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Full text of "Annual report : National Institutes of Health. Division of Research Grants"












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NATIONAL INSTITUTES OF Hrflii 

NIH LIBRARY 

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AUG 5 2000 

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BETHESDA. MD 20892-1150 



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ANNUAL ^ORT 
OF 
PROGRAM ACTIVITIES 

U.^. K;ftT.(!uAl.[liani)TE< 5F %LTH. DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY 

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DIVISION OF RESEARCH GRANTS 

DIVISION OF RESEARCH RESOURCES 

DIVISION OF RESEARCH SERVICES 

Fiscal Year 1974 



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

Report of Program Activities R 

July 1, 1973 through June 30, 1974 



ANNUAL REPORT 

TABLE OF CONTENTS 

Page 

Director's Summary -------------------- ^- 1 

Summary of the Associate Director ------------ 9 

Summary of the Assistant Director ------------ 11 

Computer Center Branch ------------------- 13 

Laboratory of Applied Studies --------------- 21 

Computer Systems Laboratory ---------------- 27 

Physical Sciences Laboratory ----------------- 41 

Heuristics Laboratory ------------------- 47 

Data Management Branch ------------------- 53 




DCRT Annual Report 
July 1, 1973 through June 30, 1974 
Office of the Director 

It has been ten years since DHEW approved the concept of a new NIH division to 
cope with computers and to help reap the many benefits anticipated from "the 
broad application of this new technology to research in the life sciences." 
The FY1974 activities of the Division of Computer Research and Technology, set 
forth in detail by the laboratories and branches in this annual report, show 
the concept was prophetic and is still essentially sound. 

This Director's Summary highlights these activities briefly and speaks to the 
future, wherein lie the opportunities and problems for computing at NIH. Four 
figures provide a visual FY74 synopsis of the size and functions of the DCRT 
components and the management and revolving fund expenditures, as well as a 
multi-year overview of growth in the NIH computer centers task load and in the 
revolving fund services rendered. 

The Past Year 

Computer Center Branch continues to provide NIH with responsive, reliable com- 
puting services and facilities of unexcelled quality and diversity. Use of 
both central systems (the IBM 360/370 system and the Digital Equipment Corpor- 
ation (DEC) PDP-10 system) grew (now more than 200,000 jobs per month). Costs 
per user job were cut 30% or more. Major hardware improvements were installed 
on the DEC system and planned for the IBM system. Major software (systems pro- 
grams) improvements were made on both. 

What is important to emphasize here is the fact that growth in quality, quan- 
tity, sophistication and efficiency of the system and in economy and ease for 
the users has continued year after year. The ability to maintain and improve 
integrated man-machine-software systems of this magnitude is significant and 
of fundamental importance to NIH program activities. A dramatic example of the 
breadth of system capability is its application to store and analyze x-ray 
crystal lographic data then to depict macromolecular configurations in 3D stereo, 
and finally to create by computer output an inexpensive microfilm stereo atlas 
of protein molecules for biochemists throughout the world. (This can be exam- 
ined with a simple polarized viewer on conventional microfiche readers.) 

The Data Management Branch is equally impressive in its area, i.e., designing 
and creating computer programs to manage and analyze data from scientific and 
administrative activities throughout NIH. In this way the Branch transforms 
the basic computing system power into useful work. The "application programs" 
are then owned and operated by the NIH scientific or administrative staff who 
have responsibility for the data. (The Branch also develops "software support" 
tools to speed the construction of their applications programs.) 

Even though the DMB report is impressive, listing almost a hundred projects in 
FY74 for the great majority of NIH institutes and divisions, it understates the 
Branch's impact on NIH activities. It does not depict the many applications 
built in previous years and still functioning well throughout NIH. The cumula- 
tive effect over the last several years has greatly strengthened the useful 
application of computers in virtually all parts of NIH. 



