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NATIONAL INSTITUTES OF HEALTH
NIH LIBRARY

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BETHESDA, WSD 20892-1150

ANNUAL REPORT
OF
PROGRAM ACTIVITIES
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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

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.

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)

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.

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.

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.

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

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.

73
CO

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.

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

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

rat

duce

70 a

rat

hou

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

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

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

, o

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

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

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

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.

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

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,

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 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

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.

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 ....

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

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

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

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.

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

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

1.0

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

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

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.

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.

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

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).

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.

hr 1

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

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.

JaMBL,—

1 CO

rti

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).

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.

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.

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).

.--

»l

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

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.

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.

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).

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.

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.

TO
TO

I* I

Z01 CT 00022-08 PSL

Project No.

1. Physical Sciences Laboratory

2. Not Applicable

3. Bethesda

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

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

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).

-1;

i "'
'''

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

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).

«l I

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).

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 ).

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

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).

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.

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".

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.

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".

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.

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

ii !

f! I

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).

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) .

73
70

(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

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

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

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

■x>

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).

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

•

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

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.

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

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"

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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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.

Publications

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

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

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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\ 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

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

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.

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.

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.

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.

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°

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. '»

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

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.

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

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.

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.

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

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 .

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.

iV^

73
73

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 .

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.

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,

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.

i S
L

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.

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.

■I

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

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.

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.

TO
73

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.

(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«,

«,
mI,

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

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.

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.

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.

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) .

■X)

Sill .

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.

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) .

•■J ,

101

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.

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-.

Nr"

1*11

105

i
i a

(If,,

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

J" (l

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.

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,,

] —

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.

■X)
73

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

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.

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.

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 .

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

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.

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.

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

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

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.

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.

TO
73

I I

fl! „

nil .

_JJ

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.

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

,831

,865

3,987

11,683

FDA

112

138

335

ADAMHA

934

694

1,088

2,716

Subtotal

,948

,701

5,260

14,909

Construction

PL 480

Training

869

349

1,305

Career Development

929

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

TOTAL, NON-COMPETING 3,480

COMPETING
NON-COMPETING

6,995
3,480

GRAND TOTAL 10,475

2,655

287

3,020

TOTAL

5,655
3,020

8,675

7.968

2,751

265

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 •

DRS

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

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.

- 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.

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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:

- 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.

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.

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Hill;

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.

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.

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

'"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.

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 "

ANNUAL REPORT

FISCAL YEAR 1975
(July 1, 1974-June 30, 1975)

DIVISION OF RESEARCH RESOURCES

National Institutes of Health
Bethesda, Maryland 20014

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.

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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 :

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

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

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,

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)

. !-

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

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.

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

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

403

449

593

591

490

10%

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

■ '!.

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,

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.

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

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

!
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.

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

4,053,288

2,314,848

2, 836, 766^

Renewal

1,099,216

329,476

438,795

Supplemental

201,372

188,357

240,847

Continuation

2,705,679

2,004,424

2,665,236

Totals

110

8,059,555

4,837,105

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

163,523

95,406

103,038

Renewal

Supplemental

Continuation

313,092

247,153

256,621

Totals

476,615

342,559

359,659

1/ Direct Costs Only

2/ Includes Indirect Costs

TABLE IV - Fellowship Applications in Laboratory Animal Science , FY 1975

Number

Amount

Type

Received

App

roved

Funded

New

27,738

Renewal

Supplemental

Continuation

21,111

Totals

48,849

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— ' -

42 3,188,025

26
1

1,645,629

22,195

1,265,469

1,559,287

378,951

Totals 110 8,059,555

22
1
10
13
_6
89

2,145,733

1,095,217

11,098

380,496

851,322

353,239

4,837,105

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

No. of
N IH Grants

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

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

■

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.

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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

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 .

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

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

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

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

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

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 Project

Project

(in millions)

1.5

9.7

2.8

140

7.9

226

8.5

634

40.5

Projected Totals for all 47 Active Grants
Number = 993
Value = $64 million

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

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

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.

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.

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OBSERVATION ON RESOURCE
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COST EFFECTIVENESS METRIC-
TOTAL COMPUTER PRODUCTION HOURS /ANNUAL AVERAGE BRB FUNDS

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 }

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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;

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.

