adaptation. 
The project of converting the Library's bibliographic records for books 
in the collection to machine readable format is underway. Mr. Michael Kremer, 
DRS Management Analysis Officer, and Mr. James De Leo, DCRT, are collabo- 
rating with the Library in implementing the system. 

Installation of a new copier has improved the important self-service to NIH 
investigators and supporting staff. 

The Library's collection of microforms including microcards, microfiche and 
microfilms has been listed by the nonprint Librarian. Guidelines for 
processing each type have been developed and nonprint items newly acquired 
and cataloged are included in the Library's monthly memorandum of new 
accessions. A modest number of current videocassettes and audiotapes have 
been acquired for use in the Library or for loan. An article on the service 
"NIH Library Offers Use of Microforms to Save Journal Shelving Space" 
appeared in the December 17 issue of the NIH Record . 

Reference and Bibliographic Services 

MEDLINE bibliographic search requests completed for calendar year 1974 
amounted to 7220, representing an increase of 1715 searches (23.7%) over 
the number of searches performed in 1973. The number of requests for 
searches in the field of chemistry through Chemical Abstracts automated 
CBAC service and in biology and related subjects through Biological 
Abstracts BIOSIS system were substantially the same as for the previous year. 

Translating Service 

Requests for oral, recorded and written translation services continued at 
the same level as last year. 



87 



Training 

The FY 1975 Branch Training Program provided individual employee development 
in the present job and more effective use of the employee in the Library. 
Employee training was completed in academic, professional, administrative, 
technical and in-Library courses and workshops. Two employees continued in 
the Adult Education program, one in the regular program, the other in a 
special training course. Three employees were enrolled in the NIH/FCC 
Upward Mobility College, one in Federal City College and one in the University 
of Maryland. 

Exhibits 

Exhibits prepared by the Library staff and displayed during the year covered 
the following topics: Radiation Safety and Nuclear Medicine (prepared by 
Radiation Safety); Asian-American Cultural Week; Spanish-American Cultural 
Week; World Population Year 1974; Black History Week; CANCERLINE Bibliographic 
Service; National Library Week; BEIB Service (prepared by BEIB); Native 
American Week; and Governmental Technical Reports in Relation to Biomedicine. 
Assistance was received from the Medical Arts and Photography Branch. 

D. Problems 

Downtime and poor quality of two of the photocopy machines continue as 
problems. One new machine has improved the situation; the acquisition of 
two additional machines replacing the old should eliminate this problem. 

A careful examination and weeding of the monographs collection remain to 
be accomplished as soon as the Scope and Coverage Statement is completed. 

The soaring cost of journal subscriptions has necessitated a reexamination 
of the Library's acquisitions policy. Second copies of some journals have 
been eliminated through the concerted efforts of the Library staff and the 
Library Advisory Committee. 

E. Program Plans 

Implementation of an automated circulation control system developed by the 
University of South Carolina will be completed. The new system, using a 
minicomputer and light pen technology, will provide more efficient service 
to Library clientele and improved control of the Library's collections. 

An analysis of additional applications of the minicomputer to other Library 
operations will be completed with the assistance of the DRS Management 
Analysis Office and DCRT staff. 

Continued expansion of the nonprint media collection is planned, based on 
specific requirements of NIH investigators. 

Conversion of the subject headings used in the Library's catalogs for 
identifying and locating medical books and journals to the specialized 



medical terminology used by the National Library of Medicine will be 
initiated. Library of Congress headings will continue to be used for 
material in other subject fields. 

Passage of Bill H.R. 2223, which has been introduced in the U.S. House of 
Representatives, with present wording of Section 108 (g)(2), may create 
problems for libraries in interlibrary loan activities and in photocopying. 

F. Publications 

Dougherty, A.E.: A Professional Training Program for Nonprofessional 
Employees. Bull. Med. Libr. Assoc . 63:64-66, 1975. 

National Institutes of Health Library: Current and Noncurrent Journals in 
the NIH Library 1974 . (Internal Use only) 

: Memorandum: Recent Additions to the 
NIH Library. Monthly ( Internal Use only") 



89 



DIVISION OF RESEARCH SERVICES 

Summary of Branch Activities July 1, 1974- through June 30, 1975 

MEDICAL ARTS & PHOTOGRAPHY BRANCH Mr. Arthur F. Moore, Chief 

I. SUMMARY 

Demands for MAPB services increased approximately 25 percent in FY 1975. 
Physical consolidation of the graphics activities has satisfied the need 
for complete unity in graphics and statistical art preparation. Deliver- 
ing finished work has accelerated. Medical illustration demands remain 
normal. Delivery of scientific photography has been reduced from 15 days 
to seven. Work has been done to establish graphic standards for statisti- 
cal materials produced by the Branch. This is a forerunner of a continued 
drive to establish a unified visual communications system, for the NIH. 
With new equipment and wider use of contract service, the Branch contin- 
ues to broaden its skills and meet increasing demands for service. 



91 



II. BRANCH PROGRAMS 

A. Objectives 

The objectives of the Branch are to provide consultation and production 
services to the NIH; to visually communicate program effort and research 
results; to provide knowledge, skills and techniques in visual design, 
medical art, applied arts, still photography and cinematography for solving 
problems of recording, communicating and presenting research activity; and 
to investigate, develop and apply new visual techniques. 

It is also the objective of the Branch in meeting NIH research program 
demands to provide professional services, competitive with commercially 
obtainable services at the lowest possible cost, and to develop specialized 
capabilities, particularly in graphic presentation, still photography, 
cinematography, and medical arts, tailored to NIH needs. 

The Branch monitors procurement of art and photography services by outside 
contract, serving as a technical adviser in obtaining needed additional 
services at the lowest cost consistent with high quality. 

B. Current Programs 

Programs of the Branch are still and motion picture photography, including 
photomacrography, photomicrography, cine photomicrography, high-speed 
cinematography, general photography, and related laboratory services; visual 
arts production including publications design and general graphics; visual 
aids including slides, vu-graphs, and other projectables; animation artwork; 
technical, general and medical illustration; exhibit design; statistical 
drafting display charts, and medical models. 

C. Program Progress and Accomplishments 

1. Increased demands for services were made of the MAPB this year, climaxed 
by the intense activity created by the first NIH Alumni Homecoming, Public 
Open House, and the Bicentennial celebration. 

2. In FY 1974, the General Illustration Section was renamed the Design 
Graphics Section and its three Units were reduced to two. However, the 
physical joining of the drafting and graphics operations did not take 
place until early FY 1975. The reorganization has been an unqualified 
success. The unit functions quickly and efficiently and is capably handling 
a constantly increasing workload; and unity of preparation has been 
accomplished. With the addition of electronic production of typography, 

the unit has been able to broaden its capabilities and reduce turn-around- 
time. 

3. In the design area, there was a substantial increase in demand for 
services. As an example, 21 of the 23 major exhibits displayed at the 
Alumni Homecoming, Open House, and Bicentennial celebration were designed 
and construction was supervised by this Section. 



92 



4. The NIH demand for medical illustration remains normal and the 
Photography Section has been able to keep abreast of a 20 percent increase 
in service by use of new equipment, improved management and wider use of 
contract services. In FY 1974, delivery of scientific photography took 

15 days, which was excessive. This year, turn-around-time, as forecast, 
has been halved. 

5. The Branch, through extensive review, has identified the graphics 
design company with the concept and expertise to research and develop a 
coordinated visual communications system for the NIH. As a start, work has 
been done on establishing standards for graphically rendering statistical 
material (charts, graphs, tables) produced by the MAPB for publication and 
projection. 

6. The Branch lost one person, increased its use of outside contract 
services by 26 percent, reflecting an increase in demand for services. 

7. Thirty- two employees spent 1332 hours attending 43 training courses 
at a cost of $4,359.00. 

8. The Branch has concluded one year of a two-year negotiated agreement 
with AFGE Local 2419. Relations have been smooth and without incident. 

The President of the Local, an MAPB employee, was elected for a second term. 

9. An ongoing program of familiarization of Branch employees with EEO goals 
continues. Seven employees attended the two-day DRS-EEO Seminar in 
November. 

D. Problems 

There remains a critical need for the NIH community to allow more lead time 
for planning and execution of audio-visual material. All too often, the 
thoughtless and needless demands for rush jobs deprives the majority of 
NIH requesters the reasonable service they deserve. The Branch has extensive 
expertise in planning and conversion of raw data into effective multi-media 
presentations. This counsel is readily available in all areas of MAPB, or 
on location, and should be used earlier and more frequently. 

E. Program Plans 

The Medical Arts & Photography Branch will pursue the development and 
implementation of a systems approach to upgrading NIH visual communications. 
It will continue to improve, enlarge, and extend its services and will seek 
more effective ways to acquaint the NIH community with its skills. The 
Branch will continue to emphasize the necessity of early counsel aud 
planning for optimum results. 



93 



DIVISION OF RESEARCH SERVICES 

Summary of Branch Activities July 1, 1974 through June 30, 1975 

Veterinary Resources Branch Dr. Robert A. Whitney, Jr., Chief 

I. SUMMARY 

The Veterinary Resources Branch provides NIH investigators with living models 
and life support systems for biomedical research. The Branch also provides 
facilities and services related to the use of these models and systems. 

VRB service functions continued to increase to meet demands of expanding 
intramural BID programs, although Branch personnel ceilings have been 
reduced 18 percent over the last seven years. Increased service with 
decreased personnel was accomplished by extensive use of overtime, improved 
animal production methods, automated processing of glassware and production 
of media, limited use of temporary positions, and contracting. 

The VRB rodent breeding colonies were designated as a World Health Organization 
collaborating center in recognition of their importance as an international 
genetic repository. A committee of the National Research Council reviewed 
this effort and recommended that it be removed from the Service and Supply 
Fund and be given separate funding. More breeding nuclei were provided this 
year to start new colonies outside NIH than have been requested in previous 
years. VRB colonies now serve as the genetic base for most NCI contract 
programs as well as the Frederick Cancer Research Center. The Catalogue of 
NIH Rodents was distributed internationally to over 1,000 researchers and 
specialists in fields of laboratory animal science. Twelve new rodent strains 
were added to the collection. 