The Computer Systems Laboratory must be viewed from a different perspective. 
The laboratory develops computer systems for those activities at NIH which need 
something beyond the power of the NIH central facility. As the CSL report notes, 
these are mostly applications wherein the requirements for data acquisition, 
analysis and response require a dedicated or local ""y shared computer. 

The CSL domain therefore includes the design, procurement, development, testing 
and installation of smaller computers and of their electronic interfaces, sys- 
tems software and applications programs. The results are not measured in hun- 
dreds or hundreds of thousands of jobs per year but rather a few projects which 
each typically span several years from genesis to completion. 

The CSL also has its cumulative impact through systems completed in prior years. 
Much of the CSL effort in FY74, as in the previous year, went into projects in 
support of clinical care, particularly the intensive care unit for heart surgery 
patients and the NIH clinical laboratories. Two new projects begun this year 
demonstrate that there continue to be entirely new applications for electronic 
engineering and computer hardware expertise in NIH biomedical research. 

The Laboratory of Applifid Studies represents another part of the spectrum of 
DCRT disciplines, which extends across computer technology, engineering, applied 
mathematics and their uses in biomedicine at NIH. The LAS report notes that its 
primary emphasis is on direct application of mathematics and statistics. In 
addition, LAS does research in these fields. Its bibliography shows that both 
endeavors are productive. 

Indeed, the LAS work illustrates within the DCRT the breadth of computing 
throughout the NIH. In FY74 the LAS staff worked in electrocardiology, nuclear 
medicine, biochemistry, neural modeling (computer and mathematical) microcircu- 
latory modeling, hardware and software systems for data analysis and a variety 
of other projects. These involved extensive collaboration with other parts of 
DCRT as well as with many NIH laboratories and branches and with coworkers out- 
side of the NIH. They use computing resources selectively but in a fashion 
which demonstrates need for the full breadth of disciplines originally speci- 
fied for the division a decade ago. 

The Physical Sciences Laboratory also applies mathematics broadly to the exami- 
nation and alucida'-.ion of biomedical phenomena at a fundamental level. Its work 
on the theory of intermolecular forces in biochemical aggregation moved forward 
accompanied by the development of new experimental techniques to confirm the 
theoretical insights. Advances in nuclear nagnetic resonance instr-umentation, 
with computer cont.'ol and analysis, led to new theoretical work on polypeptide 
coiling and new discoveries about the interaction of subatomic particles under 
varying biochemical configuration. 

The PSl expertise carried to many other areas such as the dynamics of macro- 
molecules, microorganisms and blood elements, the interpretation of kinetic 
biochemical analysis and the design of clinical trials. The PSL bibliography 
speaks to the productive collaboration of this group with investigators in 
other NIH laboratories. 



The Heuristics Laboratory applied computing methodology to information handling 
and analysis tor a wide variety of topics, extending its fundamental work on 
theorem proving to computer program verification and its pattern recognition 
efforts to liver disease cases, mass spectral data and tissue-typing screens. 
Its previous collaborative efforts in developing mass spectral data file 
searching systems now have international recognition and sponsorship and it 
began collaboration on design of a more flexible and powerful system for the 
Walter Reed (Army) chemical substructure search system. 

The HL work on data analysis and modeling saw many new users for the MLAB system, 
a more sophisticated approach to linear multiple regression analysis, and the 
development of an improved simulation model for an NICHD menstrual cycle model. 
Its bibliography also testifies to active collaboration with investigators in 
other NIH laboratories. 



The Present 

A prime influence on the DCRT at present are the personnel limitations imposed 
as part of the ceilings placed upon the NIH. Cuts in budgeted and actual DCRT 
positions have come progressively, during the very years when its new Labora- 
tories and Branches matured, became more productive and engaged fully with the 
rest of the NIH. The division absorbed these cuts and the remaining staff over- 
came them with increased individual effort and more effective use of computa- 
tional power and sophistication. But in FY74 perennial retrenchment finally 
forced a reorganization and withdrawal from a DCRT commitment to those funda- 
mental efforts embodied in its Heuristics Laboratory. 