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.

_ —

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:

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.

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

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.

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

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

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.

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

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.

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

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.

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.

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.

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

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.

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.

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

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.

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

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

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

Corder

Decker

Werner

Wingard

Alfred P. Sloan Foundation;
National Science Foundation

National Institute of
Mental Health

Table III.B. Applications of the Prophet System at
Beth Israel Hospital, Boston, Mass.

Project

1. Error analyses of amino acid
determinations

Investigator(s )

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

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

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.

National Heart and Lung
Institute

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

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

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.

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

+-> (O -r-

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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.

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.

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-

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

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-

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.

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.

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.

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

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.

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

1051

260,696

1969

1023

245,943

2,297

1970

940

231,020

1,920

1971

881

218,716

1,885

1972

907

220,490

1,801

1973

893

204,993

1,790

1974

888

238,560

1,812

1975

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

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

Increase

Cost/Posi-

Over Pre-

Cost/Pa-

Over Pre-

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

AL CLINICAL RESEARCH CENTERS

Ft 1957 - FY 1976
(Dollars in Millions)

FIGURE 1

^^^ NARRC CEILINGS
'////// EXPENDITURES

SERVICE CREDITS + APPROPRIAT CONS

W/^^^/

1967 1968 1969 1970

1971 1972 1973
FISCAL YEAR

Estimate

1974 1975 19

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

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

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

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

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

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.

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.

o
1 <s>

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-

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

I -

i : <="

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)

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

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.

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

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)

15% were made

Amount made

Percent of

Funds

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

7.3

1974

,091,795

163,769

45,149

4.1

1975

,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

Inst.

1968
95

1969

1970

1971

1972

1973

1974

1975

Medicine

100

101

104

107

Dentistry

Osteopathy

Pub. Health

Pharmacy

Ve t . Med .

Nursing

Allied Health

Hospitals

Health Dept.

Res. Inst.

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

Grant Range
(All Inst.)

Low

High

Average

Amounts (In Thousands)

FY
1968

FY
1969

$36 $ 29

219 220

74 68

FY
1970

$ 15

199

FY
1971

$ 12

210

FY
1972

$ 15

212

FY
1973

$ 27

221

FY
1974

$ 23

187

Size of Grants

(In thousands)

1968

1969

1970

1971

1972

1973

1974

1975

Under - $ 30.0

$ 30 — 49.9

50 - 99.9

100 - 149.9

150 - 199.9

200 - 249.9

—

Total No. of

Grants

102

110

113

112

117

113

108

121

FY
1975

$ 19

165

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

6/29/67-12/31/72

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

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

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

143

184

—

532

1,095

1,550

1,784

2,000,000

5,000,000

8,000,000

7,662,964*

s 38

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

$1,182,446

356,289

6,124,229

$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

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.

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.

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.

'',. 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

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.

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.

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

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.

(

■

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.

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

Dollar value

$478,000

$700,000

Number of items on rental

194

240

• 1

Utilization rate

46$

FY 1974
$65,000

FY 1975
$102,000

Percent Increas

Gross revenue

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. /

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.

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.

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.

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

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.

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,

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.

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,

> , 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.

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).

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.

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.

•

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).

Project No. Z01 RS 00002-10 BEI

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.

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.

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.

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. : .

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.

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.

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.

(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.

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.

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.

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.

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.

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.

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.

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).

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.

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

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 :

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.

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).

•

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.

Keyword Descriptors : Hypertrophy, phosphorylation, organ culture,
papillary muscle.

Honors and Awards; None

Publications: None

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 :

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.

Honors and Awards: None

Publications:

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.

"*!

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.

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-

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.

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 .

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."

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.

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.

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

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-

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.

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.

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.

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.

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.

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

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.

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.

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

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.

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.

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

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.

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.

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

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

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.

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.

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 .

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.

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.

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.

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

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

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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")

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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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

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

DRS-7RB-7

K. P. Smith

C. T. Hansen

None

H.
I

Total: l
Professional:
Others:

5
5

Objectives: To

C + -1 1 1 Q-U--; 0+ C T.T-? +1

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

Serial No. Z01 RS 00011-01 VR

1. Veterinary Resources Branch

2. Experimental Surgery and

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

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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