Open or complete disclosure formula rations for laboratory animal feeds 
developed by VRB permit competitive bidding for feed contracts, thereby 
reducing prices. Savings this year from conversion to open formula rations 
are estimated to be over $100,000 compared to the estimated costs of closed 
formula rations purchased under noncompetitive contracts. 

Pathogen-free rabbit and guinea pig colonies were successfully initiated this 
year. Nucleus colonies of guinea pigs were hysterectomy derived and estab- 
lished in the barrier in a clean, conventional area. An autoclavable diet for 
guinea pigs was successfully tested. Hysterectomy derivations were completed 
to establish all VRB rabbit strains in a new nonbarrier facility. They were 
foster nursed by SPF Edgewood Arsenal rabbits. 

A list of diseases for which NIH animals will be monitored was prepared. A 
system for carrying out the required tests is being developed. It is 
anticipated that notification of the microbial status of VRB animals will 
accompany all animals when shipped. 

Total issues of VRB-produced rodents and rabbits remained about 500,000, 
comparable to FY 1974. The use of animals produced on contract decreased from 
over 130,000 in FY 1973 to about 70,000 this year. 



95 



The Perrine Primate Center, established by DRS in FY 1974, i- s now stocked with 
350 rhesus breeders and 75 squirrel monkeys. Two contracts were awarded in 
June 1974 for additional rhesus monkey breeding colonies. By FY 1978, these 
three DRS breeding operations are expected to supply 1,000 rhesus and 100 
squirrel monkeys annually for intramural research. 

Tissue culture and media production increased 7 percent. Blood agar plates 
were issued at a 7 percent increase also. Glassware issues increased slightly 
over last year, as did the use of disposable supplies. Surgical activities 
and support stabilized at 800 procedures per year. Surgical facilities were 
relocated from Building 28 to Building 14E, increasing capacity for surgical 
procedures . 

With Phase I renovation of Building 14D completed, isolated facilities are 
available for holding 1,000 nonhuman primates. Over 1,900 primates will be 
held in this building on completion of Phases II and III renovations. 

The Branch continues to produce colony reared dogs and goats and maintains a 
canine blood donor colony. The long-term holding of ungulate animals under 
investigative study, and the procurement, quarantine, and conditioning of 
nonhuman primates, cats, and ungulates continues. Production in most areas 
is projected to be above FY 1974 levels. Emphasis is being placed on the 
development of breeding programs to supply quality animals for research. Burro 
breeding is being developed, and the foxhound colony is being enlarged. Random 
source dogs are no longer procured. 

The Animal Disease Investigation Service was reorganized to ensure rapid 
response to requests. The number of calls made to the BID's remained at last 
year's level of approximately 180. They involved consultative, diagnostic, 
and therapeutic activities and included rodents, rabbits, primates, carnivores, 
and miscellaneous feral animals. The complexity of the calls are varied and 
involved all Institutes. This service has been well received by the BID 
investigators. It has been mutually beneficial to the investigators and the 
VRB professional staff by providing a means of communication between groups. 



96 



II. BRANCH PROGRAMS 
A. Objectives 
The primary objectives of the Veterinary Resources Branch are: 

1. Issuance of research animals, animal biologies, tissue cultures, tissue 
culture media, bacteriologic media, and laboratory glassware. 

2. Maintenance of a centralized genetic repository of valued animal strains 
for the scientific community. 

3. Provision of facilities and professional staff for experimental surgery 
to include postoperative care, roentgenography, and other special procedures. 

A. Maintenance of animals during experimentation and collaborative research 
support . 

'5. Acquisition of information, through research, on animal health, care, and 
husbandry, and identifying animal models for human diseases. 

6. Provision of consultative services on animal health and husbandry, use of 
experimental animals, tissue cultures, and bacteriologic media. 

7. Establishment and supervision of production colonies of animals that are 
not commercially available to the NIH community. 

8. Monitor procurement of animals, environmental housing, and biologicals 
used in biomedical research. 

B. Current Programs 

1. Research Animal Production 

Rodents, rabbits, dogs, cats, and primates are bred and reared in the Branch's 
colonies. Some are characterized genetically and some are microbiologically 
defined. Care is taken to maintain the genetic integrity of inbred strains 
and minimize inbreeding or random bred stocks. Germfree. and specific pathogen- 
free (SPF) rodents are produced for intramural research programs requiring 
them and for replacement breeders to enhance the health status of production 
and genetic colonies. Rhesus monkeys are bred to provide either timed pregnant 
females or neonates for intramural research. 

2. Research Animal Procurement and Conditioning 

Nonhuman primates, dogs, cats, ungulates, and feral animals are purchased and 
conditioned. These animals are not well defined genetically or microbio- 
logically. Although they are of lower quality than NIH-bred animals, they 
are satisfactory for certain studies. These animals are quarantined prior to 
release for use in research programs. During the quarantine period they are 
given appropriate immunization, tested for a variety of infectious agents, and 
are treated medically as required. 



97 



A colony of blood group CEA 1, 2, and 3 negative canine donors is maintained 
for the production of normal canine blood for research use. Ungulate animals 
are maintained for the production of antisera, normal blood, or tissue 
specimens. 

Facilities are provided for investigators to perform experimental surgery on 
ungulate animals. They include modern equipment for restraint, anesthesia, 
and physiologic monitoring under aseptic conditions. Postoperative care is 
provided and radiographic facilities are available. 

Ungulates are held under observation for NIH investigators during investigative 
studies. Physiological sampling and specimen and collections are provided in 
association with these studies. 

Noninbred rodents and rabbits are procured through contracts to supplement 
in-house production. They are delivered directly to NIH investigators. 
Quality control of these species is maintained through monitoring of the 
various producers ' facilities and operations by Branch staff members . 

3. Tissue Culture and Media Production 

Several continuous cell line tissue cultures are maintained, propagated, and 
produced in large volumes to supplement I/D requirements not met by commercial 
sources or individual laboratory preparation. Media for the culture of 
bacteria, fungi, and tissue cells are produced to meet the needs of NIH 
investigators. A stringent quality control program insures that only high 
quality products, free of contamination and true to formulation, are issued. 
As a service to investigators, valuable cell lines are frozen and stored for 
long-term preservation. 

4. Processing Laboratory Glassware, Animal Cages, and Miscellaneous Items 

Laboratory glassware is decontaminated, sorted, cleaned, inspected, plugged, 
wrapped, sterilized, and issued to NIH investigators. The overall operation 
includes processing of used glassware received from investigators and the 
introduction of new glassware from replacement stock. In addition to 
cleaning animal caging for its own programs, the Branch furnishes cagewashing 
services to investigators in the Clinical Center and the Building 14-28 complex. 
Clinical Center rubber-backed carpets are also washed. A service is provided 
for ethylene oxide sterilization of heat labile patient and laboratory equip- 
ment from the Clinical Center and other I/D's. 

5. Animal Biologies Production 

A dog blood donor colony is maintained for the production of Canine Erythrocyte 
Antigen (CEA) 1, 2, and 3, formerly A-negative, blood for research use. 
Ungulates are maintained to produce a variety of antisera, blood, and tissue 
specimens for investigators. 



98 



6. Genetic Repository and New Animal Models Program 

Genetically defined rodents that are valuable models in biomedical research 
are derived and maintained to support I/D requirements and serve as a genetic 
repository for the international scientific community. 

7. Experimental Surgery, X-ray, and Related Activities 

The surgical facilities are primarily available for the use of BID investigators 
however, frequently, surgery is performed by staff veterinarians in support of 
BID programs in the development of surgical animal models. In addition, staff 
veterinarians provide surgical and clinical veterinary care to laboratory 
animals as an essential part of their responsibility to assure optimum health 
of these government-owned animals. Assistance to BID investigators is 
continuously provided in anesthesiology, surgical support, diagnostic radiology, 
and postoperative care of animals. 

The number of surgical procedures has stabilized at approximately 800 per year 
and the facilities are being used at maximum capacity. An increase of 10 per- 
cent is projected next year since the surgery unit relocated from Building 28 
to Building 14-E, permitting more surgical space. The surgery unit maintains a 
500 milliamperage radiographic unit with fluoroscopy which adds an improved 
service for research and clinical support to laboratory animal medicine. 

Experimental surgery continues to be complex with numerous, thoracic , 
cardiovascular, and abdominal procedures demanding a high level of technical 

support. Professional and technical assistance to BID investigators increased 

which resulted in improved surgical animal models and veterinary medical care. 

8. Experimental Animal Holding 

Dogs, primates, ungulates, and germfree rodents are held for varying periods of 
observation while under test by NIH investigators. Provision is made for 
physiological sampling and collection of specimens. 

9. Disease Investigation, Research, and Quality Control within VRB 

The professional staff consists: of persons trained in general clinical veterinary 
medicine and specialists in laboratory animal medicine, pathology, microbiology, 
epidemiology, nutrition, animal behavior, genetics, and animal husbandry. All 
efforts are oriented toward improving the Branch's programs by gaining new 
knowledge through research and monitoring the quality of procured and produced 
animals. 

10. Consultative Services 

Information and assistance are available to NIH investigators for solving 
problems relating to animal experimentation, health, care, and husbandry. 
Through the Animal Disease Investigation Service (ADIS) "house calls" are made 
to the I/D's to provide investigators with clinical veterinary services for 
their research animals. There is also a program to furnish each I/D a compre- 
hensive review of its animal care programs with evaluations and recommendations 



99 



for improvement. Consultative services on use of tissue cultures and 
microbiologic media are available. 

11. General Support and Management 

These basic programs listed above are also supported by Branch-wide 
administrative and management staff and transportation/delivery service. 