The particular irony of such a necessity can only be appreciated by viewing 
the course forseen by those who created the division a decade ago. The 
Steering Committee in 1963 declared: "The measure of the Division's success 
will be the extent to which it stimulates the introduction of ADP methodology 
into on-going programs." Computing facilities and services, data processing 
capabilities, computer system engineering and the application of modern mathe- 
matics to biomedicine have become a functional reality in the daily life of 
the NIH. Now is the very time when the mathematical and information handling 
research base should start making its greatest contribution to the NIH mission, 
but it is the \/ery time at which this base had to be cut. 

The Future 

The DCRT commitment is fundamental support of effective computing in NIH pro- 
grams. To this end and under the reality of FY74 cuts, a new DCRT laboratory 
was initiated this year, drawing expertise from several other parts of the 
division. This laboratory will contain a multidisciplinary nucleus of pro- 
fessionals in contact with the developments outside NIH, and like other DCRT 
laboratories it will do research. But its prime responsibility will be to 
bring modern computer based capabilities in data analysis, mathematical statis- 
tics and other mathematical methods closer to biomedicine in the NIH programs, 
both by its own activities and by support of biometry in other parts of NIH. 

At this time, moreover, extensive involvement of the DCRT program as a whole 
in NIH program activities forbids any further reduction of effort in any DCRT 



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laboratories and branches, if the fundamental DCRT commitment is to continue 
without loss of effectiveness and momentum. The original 1963 prospectus for 
"the computer division" envisioned growth from 355 employees in FY1965 to 680 
in FY1969. This prophecy may have been unrealistic, but it foretold the need 
for some new activity as the promise of computing became fulfilled in NIH pro- 
grams. Computing is now making steady strides in medicine, biomedical research 
and management. The fundamental strategy for the NIH must be to defend its 
carefully developed computing base against further retrenchment or retrogressive 
influences. 

The danger appears nowhere more clearly than the threats to the basic NIH com- 
puter capabilities posed by some administrative philosophies at other Federal 
levels. The technical expertise and managerial acumen which developed the 
central NIH hardware/software systems has been unexcelled, if indeed matched, 
elsewhere in the Federal establishment. In large measure this is true because 
the NIH leadership understood the complexity of computing in the NIH environment 
and delegated responsibility to the level where the requisite technical exper- 
tise and managerial experience could be established. Continued knowledgeable 
support by the NIH leadership will be needed to prevent erosion of the strength 
and effectiveness by external administrative requirements which lag behind the 
current technology and are virtually inapplicable to the complex, multiproces- 
sing, multiprogramming, multidisciplinary NIH environment. 

The Steering Committee Report in 1963 identified this basic problem in its 
discussion of computing in the governmental setting: "Government installations, 
particularly Federal scientific laboratories, seem to have encountered more 
serious problems than either universities or industrial centers. Administrative 
policies have been formulated with undue consideration to the use of computers 
for business or administrative applications." In spite of recognized competence 
and leadership, the DCRT and NIH carry a continual burden of educating others 
about the NIH program requirements. 

The need is for establishment of the historical perspectives and the prospective 
understanding which will allow NIH on-going programs to continue to benefit 
fully from the technology now that it has been introduced. The Steering Commit- 
tee words in 1963 are again worth rioting: "The present Committee was impressed 
by the fact that the conclusions it reached after protracted analysis, and which 
are embodied in this report, constitute, in terms of broad outlook e.,d major 
thrust, another step in a continuum first articulated almost a decade ago." 

Recognition of the continuum and its progression is a? important as appreciation M 
of the accomplishments of a single yea.'. Electronic computing i? a little more ■ 
than halfway through its second decade at NIH. It is currently a very consider- 
able success due to previous foresight and enterprise. The degree of success 
today does not reduce the need for foresight today and enterprise tomorrow. 