C. Program Progress and Accomplishments 

1. Rodent and Rabbit Production 

About 500,000 VRB-produced rodents and rabbits were issued to investigators, 
equivalent to the number produced last year. Guinea pig, rabbit, and hamster 
production decreased; rat and inbred mouse production remained unchanged, but 
there was an increased requirement for and production of VRB, noninbred mice. 
The total demand for VRB strains and stocks of mice was not satisfied because 
of limitations on current production levels due to personnel ceiling 
restrictions. Approximate animal issues were as follows: 



Inbred mice 
Noninbred mice 
Inbred rats 
Noninbred rats 
Inbred guinea pigs 
Noninbred guinea pigs 
Hamsters 
Rabbits 



Germfree rats 
Germfree mice 



230,000 

170,000 

10, 000 

25,000 

15,000 

11,000 

2,000 

2,000 

m 

The Frederick Cancer Research Center (FCRC) continued to rely on VRB 
foundation colonies as the genetic base for their rodent colonies. Pedigreed 
mouse and rat strains were supplied from VRB barrier-maintained colonies. 
However, preparations were made to supply them germfree pedigreed stock. VRB 
has also assumed the responsibility of maintaining the genetic base for a 
variety of other NCI contract programs requiring germfree pedigreed stock. 

A breeding nucleus of hysterectomy derived guinea pigs was established in a 
clean conventional area. A nucleus of guinea pigs was also established in the 
barrier. Foundation stock for the inbred strains will be hysterectomy derived 
and foster nursed by those animals to create pathogen-free foundation and 
expansion colonies. 

Efforts continued to develop acceptable pathogen- free rabbits. VRB strains 
were hysterectomy derived and foster nursed in a clean conventional area by 
pathogen-free stock provided by Edgewood Arsenal. The rabbits remain free of 
the usual pathogenic organisms, including Bordetella and Pasteurella; however, 
mortality is excessive from nonspecific gastrointestinal problems. "Pathogen- 
free" rabbits were received from two other sources with the hope that their 
gastrointestinal flora would eliminate the enteric problem. The plan was 
thwarted because in both cases the rabbits were found to harbor pathogenic 
organisms. 



100 



Several changes were made in the conventional guinea pig colonies to increase 
production and enhance the quality. Major accomplishments were the elimination 
of vegetable supplementation to the inbred pedigreed colonies and the 
successful testing of an autoclavable diet. A shorter breeder rotation system 
was initiated and surveillance of breeder performance and replacement was 
intensified. Inbred guinea pig production began to increase in the last 
quarter following a decline earlier that contributed substantially to a 
revolving fund deficit. 

The reorganization of the Small Animal Section was implemented with the 
establishment of a WS supervisor for each building, a cagewash unit, an 
ordering and contracts office, an administrative assistant, and a professional 
services group. This concludes a two-year process. It was immediately 
apparent following the change that the new supervisors and improved organization 
create a potential for greatly improving the effectiveness of the section. 

2. Large Animal Production 

The conventional canine breeding colony currently consists of 162 bitches and 
12 dogs. Culling continues to be directed towards eliminating poor producers 
and animals with hip dysplasia. The inbred foxhound colony consists of one 
English and three American (two Walker and one Trigg strain) foxhound lines. 
Development of these lines is being directed principally towards providing a 
genetically uniform research dog for NIH investigators by eventually cross- 
breeding the lines. 

A contract was established to breed and provide purebred foxhounds for NIH 
research at a rate of 500 per year. Availability of purebred stock from the 
NIH Animal Center and contract sources has eliminated the need to rely upon 
random source foxhounds and random source mongrel dogs as standard NIH research 
animals. 

The cat breeding colony was terminated during FY 1975. 

The goat breeding herd was expanded from 16 to 20 does and 2 bucks. Goats 
produced from the breeding herd will be held until approximately one year of 
age before issue. 

3. Nonhuman Primate Production 

The Perrine Primate Center was established by DRS in FY 1974. The facility has 
been managed by VRB since its establishment and is currently stocked with 350 
rhesus and 75 squirrel monkey breeders. These colonies are planned to be 
maintained at 700 and 150 adult breeders, respectively. Two contracts were 
awarded; one to Hazleton Laboratories and the other to Gulf South Research 
Institute in June 197-4, to establish 700 additional rhesus monkey breeders. 
As of June 1975, VRB expects to have supplied the necessary adult breeders to 
the contractors. By FY 1978, these DRS breeding operations are projected to 
supply 1,000 rhesus and 100 squirrel monkeys annually for intramural research. 



101 



Cutbacks in rhesus monkey exports from India in 1974- prompted VRB to initiate 
domestic breeding programs. Further cutbacks are expected in FY 1976. 
Procurement and availability of most New World monkeys is virtually nonexistent. 
Supplying monkey models for research appears to be largely dependent on 
domestic breeding resources. Further restrictions on monkey supply may warrant 
expansion of existing breeder colonies and establishing additional colonies to 
assure critical primate needs. 

The timed-pregnant rhesus monkey breeding colony stabilized at approximately 
260 animals of which 14-0 animals cycle regularly. The balance represents 
males, new breeders, and breeders received from contract sources that are 
available for recycling through contract breeding or intramural research. This 
colony was supplemented with a research contract which supplied 72 timed 
pregnant rhesus monkeys to complement the intramural colony production of 80 
timed pregnant monkeys. A total of 152 timed pregnant animal models were 
supplied for intramural research use. A new 3-year contract is being imple- 
mented to provide up to 100 timed pregnant rhesus monkeys per year. In 
addition, three contracts were awarded during the year for timed pregnant 
baboons. Two of these contracts are fixed fee contracts in which the 
Government purchases the use of the timed pregnant baboons for intramural 
research and owns the fetuses and products of conception. The third contract 
established an NIH-owned colony of breeder baboons at the contractor's site 
and reimburses the contractor's costs for establishing a monthly supply of 
timed pregnant baboons for intramural research programs. 

4. Research Animal Procurement and Conditioning 

a. Rodents and Rabbits 

The total purchase of rodents and rabbits from contractors further decreased 
from 132,500 in Ti 1973 to approximately 70,000 this year. There was a decline 
in the use of noninbred mice, rats, and hamsters from contract sources, but a 
twofold increase in the use of contract rabbits. An itemized list of animals 
purchased on contract is as follows: 

Rabbits— Dutchland 6,200 

Sprague Dawley Rats — Taconic 27,000 

Hamsters — Lakeview 6, 500 

Swiss Mice— Taconic 25,000 

Rats— Charles River 2,500 

In addition, VRB arranged for the Frederick Cancer Research Center to supply 
NIH investigators about 2,000 Hartley guinea pigs and over 6,000 inbred and 
nude mice. Arrangements are being made to initiate a Hartley guinea pig 
contract in which VRB will supply the breeding stock. 

b. Large Animals 

Requests for random source cats were 800 to 850 for FY 1975. 

Approximately 4-84- ungulate animals were purchased, quarantined, conditioned 
and issued during FY 1975. In addition, some 50 domestic fowl, including 
ducks, chickens, and turkeys were utilized. 



102 



Rhesus (Macaca mulatta ) monkey issues for FY 1975 are estimated at about 4,137 
which represents an increase of about 626 over FY 1974. 

VRB quarantined, selected, and delivered 1,304 rhesus monkeys to Gulf South 
Research Institute, Hazieton laboratories, and Perrine as initial breeding 
stock for rhesus production colonies. 

Other species of monkeys (M. fascicular! s, M. arctoides , Erythroc ebus patas, 
baimiri scxureus, Cercopithecus aethiops , Aotus trivifgatus , and CallithrTx 
sp. ), contributed small numbers to the overall quarantine and conditioning 
program. * 

5. Tissue Culture and Media Production 

Based on the first 8 months of FY 1975, the number of requisitions processed 
for tissue culture and media will total 14,000; a 7 percent increase over last 
year. The volume of media produced will be 70,000 liters of bacteriolgic 
media and 69,000 liters of tissue culture media for a total of 139,000 liters 
This total represents an 8 percent increase over last fiscal year, and 
reflects for the first time in years an increase of bacteriologic media over 
tissue culture media. 

Issues of blood agar plates of all types, including horse, sheep, and human 
blood plates will total 159,000 this year, a 7 percent increase. 

In addition to blood agar plates, there will be another 406,000 plates of 
other types for a total of 565,000 plates for the fiscal year. This is a 
7 percent increase over last year. 

Issues of tissue culture cells as cell suspension will show a slight decrease 
of 3 percent with a projected total of 200 liters of suspension produced. 

Tissue culture cell freezing and storage services continued to be a popular 
service with NIH investigators. A projected total of over 1800 ampoules of 
cells will be frozen this year and 2000 ampoules of cells maintained in the 
irozen cell bank to support research programs requiring this service This 
represents a slight decrease over last fiscal year and reflects a tendency 
of the investigators to use their own storage facilities because of the 
convenience. 

Renovations to provide filtered air to the room housing the automatic 
bottling system for media dispensing are scheduled for completion late in the 
fiscal year, almost a year after originally planned, due to contractor delays 
in correcting minor problems in the installation. Adaptation of a cartridge 
filter system for sterilization of tissue culture media just prior to the 
dispensing point of the bottling system is under test. The cartridge system 
is much more compact than the membrane system used for manual filtration and 
also allows for increased volume of production lots of media. This change 
together with the filtered air to provide a cleanroom atmosphere, should ' 
extend the capability for sterile media dispensing to tissue culture, as well 
as bacteriologic media. 



103 



After a period of modification and testing an automatic labeling system has 
been synchronized with the conveyor belt on the bottling machine to make and 
apply labels to the bottles as they are filled and capped. This method is 
expected to greatly reduce the time spent in manual application of labels to 
the bottles. 

6. Processing Glassware, Animal Cages, and Miscellaneous Items 

Glassware issues to the Institutes and Divisions projected through the end of 
the fiscal year will total about 8,429,000 pieces; a slight increase over last 
year. A total of 294>000 cages, racks, and associated pieces of equipment 
will be processed. 

In order to provide adequate coverage on the night shift as well as the day 
shift, an additional employee was trained in the regeneration process 
required for the large, mixed bed deionizer. This should prevent the 
occasional call back time required in the past when the water quality dropped 
in specific resistance during the evening hours and required someone from the 
day shift to return for regenerating. A Wilbur terminal was installed in the 
Glassware Unit to enable direct input for the OFM billing reports and 
correcting errors generated by faulty information appearing on glassware 
order forms. 

A new form for glassware orders and issues was introduced this year. This new 
form will provide a record of not only glassware issued, but items of glass- 
ware ordered, and some indication of how well the Unit is meeting the demand 
for glassware. The percentage of each item ordered and supplied by size and 
type of glassware should provide useful data. 

A workload measurement study was conducted in the Unit this year with the help 
of the Management Analysis office, to calculate new average processing times 
for individual types of glassware. As a result of this study, several workload 
improvement recommendations were made and are being implemented. As a prelim- 
inary step, a large glassware drying unit, which is no longer required, was 
removed to create space for installation of a proposed conveyor system to be 
adapted to the M-2 washer. This conveyor system should reduce the manual 
handling of glassware baskets as they are filled and transported to the machine 
for washing. 

7. Animal Biologies Production 

Domestic turkeys and ducks were utilized in small numbers to produce normal 
blood and antisera for specific research projects. 

The canine blood donor colony, which consists of 258 dogs, produced 3, 500 units 
(1 unit = 500 ml) of blood. 

Biologies production from ungulate animals is about the same as during FY 1974- 
Projected production includes 14-00 liters of ungulate blood for the year. The 
size of the ungulate herd being maintained for all purposes increased from 550 
to 610 during FY 1975. 



104 



8. Genetic Repository and New Animal Models Program 

VRB rodent colonies were designated as a World Health Organization 
collaborating center in recognition of the importance of this collection of 
animal models for biomedical research. The one other collaborating center 
designated was the Laboratory Animal Center of the Medical Research Council 
of Great Britain. The director of that center served as a consultant to VRB 
during a WHO sponsored visit this year. 

A committee of the National Research Council studied the VRB small animal 
program. It concluded that the repository effort should be separately 
financed through management funding and not supported by inflating the price 
for animals. About $500,000 was determined to be the annual cost for 
maintaining the repository. 

A Catalogue of NIH Rodents was published and distributed to about 257 NIH 
investigators and 765 researchers and specialists in animal science worldwide. 
It describes characteristics of the over 100 strains and stocks of rodents and 
rabbits maintained. In addition to supplying animals for intramural investi- 
gators, breeding nuclei from these colonies serve as a resource for the 
international biomedical research community as many of the stocks, strains, and 
substrains are not available elsewhere. Over 300 investigators were provided 
with litters of inbred animals to start colonies. This is a twofold increase 
over FY 1974- • Also, several hundred noninbred animals were provided as 
breeding stock. Several commercial producers were also provided with breeding 
stock. Requests were particularly numerous for the rat with diabetes insipidus 
and hypertension, inbred NZB and NZW mouse strains, and inbred guinea pigs. 

A program to assist investigators in obtaining new animal models to meet 
previously unfilled research needs continued. In some instances, new strains 
of existing laboratory animals exhibiting unique physiological or anatomic 
characteristics were used. In others, animals having characteristics 
required in a particular research problem were adapted from nature. New models 
are hysterectomy derived and foster nursed or hand nursed prior to introduction 
into the NIH colonies. Twelve new strains were added to the repository at 
the request of NIH investigators. They are: 

Mice Rats European Giant Hamster 

BALB/eCRN WFU/CrN Guinea Pig 

A.9AKR SHRSP/A1N 

Dwarf (dw) SHRSP/A3N PCA (passive cutaneous 

Motheaten (me) Corpulent (cp) anaphylaxis) 

Dystrophic-2 ( dy-2 ) 

BDL-ky (kyphoscoliosis) 

9. Experimental Surgery, X-ray, and Related Activities 
a. Building 14E and 28 Facilities 

The surgical facilities are primarily available to B/I/RD investigators; 
however, surgery was frequently performed by staff veterinarians assigned to 



105 



the Section at the specific request of investigators. Assistance to 
investigators was provided in anesthesiology, surgical support, diagnostic 
radiology and postoperative care of animals. 

The number of surgical procedures stabilized at approximately 800 per year and 
the facilities were used at maximum capacity. An increase of 10 percent is 
projected next year since the Surgery Unit relocated from Building 28 to 14-E 
and will provide more surgical space. The Surgery Unit maintains a 500-milli- 
amperage radiographic unit with fluoroscopy which adds an improved service for 
research and clinical support to laboratory animal medicine. 

b. Animal Center Ungulate Surgery 

Activities in ungulate surgery declined. Projects utilizing sheep for 
intrauterine fetal surgery have ceased. Surgery was utilized for porcine skin 
transplantation procedures, collection of fetal pig serum, and to treat a 
variety of clinical conditions. Miniature swine breeding is continuing to 
develop four inbred lines of immunologically distinct animals. Five sows 
produced progeny this year. 

Radiographic procedures increased from 250 exposures in FY 1974 to 420. 

10. Experimental Animal Holding 

a. Primates 

Renovations for Phases II and Illof Building 14D will be awarded to contractors 
before the end of FY 1975, and estimated completion date is 12 months after the 
award date. This renovation is a joint program between DRS and BoB which will 
provide a centralized research primate holding facility. The new renovations 
are designed to permit infectious disease studies, provide a safe working 
environment for personnel, and minimize cross-infection among primates. The 
total capacity of the facility, including the conventional primate facilities 
of Phase I renovations, will establish one of the largest primate research 
facilities in the country with a maximum primate population of ever 1900 
animals. 

b. Large Laboratory Animals 

The research holding facilities of Building 28 has increased its scope of 
research support by greater diversity of animal species including: dogs, cats, 
miniature swine, goats, sheep, and other large laboratory animals. In addition, 
new collaborative DRS research programs with NCI and NHLI were initiated. 
Continued use of a contract to hold dogs off the Bethesda campus allowed 
improved utilization of space for studies requiring constant investigator 
attention. The atherogenic diet study in dogs in Building 14E will relocate 
to Building 28. 

The population of research animals in this facility averages approximately 360 
per month. Additional research animals, requiring only infrequent investi- 
gator manipulation, are maintained on contract. This has permitted a more 
suitable animal density population per kennel to achieve better animal care 



106 



management. Recent renovations of two large animal wards in Building 28 
significantly improved animal welfare, and improved the research environment 
and employee working conditions. 

11. Animal Nutrition 

VRB-developed, open formula rations continue to be used throughout the NIH. 
Purchase arrangements were made through competitive contracts for three new 
open formula rations; autoclavable rations for rats and mice, rabbits and 
guinea pigs. Based on current prices, the open formula rations purchased under 
competitive contracts cost 36 percent less than the closed formula rations 
purchased under noncompetitive contracts. When this price differential is 
applied to the open formula feeds purchased under competitive instead of 
noncompetitive contracts, an apparent savings of approximately $115,000 will 
be realized by NIH during the contract year. 

The NIH, open formula ration for conventionally reared rats and mice was 
adopted as a standard reference ration by committees of the American Institute 
of Nutrition and the National Research Council. 

The proximate nutrient, calcium, and phosphorous concentrations in NIH contract 
animal feeds were monitored. This information is useful in demonstrating to 
investigators the variation in nutrient concentrations among production batches 
of a given ration. 

The contract to conduct nutrient analyses on experimental rations was expanded 
to include assays for various feed contaminants. At least one sample collected 
from all animal feeds purchased under NIH contracts has been assayed for heavy 
metals and pesticide residues. To date, the concentrations of these potential 
contaminants have been either undetectable or within acceptable ranges. 

An open formula, autoclavable ration containing 18 percent crude protein is 
being fed to SPF production colonies of rats and mice on a trial basis. There 
has been no apparent decrease in the reproductive performance of animals fed 
this ration as compared to animals fed a commercial ration containing 24 " 
percent crude protein. Similar results were obtained under experimental 
conditions. 

12. Animal Health 

a. VRB Animal Health Problems 

A pinworm eradication program was initiated in conventional mouse production 
colonies. Piperazine was proportioned into the drinking water continuously 
for a one-month period while the buildings were being disinfected with an 
iodophor to destroy pinworm ova. Following this, treatment was alternated 
every other week and untreated, helminth-free sentinal animals placed in the 
rooms were monitored to determine whether total eradication was achieved. 
Plans were made to use dichlorvos to treat a mite infestation discovered in 
inbred mouse production colonies. 



107 



An outbreak of Tyzzer's disease occurred in C-wing rabbits early in the year. 
Tylosin in the drinking water was found to be therapeutically effective, stopping 
the outbreak after only 20 deaths. A major epizootic may have been averted 
since the C-wing rabbits have been free of the disease and are probably highly 
susceptible. Inasmuch as the causative agent is a spore former, it is considered 
likely that it will gain entrance into the colony again. The indirect fluor- 
escent antibody technique has been used in preliminary studies of the natural 
history of the disease and to demonstrate antigenic similarities between the 
causative agent in rabbits and the agent recently isolated from horses. 
Because of shortcomings of this method for serologic survey work, several 
antigens are being tested in the development of a complement fixation test. 
As more is learned about the antigens, hopefully, the preparation of a vaccine 
will become possible. 

Although Tylosin was effective in treating C-wing rabbits for Tyzzer's disease, 
its use appeared to precipitate a severe outbreak of enterocecocolitis which 
resulted in 108 deaths in one month. Enterocecocolitis has been present in 
C-wing rabbits for several years, causing an average of about 20 deaths per 
month. Culture results have indicated that it is caused by imbalances of 
intestinal microflora, particularly overgrowth of E. coli, which may be stimu- 
lated by the use of certain antibiotics such as Tylosin. It is postulated 
that these cesarian-derived rabbits are "too clean" and that additional 
bacteria are needed to broaden the intestinal microflora to provide effective 
competition for E. coli . For this reason, attempts were made to acquire 
specific pathogen-free rabbits from other sources to act as microfloral donors. 
Two attempts failed. The rabbits from one source had coccidiosis and those 
from another source were infected with Bordetella bronchi septica . 