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Summary of the Associate Director 
July 1, 1973 through June 30, 1974 

The DCRT Scientific and Technical Information Office (STIO) became involved 
by error in the departmental attack on public relations puffery. Fortunately 
the basic duties of the STIO, set forth in 1970, were clear and dispelled 
the error quickly. The new emphasis on "inquiries" and "reports" fits the 
established STIO functions. 

The implication that "information" is henceforth a dirty word in DHEW may pose 
semantic problems for DCRT. Computers are, after all, information processing 
machines; information processing, with or without computers, is a large part 
of the NIH job; and the STIO has a functional responsibility for "communi- 
cation" of information about the processing of biomedical data by computer 
based techniques. This function amounts to more than answering inquiries and 
generating reports. 

The STIO edited and published two DCRT Technical Reports during the year: 
No. 9, A Structured Assembly Language Source Program Generator and No. 10, 
The Carcinogenesis Bioassay Data System . Both describe systems developed 
within our Data Management Branch. The office set up a standing Review 
Committee, composed of representatives of each Lab and Branch, to support 
standards of style and substance in the Technical Report series. 

The office continued to receive and answer inquiries from outside NIH. In 
the main, these ask about medical applications, careers in computing and 
specific computer software or scientific information centers. The office 
arranged formal visits for two national organizations: The American Medical 
Writers Association and The National Association of Medical Explorers. To 
answer questions of visitors to the Computer Center and to other parts of 
DCRT, the STIO designed an exhibit in conjunction with Medical Arts and 
Photography, DRS, and installed it in the lobby between Buildings 12 and 12A. 
It contains short "reports" about the functions of the Division and its 
Laboratories and Branches. A fuller set of brief reports on DCRT components 
and activities is planned, partly for this exhibit but equally important for 
rapid and effective briefings of the many technical and managerial visitors 
who come to DCRT from many parts of the world and the Federal government., 



More extensive specific 
STIO distributed a bull 
nical reports to NIH sc 
level . The items were 
in a wide range of mana 
were requests for techn 
The bulletin was discon 
direct readers to DCRT 
major interest for spec 



reports for the NIH staff have been suggested. The 
etin of recent DCRT library acquisitions and tech- 
ientists and administrators at the Lab and Branch 
a sample deliberately selected to explore interests 
gerial and scientific computing topics. Most responses 
ical materials which are already routinely announced, 
tinued and more direct approaches will be used to 
library acquisitions and to find out the topics of 
ial reports. 



As in previous years, the office was responsible for many recurring adminis- 
trative reports, clearances and archival functions in support of Division 
programs. 



- -7 -' - -- 

and related fields, adding about 200 new books and 100 technical reports. 
Five new periodicals were added and four were cancelled or ceased publication. 
The library continues as a unique resource for NIH and for many scientific 
or technical workers in the Washington area. Almost half of those who borrowed 
books were not DCRT staff. 

Library operations were enhanced by a new automated circulation record system, 
adapted from that developed for the EPA library. It has been used for a year 
and supports our circulation policy very successfully by permitting borrowers 
to keep books for an extended period and at the same time quickly and effi- 
ciently locating books when they are needed by other users. Borrowers peri- 
odically receive a listing of materials checked out to them, making it easy 
for them to keep track of and return their individual holdings. 

The library added the NLM MEDLINE to its services on a trial basis. The 
response was promising, with very active use during the first two months of 
1974 by medical students in the "Computers in Clinical Medicine" elective. 
A terminal is planned ir, the library when a telephone line becomes available. 
This should stimulate more use of the system. The STIO will undertake an 
evaluation of its utility as an information service in our environment. 

For the coming year we are considering (1) a survey to eliminate unused 
journals, (2) weeding the monograph collection to discard outdated materials, 
(3) further development of an in-house training program for the library 
assistant and (4) additional automation of selected library functions. 

The Computers in Clinical Medicine elective was given for the third year as 
part of the NIH Clinical Elective program for medical students. For the 
first time it incorporated a two day seminar with invited experts, Drs. 
Howard Bleich, Jerome Cox, William Yamamoto and Homer Warner. This addition 
was quite successful, in large part because of the high quality of the 
students. Several students from this and previous years intend to return 
to NIH for Associate positions. T!ie elective does, however, place a con- 
siderable load on DCRT and other NIH staff, and it will' undergo a detai^'sd 
evaluation and possible redesign before it is offered again. 



10 



Summary of the Assistant Director 
July 1, 1973 through June 30, 1974 

The Office of the Assistant Director, DCRT, provides four basic capabilities; 

1. It serves NIH as the focus for NIH-wide coordination of ADP 
policy matters. 

2. It serves NIH as a central point of contact with PHS, .the 
Office of the Secretary, other DHEW agencies, GSA and 0MB, 
relative to NIH ADP policy questions. 

3. It 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 

4. It supporiis the Director of DCRT by providing advice on 
resource acquisition and allocation necessary for DCRT to 
support the above functions. 

The coordination role is most often exercised in connection with the fact 
that all proposals for contracts or procurement actions involving ADP 
equipment, services, programming or design are cleared through this office 
prior to being executed. This provides a continuous opportunity to alert 
program or contract officials to opportunities to reduce costs and/or avoid 
duplications and to avoid difficulties with higher echelons. 

During FY74 extensive assistance was, for example, provided to ODA/NIH to 
develop an RFP, evaluate proposals and negotiate a $304,310.00 contract to 
develop a single comprehensive Material Management System for NIH. Our 
support of NCI's effort to develop a primary Cancer Research Center at 
Fort Detrick in Frederick, Maryland, continued. Significant unnecessary 
costs were avoided and capabilities improved by arranging for the prime 
contractor at Fort Detrick to himself develop an ADP capability in lieu of 
subcontracting. Assistance was provided to the National Library of Medicine 
in beginning the long process of obtaining PHS, OS and GSA approval for a 
major ADP hardware upgrade. 

A major undertaking started during FY73 but continuing into FY74 was the 
technical and management leadership for NIH's effort to develop its second 
comprehensive ADP Plan. This plan, now an annual effort, attempts to lay 
out a two year projection for ADP equipment, manpower, contracts and 
business data systems for all components of NIH. This planning process 
creates an orderly opportunity for ADP users to take stock of their goals 
and accomplishments. The second annual plan covered NIH ADP efforts 
exceeding $31 million for FY74. An NIH wide study of systems handling 
data concerning NIH grants was a direct result of apparent duplication and 
overlaps detected during the planning cycle. Work on the third annual plan, 
that for FY75, was underway at the close of the period covered by this 
report. 



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Page two 

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 management 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 FY74 the PHS was recreated including an ADP Policy Office. The 
Assistant Director continues to provide extensive assistance to PHS to 
attempt to mold that office into an entity which can be helpful to NIH 
rather than becoming a hindrance. The Office of the Assistant Director 
lent extensive help to a study, commissioned by the Executive Officer, PHS, 
that resulted in a major PHS decision to consolidate all Parklawn ADP 
facilities. Under the guidance of the Office of Assistant Director, a 
systems study and a draft RFP were developed to allow an upgrade of DCRT's 
PDP-10 image Processing Computing Facility. Similar efforts were started 
regarding the main DCRT operated NIH central facility. 

As regards DCRT's own operation, the Office of the Assistant Director 
coordinates all ADP procurements, contracts and work orders which have a 
technical or engineering impact on our computer operations. By bringing 
an understanding of technical considerations into these matters, better and 
more responsive services are obtained from the central service groups. 
During FY74 the initial phases of two major physical site changes were 
coordinated. One is an addition to Building 12 to provide storage space 
and relocate office space. The second will be a gradual conversion of the 
second floor of Building 12 to machine space. 