The barrier-maintained mouse colony suffered its worst recorded outbreak of 
hemothorax. The outbreak lasted 2 months. All strains of mice were affected, 
and virtually all males over the age of 6 months were lost. As previously 
described, this disease appears to be a noninfectious condition of male mice 
characterized by myocarditis and prolonged clotting time. The cause of the 
sporadic outbreaks is not known. It has been postulated that some noxious 
substance, which secondarily increases the mouse's requirement of vitamin K, 
periodically finds its way into the ration. Supplemental vitamin K was added 
to the diet of the barrier mice but, unfortunately, this was at about the time 
the outbreak was subsiding so that the effect was impossible to evaluate. 
A beneficial effect was suggested, however, by the finding that only a few 
scattered hemothorax fatalities occurred in the 9 months since the supplemental 
vitamin K was started. The results of a recent pilot study indicate that the 
disease can be reproduced by feeding mice excessive vitamin A, which is known 
to increase the mouse and rat requirements for vitamin K. 

The incidence of Johne's disease in goats increased. Fecal culturirg for 
Mycobacterium paratuberculosis in the goat herd was continued during FY 1975. 
The incidence of Johne's disease declined from 21 cases in 1972 to two in 1973 
and rose to five in 1974. Culturing will be continued indefinitely on a semi- 
annual basis. The disease is considered difficult to eradicate since the 
causative organism is relatively stable in the environment and its detection in 
animals incubating the disease is laborious. Goats may incubate the disease 
for several years before fecal cultures reveal the causative agent. Current 



108 



information indicates that Johne's disease is endemic in Maryland and that 
anyone buying goats on the open market will, in time, purchase animals with 
the disease. 

The monkey breeding facility at Perrine, Florida, experienced an outbreak of 
progressive debilitating disease characterized by alopecia, acneform dermatitis, 
facial edema, squamous metaplasia in palpebral glands, hypertropic gastritis 
and death. Many of the clinical and histopathologic findings are compatible 
with hypovitaminosis A which, in rhesus monkeys receiving adequate amounts of 
dietary vitamin A, points to the possibility of toxic exposure to chlorinated 
hydrocarbons. Preliminary chromatographic analysis of tissue specimens from 
affected monkeys indicatesthat the toxic substance may be polychlorinated 
biphenyls (PCB's). PCB's are known to be rapidly toxic for rhesus monkeys in 
very low dose, 2 ppm in feed, and to produce similar lesions to those occurring 
in the Perrine monkeys. 

Brucellosis testing is now performed annually in the swine and goat herds and 
in the sheep flock. All new acquisitions are tested during the quarantine 
period. No new cases were observed. 

Urolithiasis was diagnosed in 12 goats (wethers) and six sheep (wethers). 
Three of the cases were fatal. The disease is thought to be associated with 
the exclusive feeding of grain concentrates, and may also be related to 
mycoplasma infections. 

b. B/I/D Animal Health Problems 

No large-scale epizootics such as mouse pox occurred in the B/I/D' s this year. 
Examples of lesser problems included the occurrence of cervical lymphadenopathy 
in rats purchased on contract from a VRB contractor. The rats showed facial 
edema and failed to sustain Walker carcinomas. Autopsies on animals on the 
day of arrival in the laboratory revealed tracheitis and pronounced 
peritracheal lymphadenopathy. Pasteurella pneumotropica was isolated from the 
lymph nodes in six of eight animals cultured. The commercial colony was found 
to be serologically positive for Sendai virus, which is reported to augment the 
pathogenicity of P. pneumotropica infections. The company that produced the 
rats was required to correct the problem. 

Assistance was extended to the B/I/D 's also in the form of participation in 
collaborative research of several types, including hepatitis A & B trans- 
mission studies and studies of the effects of thymus- and bone marrow-derived 
lymphocytes on the pathogenesis of autoimmune disease In NZB mice. 

13. Animal Disease Investigation Service 

The Animal Disease Investigation Service answered 182 calls for assistance 
from the B/I/D' s, or approximately the same number as last year. These 
involved consultative, diagnostic, and therapeutic activities. Animal species 
encountered were varied; including rodents, rabbits, primates, carnivores, and 
miscellaneous feral animals. The complexity of the calls also varied and 
involved all Institutes. Ninety-four of the investigations required supple- 
mental pathology exams, 38 required microbiologic testing and 30 utilized 

109 



clinical pathology tests. This service has been extremely well received by 
B/I/D investigators. The service continues to be mutually beneficial to 
investigators and to the VRB professional staff. 

D. Problems 

Problems of animal disease are referred to in Part II, C, 12, a and b. 

It now appears that the program initiated in 1968 to hysterectomy derive 
foundation colonies for all mouse and rat strains and stocks may not result, 
as expected, in the issuance of strictly pathogen-free animals to investigators. 
Although VRB barrier colonies remain uncontaminated for periods beyond expecta- 
tion, the production colonies in conventional facilities were reinfested with 
internal and external parasites. Whether this was due to inadequate decontam- 
ination of facilities or a recontamination by a flourishing resident feral 
rodent population in the Building 14-- 28 complex is undetermined. Perhaps the 
design, construction, location, state of repair, and age of the buildings 
housing the present rodent colonies make it unrealistic to expect maintenance 
of a totally pathogen-free status of rodents following hysterectomy derivation. 
The facilities for rodent production are not barriers and are in close proximity 
to quarters for primates, sheep, and carnivores. Nonetheless, the effort to 
produce pathogen-free rodents will continue. 

Some General Schedule (GS) Biological Laboratory Technicians working in the 
barrier are being paid less than some Wage Grade (WG) animal caretakers in 
conventional colonies performing less technically skilled work. The conversion 
of these employees to GS pay scale has worked to their disadvantage because of 
large WG pay increases. General Schedule technicians in the gnotobiotics unit 
and professional services staff, as well as the barrier, are inadequately 
compensated compared to WG employees. Unless the situation is corrected, 
recruitment of qualified employees into these areas will become impossible. 
Employees presently assigned these jobs are becoming interested in leaving or 
returning to WG animal caretaker positions. 

E. Program Plans 

Consideration will be given to requesting approval to establish a committee to 
advise VRB whether strains warrant being added to or dropped from the genetic 
repository, as recommended by the NRC committee reviewing NIH rodent activities. 

A computerized record keeping system is being developed by VRB personnel and 
the DRS management analysts. Primary emphasis is on collection of data on 
rodent breeding performance. Mating and mortality data will also be collected. 

An expanded program of genetic monitoring is necessary to provide adequate 
safeguards for the integrity of inbred strains. A routine testing program 
involving test matings, histocompatability testing, and mandible analysis will 
be established. 

Present obsolete cages for rabbits and guinea pigs will be replaced as soon 
as funding is available and an acceptable design tested. The evaluation of 



110 



a semiautomated cage for rabbits continues and plastic cages for guinea pig 
harems are being tested. 

The disease surveillance program for the rodent colonies must be enhanced to 
ensure prompt detection of disease through VRB monitoring. The effort to free 
all rodent strains and stocks of disease through hysterectomy derivation will 
continue. Methods will be developed for applying this practice to guinea pigs 
and rabbits. This requires a cooperative effort in areas of nutrition, 
microbiology, and genetics. 

An effort will be made to survey requirements of investigators for rodents 
beyond the capability of in-house production and to initiate new contracts to 
meet these needs where possible, using VRB colonies as the genetic base. 

Studies to define the major nutrient requirements of different species and 
strains of inbred rodents will continue. Efforts will continue to develop 
open formula rations purchasable through advertised contracts to replace closed 
formula rations purchased through negotiated, sole source contracts. 

It is expected that the Carnivore Unit will be reorganized before the end of 
FY 1975; canine long-term holding will replace random source dog activities. 
A canine socialization program was initiated and will be developed for 
continuing application to colony reared dogs. Continued expansion of the 
canine breeding colony by purchase of quality dogs from outside sources will 
be pursued. Contract production of purebred foxhound puppies (approximately 
500/year) will be continued into and beyond FY 1976. Plans are being developed 
to create outdoor housing space for growing puppies. This program will permit 
purebred production to expand by 200-300 per year. 

The dairy goat and burro breeding herds will be expanded during FY 1976. About 
15 jennies will be bred in FY 1975 and are expected to foal in the spring of 
FY 1976. 

Health surveillance of ungulate herds and flocks will be expanded and 
intensified during FY 1976. Emphasis will be placed on identification and 
containment of equine diseases because of implementation of a burro breeding 
program. 

Further definition of the blood groups of dogs in the canine donor and 
breeding colonies will be undertaken when "typing" anitsera becomes available 
from outside sources. 

Contract primate breeders will have been supplied all necessary breeding 
stock before the end of FY 1975. Thereafter, efforts will be directed toward 
supplying the contractors with replacement rhesus breeding stock on a 
continuing basis. Animal Center programs will be readjusted in order to 
provide holding space for young monkeys produced by contractors. 

Improvement of leased property, consisting of some 200 acres of pasture and 
several buildings adjacent to the Animal Center will provide space for 
programs utilizing sheep, swine, and burros. Partial improvement of a pole 
barn and installation of fences enclosing about 4-0 acres will permit expansion 



111 



of sheep activities (100-200 head) early in FY 1976. Expansion of swine 
breeding/holding activities is anticipated late in FY 1976 with the erection 
of a temporary farrowing/holding structure. 

Within the limits of current manpower restrictions and space limitations, 
continued efforts will be made to expand or improve automation of media 
production. Continually increasing demands for bacteriologic media in plates 
require the development or purchase of improved automated equipment for this 
area of production. Quality control procedures will be expanded to focus 
more emphasis on those aspects of bacteriologic media production which can be 
monitored with limited space and personnel. 

The possibility of using automatic data processing methods for inventory and 
ordering of supplies will be explored. The shortages of various items of 
supply make more efficient inventory and ordering methods mandatory if 
production slowdowns are to be avoided. 

A survey is being conducted by PEB to determine costs associated with the 
current methods for regeneration of the large mixed bed deionizers. Items 
monitored will include water usage per day, cost of caustic soda and hydro- 
chloric acid for regeneration, and labor costs. Consideration will be given 
to the possibility of contracting for this service, automating the present 
equipment, or continuing the present manual system of regeneration. 

The possibility of replacing the outdated cage and rack washers in the Clinical 
Center cagewashing unit is being explored. The proposed consolidation of the 
NCI animal rooms in the B corridor adjacent to the cagewashing unit is expected 
to increase the workload on existing equipment and personnel. Purchase of new 
equipment is recommended as the expense of upgrading existing equipment, due 
to its age, is uneconomic. 