12 



July 1, 1973 thru June 30, 197U 



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 



MI SSION 

The Computer Center Branch designs. Implements and operates a 
large general-purpose computer utility to meet most effectively 
the dynamic and diverse requirements of both fJ.I.H. research 
investigators and managers In the support of modern medicine. 
This charge includes the original development of new system 
facilities to meet the unique requirements of the NIH mission In 
order to bring the full power of the computer to bear on 
problems at every level of biomedical research In many diverse 
locations. The core of this computer utility is a network of 
computers and remotely located terminals, which, by means of a 
modern communications network, extends the power of the computer 
directly Into research laboratories and administration offices 
throughout N.I.H. This provides immediate access to the 
computer from thus minimizing delays In the research program and 
making more efflcent use of critical manpower than more 
traditional methods. An Inherent responsibility of the Computer 
Center is the continued research and development of new methods 
to extend the network even further into the research environment 
while continually adapting to the constant Impact of new 
knowledge and program direction. 



A full spec 
Inst I tutes 
recovery) 
programming 
job entry, 
processing, 
terminals a 
aval lable 
Information 
N.I.H. me 
introduced 
where they 
problems of 



trum of computational services Is provided to all 

and Divisions of the NIH on a fee-for-serv ice (cost 

basis. These facilities Include conversational 

, graphics, microfilm output, text editing, remote 

time sharing, data base management and batch 

Large systems as well as mini-computers and 

re tied together providing a "distributed capacity" 

at many levels. Research Into the computer and 

sciences coupled with close cooperation between the 

dlcal Investigators and the computer scientist have 

computers directly Into the research environment 

can perform most effectively In attacking the complex 

medical research. 



The medical research programs of N.I.H. require the most 
powerful and flexible of computer services and tools available 
today. The computer network provided must have a distributive 
power that Is easily accessible when needed to scientists in the 
laboratory itself. The goal Is to mold, polish and, in general. 



I Htf 



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enhance the computer Into a complete tool for medical research 
and its administrative support. New areas of computer 
applications are sought out continuously in conjunction with a 
comprehensive training program to inform research investigators 
of the latest methods in the use cF computers to most 
effectively meet the unique requirements of their individual 
laboratories. 

197U ACTIVITIES 

Throughout 1973, users of the NIH Computer Center .continued to 
demonstrate outstanding innovation in the application of all 
computational services to the mission of the agency. Users 
rapidly adapted existing programs to talce maximum advantage of 
new time-sharing services as they became available and continued 
to develop a never ending stream of new programs using 
traditional batch processing services. 

The overall worl<load of the Center continued to increase at its 
normal growth rate of 25^ per year for the seventh consecutive 
year. The use of batch processing services increased throughout 
the year to a workload of 3,200 jobs per day with over 80^ of 
them being completed with results available to the user in less 
than two hours. 

The use of interactive terminal systems (V/YLBUR, TSO, and CPS) 
experienced the most dramatic increase (33|) to over 2,500 
sessions per day. A new record for the number of simultaneous 
UYLBUR users was set at 189 in April while the new TSO service 
established its first plateau of 36 simultaneous users. As the 
number of l<eyboard terminals using the NIH Computer Utility grew 
to 800/ the number of telephone lines accessible to the system 
was increased to over 250 to minimize the frequency of busy 
signals received when dialing the interactive services. 

The current worJcload, along with the projected increase in 
demand for services, has precipitated ? system study addressing 
the problems ot expanding the computational capacity of the 
system and improving response time for interactive services. 
This study has shown a need for significantly increased CPU 
power within the mul ti -processor utility. Procurement 
procedures are now being followed so the Computer Center can 
acquire the necessary capacity before service to the NIH 
community degenerates to an unacceptable level. The study has 
also identified a need for virtual hardware and its associated 
software techniques in order to maintain rapid response for the 
interactive terminal user. These techniques will also improve 
system efficiency and will eventually permit the relaxing of 
some technical constraints currently placed on users of the 
Utility. The study also identified the need for new 
telecommunication controllers to provide users the ability to 



14 



communicate with the system using CRT terminals at speeds of 
1200 baud. The controller will also allow more efficient use of 
existing teleprocessing ports. A variety of terminals, 
operating at different speeds with different protocols, will all 
be able to call the same telephone number thus reducing the need 
for redundant system resources. 