F. . Publications 

Bacher, J.D. and Potkay, S. : Intussception of the Small Intestine (ileum): 
What is your diagnosis? J. Amer. Med. Assoc , 164: 1135-1136, 1974- 

Ganaway, J.R.: Bacterial, mycoplasma, rickettsial disease. In Wagner, J. 
and Manning, P. (ed. ): Biology of the Guinea Pig . New York, N.Y., Academic 
Press, in press. 

Ganaway, J.R. : Bacterial Zoonoses of Laboratory Animals. In Melby, E.C., Jr. 
and Altman, N.H. (ed.): CRC Handbook of Laboratory Animal Science , Vol. II. 
Cleveland, 0., CRC Press, 1974, pp. 243-257. 

Potkay, S., Bacher, J.D., and Pitts, T.W. : Feline Infectious Peritonitis in 
a Closed Breeding Colony. Lab. Anim. Sci ., 24: 279-289, 1974. 

Potkay, S. and Bacher, J.D.: The Research Dog: Random Source or Colony Bred? 
In Harmison, L.T. (ed. ) Research Animals in Medicine . DHEW Publication 
No. (NIH) 72-333, 1973, pp. 1061-1065. 



112 



Scott, R.N., Faraci, R.P., Goodman, D.G., Militano, T.C., Gaelhoed, G.W. , 
and Chretien, P.B.: The role of inflammation in bronchial stump healing. 
Ann. Surg , in press. 

Strandberg, J.D. , and Goodman, D.G. : Animal Model: Canine Mammary Neoplasia. 
Am. J. Pathol ., 75: 225-228, 1974. 

Whitney, R.A., Jr.: A Domestic Primate Production Feasibility Study. In 
Bermant, G. and Liadburg, D.G. (ed.): Primate Utilization and Conservation . 
John Wiley, & Sons, Inc., 1975, pp. 163-167. 



113 



III. INDIVIDUAL PROJECT REPORTS 

Serial No. Z01 RS 00001-05 VR 



1. Veterinary Resources Branch 

2. Small Animal Section 

3. Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 



C. GENETIC ANALYSIS AND ANIMAL MODEL DEVELOPMENT 

D. DRS-VRB-3 

E. C.T. Hansen 

F. K.P. Smith 

G. Laboratory of Bacterial Products, BoB 
Laboratory of Immunology, NIAID 
Laboratory of Pathology, GLC, NCI 

H. Total: 1.0 
Professional: 0.5 
Others: 0.5 

I. Objectives : l) To study the role of genetic and environmental components 
involved in the dynamics of reproductive performance of inbred strains of 
animals, 2) genetic monitoring of inbred strains, and 3) develop new 
animal models utilizing the existing gene pool and new and exotic species. 

Methods Employed : Comparison of tumor frequencies between conventional 
and SPF inbred strains suggests for the most part that establishing these 
animals in an SPF environment does not affect either the age of onset or 
frequency. One exception has been in the C3H/HeN strain in which the 
appearance of mammary tumors occurs at a somewhat earlier age and the 
growth of the tumor is more rapid. 

The genetic analysis of blood pressure continues. Measurements in the 19 
inbred strains of rats show almost a normal distribution of blood pressures 
suggesting a complex form of inheritance. Blood pressure measurements in 
progeny of crosses of a selected number of these rat strains is now 
underway. A series of diallel crosses between a number of these strains 
show a marked sex difference in the pattern of inheritance. In female 
progeny, the evidence suggests an additive form of inheritance whereas in 
males, the inheritance appears to be nonadditive. 

Selected breeding for the sensitivity and resistance to the effect of 
histamine after treatment with B. pertussis has reached the eighteenth 



115 



generation. Sensitivity has increased to 85 percent in the sensitive 
strains and decreased to 3-5 percent in th resistant strain from an 
average sensitivity of 30 percent in the unselected base population. 

A program has been undertaken to develop a mating system for the 
maintenance of outbred SPF nucleus colonies of mice and rats. The goal of 
this program is to develop a system which meets the requirements for 
maintaining a stable gene frequency, minimize inbreeding and reduce the 
requirement for close professional supervision. Several revisions have 
been made during the course of this program and the present technique 
appears to be successful in meeting the majority of the requirements. 

A long-term study with the nude (athymic) mouse continues. This animal 
is very unique in that the thymus fails to develop with the result that 
half of the immune mechanism is absent. The potential of this animal for 
immunological and cancer research is considerable. The project consists 
of two phases. First, to develop techniques and procedures for large-scale 
production since it is extremely susceptible to various infections. Second, 
to establish this gene on a number of inbred strains to study the effect 
that the absence of the thymus mediated immune system has on established 
immune responses and tumor frequencies of these inbred strains. A program 
has been undertaken to backcross the nude gene into 19 inbred mouse 
strains. Two of these 19 strains have reached a minimal level of identity 
and can now be used for research purposes. 

Significance : The significance of these projects is to develop, by the use 
of genetic procedures, new animal models which have an application to 
biomedical research. 

J- Genetics; genetics, population genetics, inbreeding; mammals, mice; 
mammals, rats. 

K. Continuation 

L. None 



< 



* 



r 



116 



Serial No. Z01 RS 00002-0.4 VR 



1. Veterinary Resources Branch 

2. Small Animal Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

C. DEVELOPMENT OF DIETS FOR LABORATORY ANIMALS 

D. DRS-VRB-4 

E. J. J. Knapka 

F. F. J. Judge 
K. P. Smith 

G. None 

H. Total: 2.0 . 
Professional: 0.5 
Others: 1.5 

I. Objectives : 1) To formulate and evaluate open formula rations designed 
to improve the nutritional status of laboratory animal colonies, and 2) 
to accumulate data regarding the specific nutrient requirements of various 
strains of inbred laboratory rodents. 

Methods Employed : A series of factorial-designed feeding trials are 
. conducted to determine the effect of various diets differing in nutrient 
concentrations and physical form on the growth and reproductive performance 
of the species involved. Criteria of evaluation include number of 
pregnancies, number of offspring weaned, weight of offspring weaned, and 
the post-weaning growth rate of offspring. These data are coded for 
computer analysis by the appropriate statistical methods. 

Major Findings : Mouse reproduction data collected under practical 
conditions verify experimental data indicating no decrease in reproductive 
performance when dietary concentrations of crude protein is decreased 
from 24 to 18 percent. 

Data collected from a study designed to evaluate the effect of high 
concentrations of thiamin in autoclavable mouse rations indicate the 
concentrations of thiamin fortifications used in commercial rations are 
considerably in excess of requirements. These data also indicate there 
are no antimetabolites produced that affect mouse reproduction during 
autoclaving of feeds containing high concentrations of thiamin. 



117 



The concentrations of ascorbic acid required in autoclavable guinea pig 
rations have been established. Limited data have been accumulated that 
indicate metastic calcifications in guinea pigs can be controlled by- 
altering dietary mineral concentrations. 

Significance: The development of open formula rations for NIH production 
and research animal colonies is advantageous because 1 ) production of 
rations is not restricted to a single mill in the event of a fire or 
bacterial contamination, 2 ) investigators have the opportunity to know the 
complete nutritional status of animal colonies 3) a basis is provided for -■ 
the improvement of rations for particular stocks or strains of animals, 
and 4 ) competitive procurement of essentially the same product can be 
accomplished over many years. 

The efficiency of maintaining production and research colonies of laboratory 
animals can be markedly improved if rations can be developed that supply 
nutrients in concentrations nearly equal to the requirement of the strain 
of animal involved. 

Proposed Course : Continuation 

J. Models, biological; nutrition, diet; growth; reproduction; food, animal 
feeds. 

K . None 

L. Knapka, J.J. and Judge, F.J.: The Effects of Various Levels of Dietary 
Fat and Apple Supplementation on Growth of Golden Hamsters ( Mesocricetus 
auratus). Lab. Anim. Sci . 24: 318-325, 1974. 

Knapka, J. J., Smith, K.P., and Judge, F.J.: Effects of Open and Closed 
Formula Ration on the Performance of BALB/eAnN, C57BL/6N, and Swiss Mice. 
Lab. Anim. Sci. 24: 480-437, 1974. 



118 



Serial No. Z01 RS 00003-02 VR 



1. Veterinary Resources Branch 

2. Small Animal Section 

3. Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 



SELECTION FOR 6-WEEK WEIGHT IN INBRED AND N0NINBRED 
STRAINS OF MICE 



D. 


DRS-7RB-7 




E. 


K. P. Smith 




F. 


C. T. Hansen 




G. 


None 




H. 
I 


Total: l 
Professional: 
Others: 



5 
5 


I. 


Objectives: To 

C + -1 1 1 Q-U--; 0+ C T.T-? +1 


ie 



To determine if a significant amount of genetic variation 



still exists within highly inbred strains of mice. 

Methods Employed : The design includes three strains of mice — two inbred 
(C3HVHeN and NGP) and one noninbred (GP). There are 72 mating pairs per 
strain. In each strain there are three groups: l) 12 pair of brother x 
sister matings, 2) 24- pair of random matings, 3) 36 pair of random matings 
which are selceted for 6-week body weight. Th experiment will include 
six generations. 

Major Findings : After four generations, there was no response to selection 
for 6-week body weight in the C3H + /HeN strain. This result indicates there 
is no remaining genetic variation in the C3H + /HeN strain and it was 
discontinued after the fourth generation. After five generations of 
selection in the GP strain, there has been a large response to selection. 
There is a 5 gm. difference between the GP control line and the GP selected 
line. These results indicate that 38 percent of the variation observed in 
6-week weight is due to genetic differences. 

Significance : If it can be demonstrated experimentally that all of the 
genetic variation in a quantitative trait such as 6-week body weight has 
been eliminated from highly inbred strains, it should be possible to 
simplify the mating systems used and reduce production costs. 

Proposed Course: Continuation 



119 



J. Genetics, population genetics animal; genetics study section; body weight; 
mammals, mice Swiss; mammals, mice C3H/HeN; genetics, population genetics, 
inbreeding . 

K. None 

L . None 



^ 



120 



Serial No. Z01 RS 0000-4-14 VR 



1. Veterinary Resources Branch 

2. Comparative Pathology Section 

3. Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

C. TYZZER'S DISEASE 

D. DRS-VRB-5 

E. James R. Ganaway 

F. Rebekah S. McReynolds 
Anton M. Allen 
Thomas D. Moore 

G. University of Kentucky (Dr. T.W. Swerczek) 

H. Total: 1.7 
Professional: 1.0 
Others: 0.7 

I. Objectives : To characterize the etiologic agent. To study the pathogenesis 
of the disease through experimental transmission studies. To develop sero- 
logic techniques for detection of antibody. To develop a means to control 
and/or prevent the disease. 

Methods Employed : Microbiology, immunology and pathology. 

Major Findings : The disease continues to occur enzootically in the NIH 
rabbit production colony. Biological characterization and comparison of 
isolants from laboratory rabbits and a foal which died of Tyzzer's disease 
continues. Several antigen preparations have been tested in the develop- 
ment of a complement fixation test. 

Significance : Within the past decade, this disease has been diagnosed for 
the first time in nine different species of animals including rats, hamsters, 
gerbils, rabbits, cats, muskrats, wild hares, nonhuman primates, and horses. 
The natural history of this disease remains unknown. The etiologic agent, 
a gram-negative, spore-forming, obligate intracellular parasite, is unique 
in the field of microbiology and remains unclassified. This disease occurs 
throughout the world, causes fatal epizootics in a wide variety of species, 
and is one of the most important diseases of laboratory animals which 
interferes with and complicates biomedical research. 



121 



Proposed Course : Continuation 

J. Bacterial diseases; liver disorders, hepatitis; gastrointestinal disorders, 
enteritis, colitis; mammals, lagomorphs. 

K . None 
L. None 



122 



Serial No. Z01 RS 00005-01 VR 



1. Veterinary Resources Branch 

2. Comparative Pathology Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

C. SUPPRESSION OF PSEUD0LYMPH0MA IN NZB MICE WITH 
SYNGENIC YOUNG THYMOCYTES 

D . None 

E. Dawn G. Goodman 

F. M. Eric Gershwin, N1AMD 
Alfred D. Steinberg, NIAMD 
Robert A. Squire, NCI 

G. Arthritis and Rheumatism Branch, NIAMD 

Carcinogenesis, Division of Cancer Cause and Prevention, NCI 

H. Total: 0.5 
Professional: 0.25 
Others: 0.25 

I. Objectives : To determine the effect of restoration of immune competent 
cells with and without immunosuppression on the development of pseudo- 
lymphamatous infiltrates in NZB mice. 

Methods Employed : NZB mice are used. Mice are treated with young thymocytes , 
young spleen cells, young bone marrow cells, a combination of all three types 
of cells, or with old spleen cells on a regular schedule. These groups are 
subdivided with one group also receiving Imuran. In addition, two control 
groups, one with no treatment and one treated only with Imuran are used. 

At the end of a year, the mice are sacrificed and autopsies performed on 
animals. The various lesions present will be evaluated histologically 
and correlated where possible with treatment group. 

Major Findings : Currently unknown. 

Significance : Elucidation of some thymocyte functions with possible 
implications in control of neoplastic diseases is hoped for. 

Proposed Course : Continuation 
J. Mammals, mice NZB; blood cells, B lymphocytes; blood cells, T lymphocytes. 
K . None 
L . None 

123 



Serial No. Z01 RS 00006-03 VR 



1. Veterinary Resources Branch 

2. Small Animal Section 

3. Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 



C. DIFFERENT LEVELS OF DIETARY PROTEIN FOR LABORATORY RATS 

D. DRS-VRB-2 

E. Anton M. Allen 
Joseph J. Knapka 

F. K.P. Smith 

G. None 

H. Total: 0.5 
Professional: 0.25 
Others: 0.25 

I. Objectives : To evaluate the effect of various levels of dietary crude 
protein on the reproductive performance, various physiological systems, 
pathology, and longevity of nonnbred stocks of rats. 

Methods Employed : A series of factorial designed, long-term feeding trials 
are conducted involving rations containing various concentrations of crude 
protein. Throughout the study various reproductive trials and physiological 
determinations are recorded. At predetermined intervals, rats from each 
treatment group are sacrificed for pathological evaluation. 

Major Findings : Analyses of pathology data have not been completed. 

Proposed Course : Continuation 
J. Proteins; nutrition; mammals, rats. 
K . None 
L . None 



124 



Serial No. Z01 RS 00007-01 VR 



1. Veterinary Resources Branch 

2. Comparative Pathology Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974- through June 30, 1975 

C. ENVIRONMENTAL TOXICOSIS OF RHESUS MONKEYS— PERRINE 
PRIMATE FACILITY 

D . None 

E. George L. Clarke 

F. Anton M. Allen 
Alhert E. New 
Norman Altman 

G. Perrine Primate Research Center 

H. Total: 0.5 
Professional: 0.4 
Others: 0.1 

I. Objectives : To determine the cause of progressive debilitation and death 
among the rhesus monkeys housed at the Perrine, Florida, facility. 

Methods Employed : The problem is being studied by histopathological, 
■ clinical, pathological, and epidemiological means. The history and 
pathology is suggestive of a. toxicosis produced by exposure to polychlori- 
nated biphenyls (PCB). Tissues and materials suspected of containing these 
compounds are being analyzed by gas chromatographic and mass spectrophoto- 
meter methods. 

Major Findings : Preliminary investigations indicate the presence of 
PCB's in tissues of affected animals. 

Proposed Course : Continuation 

J. Toxicology; halobenzenes, PCB and PCT; mammals, primates. 

K . None 

L. None 



125 



Serial No. Z01 RS 00008-01 VR 

1. Veterinary Resources Branch 

2. Comparative Pathology Section 

3. Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 



C. NEOPLASIA IN THE NUDE MOUSE 

D. None 

E. George L. Clarke 

F. Carl T. Hansen 

G. Carcinogenesis Branch, NCI 

H. Total: 0.3 
Professional: 0.2 
Others: 0.1 

I. Objectives : To determine the prevalence and types of neoplasia that occur 
in this inbred strain which is genetically deficient in cell mediated 
immunity. 

Methods Employ ed: Retired females are maintained behind the barrier at 
Building L4C for aging and sent to the Comparative Pathology Section when 
they show any signs of abnormality. Males are sent to the Section 
following retirement and are maintained in relative isolation in the 
Horsfall units and killed when they exhibit any abnormal signs. 

Major Findings : There are sketchy reports that claim nude mice have a 
relatively low rate of neoplasia. Numerous cases involving neoplastic 
changes have been observed to date, involving many organ systems. 

Significance : If nude mice in fact do experience a significant rate of 
neoplastic disease, this will be a worthwhile contribution to the 
scientific literature. 

Proposed Course : Continuation 

J. Mammals, mice; neoplasms; immunopathology, immunologic deficiency disorders. 

K. None 

L. None 



126 



Serial No. Z01 RS 00009-02 VR 



1. Veterinary Resources Branch 

2. Experimental Surgery and 

Medicine Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

C. SODIUM CYANATE NEUROTOXICITY IN Macaca nemastrina primates 

D. DRS-VRB-8 

E. David K. Johnson 

F. Robert A. Whitney, Jr. 
French Anderson, NHLI 

G. Section on Molecular Hematology, NHLI 

H. Total: 0.6 
Professional: 0.3 
Other: 0.3 

I. Objectives : Sodium cyanate, a chemotherapeutic agent for Sickle Cell 
disease, inhibits irreversibility of the sickling of erythrocytes from 
patients with this disease by reacting specifically with the N^-terminal 
valine of the hemoglobin molecule without significantly destroying 
erythrocyte metabolism or function. It has been suggested that sodium 
cyanate may elicit neuropathology in pigtail monkeys, Macaca nemastrina . 
The outcome of this study will provide information for development of 
further clinical studies for use in humans suffering from Sickle Cell disease. 

Methods Employed : Twenty adult female pigtail monkeys, Macaca nemastrina , 
will be divided into four groups; one as a sham control and the other three 
groups will receive daily subcutaneous injections of sodium cyanate at 4.0, 
mg/kg; 25 mg/kg; and 15 mg/kg, respectively. Selected animals will be 
humanely killed and perfused for neuropathological examination. Clinical 
neurological examination and clinical laboratory tests will be run routinely 
during the course of the experiment. Baseline hematology, clinical 
chemistries, and neurological evaluations have been compiled over 3-month 
stabilization period. 

Proposed Course : Initiate the sodium cyanate testing experimental protocol 
in one month. 

J. Hemoproteins, hemoglobinopathies, sickle cell anemia; cyanates; mammals, 
primates; models, biological; neurotoxins. 

K . None 
L. None 

127 



Serial No. Z01 00010-03 VR 



1. Veterinary Resources Branch 

2. Experimental Surgery and 

Medicine Section 

3. Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 



C. Erythrocebus patas MONKEY AS AN ANIMAL MODEL FOR 
CARDIOVASCULAR RESEARCH 

D. DRS-VRB-9 

E. David K. Johnson 

F. Donald L. Fry, NHLI 
Robert Mahley, NHLI 

G. Section on Experimental Atherosclerosis, 0DIR, NHLI 

H. Total: 3-0 
Professional: 0.75 
Other: 2.25 

I. Objectives : 1) To determine the suitability of the patas monkey for 

atherosclerotic studies as they relate to human disease. Positive findings 
would provide an animal model from an African source, and 2) to determine 
whether the patas monkey has advantages as an animal model for cardio- 
vascular studies over those presently available. 

Methods Employed : Fifty patas monkeys ( Erythrocebus patas ) were purchased 
and maintained on monkey chow for 4 months while baseline data was 
obtained. They were randomly divided with equal sex distribution into one 
group of 10 animals receiving monkey chow, one group of 20 receiving high 
fat-low cholesterol, and one group of 20 receiving high fat-high cholesterol, 
Monthly blood samples were drawn and hematological, serum chemistries, and 
serum lipid profiles were obtained. 

Major Findings : The test group receiving high fat-high cholesterol had a 
rise in serum cholesterol levels which persisted while being fed ohe 
atherogenic diet. The serum lipid profiles of the other two groups were 
similar. After 12 months on the study, one-half of each group was humanely 
killed and necropsies performed with emphasis placed on the cardiovascular 
system. Atherosclerosis lesions were evident in the high fat-high choles- 
terol group. After the end of an additional 12 months, the balance of the 
animals were humanely killed and necropsied. More severe atherosclerosis 
was evidenced in the high fat-high cholesterol group with evidence of some 
coronary artery disease and a few cases of cholesterol gallstones. The 

high .fat-low cholesterol animals had some indication of mild disease, and 
detailed histological and histochemical evaluations are now in progress. 

128 



Proposed Course : The patas monkey is a suitable primate animal model for 
atherosclerosis. Arterial lesions, serum lipids, and serum chemistries 
have characteristics comparable to human disease. The next study -will be 
to divide 4-0 patas monkeys into three groups: a test group receiving a 
diet similar to a typical American diet, another group a diet with added 
cholesterol, and a control group. This study is proposed for a minimum of 
2 years duration with similar parameters followed. 

J. Mammals, primates; models, biological; cardiovascular disorders 
arteriosclerosis, atherosclerosis; cholestane series, cholesterol; 
lipids, blood. 

K. None 

L. In preparation 



129 



J. 



Serial No. Z01 RS 00011-01 VR 

1. Veterinary Resources Branch 

2. Experimental Surgery and 



3. 



Medicine Section 
Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974- through June 30, 1975 



C. EFFECT OF SEASON ON PITUITARY AND GONADAL HORMONE 
LEVELS IN ADULT MALE MACAQUES 

D. None 

E. David K. Johnson 

F. Gary D. Hodgen 

G. Section on Endocrinology, Reproduction Research Branch, NICHD 

H. 



Total: 
Professional: 
Others : 



1.25 
0.25 
1.00 



Objectives : Season changes in breeding efficiency among colonies of 
rhesus monkeys remains a controversial issue with little pertinent scien- 
tific data available. Effects of season on hormonal parameters important 
in male fertility gonadal secretions are involved. Measurements of 
Follicle Stimulating Hormone, Leutining Hormone, Testosterine, and 
Androsternedione in peripheral serum will be assayed for 5 consecutive 
days every month in ten adult breeder male monkeys. Correlations between 
hormone levels, breeding efficiency, and season will be determined. 

Mammals, primates; reproductive hormones, gonadotropins; reproductive 
system, gonads. 



K. None 



L . None 



130 



* 



Serial No. Z01 RS 00012-01 VH 



1. Veterinary Resources Branch 

2. Experimental Surgery and 

Medicine Section 

3. Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 



C. HORMONE LEVEL DURING THE POSTPARTUM INTERVAL 
IN NURSING AND NON-NURSING MACAQUES 

D . None 

E. David K. Johnson 

F. Gary D. Hodgen 

G. Section on Endocrinology, Reproduction Research Branch, NICHD 

H. Total: 2.0 
Professional: 0.50 
Others: 1.50 

I. Objectives : The interval from delivery to the first fertile menstrual 
cycle in rhesus monkeys is not known. Breeding management requires such 
information to maximize the use of breeder males for space management 
planning and efficiency in timed-mating protocols. Five nursing mothers 
and five non-nursing mothers will be bled daily for 90 days beginning one 
day after delivery. Serum levels of Follicle Stimulating Hormone, 
Leutinizing Hormone, Estradiol, Estrone, and Progesterone will be measured 
to identify the onset of ovulatory menstrual cycles. 

J. Mammals, primates; reproductive hormones, gonadotropins; reproductive 
system, gonads. 

K . None 

L . None 



131 



Serial No. Z01 00013-01 VR 



1. Veterinary Resources Branch 

2. Animal Center Section 

3. Poolesville 



PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 



C. MYCOPLASMA INDUCED CAPRINE KERATOCONJUNCTIVITIS 

D . None 

E. Ervin J. Baas 
Michael Barile (BoB) 

F. R.M. Franklin 

G. Mycoplasma Section, Laboratory of Bacterial Products, BoB 
Wilmar Ophthalmology Institute, The Johns Hopkins University 

H. Total: 0.4 
Professional 0.2 
Others: 0.2 

I. Objectives: To deterimine: l) if Mycoplasma conjunctivae is the 
etiological agent of natural occurring caprine keratoconjunctivitis 
(pinkeye) and arthritis, 2) if the disease or similar pathological changes 
can be induced experimentally, and 3) whether the goat is a suitable animal 
model for Reiter's Syndrome ( irridocyclitis, urethritis, polyarthritis, 
conjunctivitis) in humans. 

Methods Employed : Naturally occurring cases of conjunctivitis and 
arthritis in goats are being studied by bacteriological, serological, 
pathological, and serum chemical methods. This information is being 
utilized to further understand and contribute to the experimental 
induction and pathogenesis study of the disease. The experimentally 
induced disease is being studied by the previously mentioned parameters. 

Major Findings : Natural epizootics occur in cyclic periods. Subsequent 
to these periods, arthritis develops in some goats. Serum antibodies do 
not increase but local antibody can be obtained from synovial fluid of 
the affected joints. Experimental conjunctival disease can be induced 
more readily in adult goats than young immature goats. Immunological 
data obtained do not indicate that definite immunity is acquired. 

Proposed Course : Continuation 

J. Eye disorders conjunctivitas, keratoconjunctivitis; arthritis; Reiter's 
syndrome; immunity, cellular, lymphocyte transformation; bacteria, myco- 
plasmatales, mycoplasma; models, biological; mammals, ungulates, goats. 

K. None 

L. Manuscript in preparation 

132 



' 



Serial No. Z01 RS 0001/4-01 VR 

1. Primate Quarantine Unit 

2. Animal Center Section 

3. Poolesville 

PHS-NIH 

Individual Project Report 

July 1, 1974 through June 30, 1975 

C. EVALUATION OF EFFICACY OF M. bovis PPD TUBERCULIN TO DETECT 
TUBERCULOSIS IN WILD CAUGHT INDIAN Macaca mulatta 

D. None 

E. David M. Renquist 

F. Donald W. Johnson 
L.D. Konyha 
Albert E. New 

G. Animal and Plant Health Inspection Services 

USDA, Hyattsville, Maryland (Ames, Iowa) 
Department of Veterinary Clinical Sciences 
University of Minnesota, St. Paul, Minnesota 

H. Total: 0.12 
Professional: 0.07 
Others: 0.05 

I. Objectives : To determine the efficacy of Mycobacterium bovis purified 
■ protein derivative (PPD) tuberculin as compared to that of the standard 
veterinary mammalian tuberculin in the early detection of naturally 
acquired tuberculosis in rhesus monkeys. 

Methods Employed : Approximately 50 tuberculous monkeys, identified during 
routine testing, will be placed in isolette cages and their comparative 
reactivity to veterinary tuberculin and PPD will be determined. Twelve to 
20 fully conditioned, tuberculosis- free monkeys will then be paired with 
tuberculous monkeys. Each pair will be tested at weekly intervals with 
specific dilutions of veterinary tuberculin and PPD. Skin reactions will 
be measured and photographed and lymphocyte transformation studies 
performed. When tuberculosis is diagnosed in the conditioned monkey, the 
pair will be killed and necropsies will be conducted. The results will 
be recorded and tissue samples will be collected for histopathologic 
evaluation and Mycobacterium isolation and identification. 

Major Findings : Data are insufficient to provide details. 

Significance: No determination because of insufficient data. 



133 



Proposed Course : Continuation 

J. Immunological tests and immunoassay, tuberculin tests; actinomycetales, 
mycobacterium tuberculosis; mammals, primates. 

K. None 

L. None 






134 



Serial No. Z01 RS 00015-01 VR 



1. Veterinary Resources Branch 

2. Office of the Chief 

3. Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1974- through June 30, 1975 

C. DEFINING THE NUDE MOUSE MODEL 

D. None 

E. Robert A. Whitney, Jr. 

F. Carl T. Hansen 
James R. Ganaway 
Anton M. Allen 
C.K. Hsu 
Robert Purcell 
Paul Holland 

G. Department of Laboratory Animal Medicine 
Johns Hopkins University, Baltimore 

Laboratory of Infectious Diseases, NIAID 

Blood Bank, Clinical Center, NIH 

H. Total: 0.3 
Professional: 0.2 
Other: 0.1 

I. Objective : To determine the susceptibility of the nude, athymic mouse to 
viral, parasitic, and bacterial diseases, and to define the role of the 
thymus activated "T" lymphocytes in susceptibility and pathogenesis of 
infectious diseases. 

Methods Employed : Weanling nude mice are transferred directly from the 
Building 14G barrier to presterilized, germfree isolators. Protecting 
this highly susceptible animal from the conventional environment with the 
flexible plastic isolator system has proven extremely successful. Many 
nudes, who have a 4-month life span in conventional animal quarters, are 
still surviving after 15 months in our isolator system. 

This project originated as an attempt to infect nude mice with human 
heptitis A and hepatitis B. Serum from a human known to be infected with 
"B, " and from a chimpanzee known to be infected with "A" was injected I.V. 
into separate groups of animals. 



135 



Major Findings : In collaboration with Johns Hopkins University, nude 
mice in isolators were also exposed to known numbers of infectious 
Schistosome larvae. After over 12 months' of testing for the antigen and 
antibody for B and for liver enzyme changes associated with A infections 
it was concluded that, despite their lack of a cellular immune response, 
the nude, athymic mouse is not susceptible to human viral hepatitis. In 
the schistosome work, nudes, while developing heavy infections, do not 
show the tissue granulomas seen in conventional mice infected with 
schistosomes. This demonstrates the role of cell mediated immunity in 
the pathogenicity of this disease. 

Significance : This congenital, athymic state, with its resulting lack 
of cell mediated immunity in the nude mouse, may be one of the most 
signigicant events in the evaluation of animal models for human disease. 
It must be defined in a number of areas to realize Its potential and 
limitations in biomedical research. 

Proposed Course : Continuation 

J. Models, biological; manal, mice; immunity, cellular immunity. 

K . None 

L. Two manuscripts in preparation. 



136 



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