Increased workload, larger systems 
operating efficiency combined to 
rate reductions ever announced 
Center. Beginning January 1, IS?** 
terminal elapsed (logon) time rat 
users of the Center. On that date 
all interactive systems, WYLBUR 
the DECsystem-10 were reduced 25^ 
hour. Tlie batch processing rate 
change. The basic machine unit ra 
processing work was reduced a fu 
of $1.70 per resource minute 
differential was increased an 
cheaper to process work at nigh 
coefficients were adjusted result 
6% for private tape and disk users 



, and internal improvements on 
permit the most significant 

for users of the NIH Computer 
, both batch processing and 
es were reduced 25-30^ for all 
, elapsed terminal time for 

(MILTEN), TSO, CPS, CICS, and 
to the new rate of $3.00 per 

experienced the most dramatic 
te for all classes of batch 
11 301 resulting in a new rate 
and the night processing 
additional S% making it 25% 
t. Tape and disk mounting 
ing in an overall reduction of 



Tliese rate reductions were made possible primaril 
the constantly increasing demand for computational 
the many users of the NIH Computer Center. As th 
Utility expanded both in size and function to meet 
the economies of scale contributed significant 
operating costs. Since the fixed costs and ove 
system do not increase in direct proportion to 
capacity, the effect is to reduce per unit costs 
This represents the seventh consecutive year du 
iJIH Computer Center has been able to offer rate 
its users. 



y because of 
services from 
e NIH Computer 
this demand, 
ly to reducing 
rhead of the 
its processing 
even further, 
ring which the 
reductions to 



Continuous efforts by the Computer Center Staff to improve the 
internal operating efficiency of the NIH Computer Utility also 
contributed significantly to reducing operating costs. Monitors 
were used extensively to tune the system to the unique 
characteristics of the NIH workload. Channels, disks, tapes, 
and unit record equipment were reconfigured to obtain maximum 
throughput. Ulder communications controllers were replaced by 
more modern units offering new functions as well as improved 
price/performance. Major parts of the operating system were 
modified extensively to gain improvements *n internal 
performance as well as increased reliability and function. 

In December the transfer of all interactive data lines to a 
newly installed "data switch" was begun in an effort to separate 
the data traffic from the overburdened NIH voice switchboard. 



\n^' 



15 



The system itself also received new communications controllers 
to provide Increased accessab 1 1 i ty to the system. During the 
year the number of batch RJE terminals entering the system 
increased substantially and their transmission rate was 
increased from U^SOO to 7,200 baud to allow higher speed remote 
printing. As of the close of the year, almost 93% of all work 
processed at the Center was received over the teleprocessing 
network. 

As users developed new on-line data base applications the demand 
for on-line disk space Increased dramatically. Additional FILE 
packs, PDS packs, TMP packs, work space packs, and private packs 
were added to the system In an attempt to meet this need. Over 
7 billion bytes of directly addressable disk space contains over 
80,000 users datasets on-line at all times; a necessity for 
effective use of interactive systems. 

In an attempt to keep pace with the changing requirements of the 
NIH computer users, many past restrictions were eliminated or 
eased and new systems software facilities were Implemented. The 
maximum allowable region size for all job classes was Increased 
50% to 300K bytes to permit the development of larger 
applications programs without the necessity for segmentation or 
overlays. A new disk mapping facility was developed to provide 
users with more detailed information on the type and status of 
their on-line datasets. A new tape copy utility was developed 
to allow users to copy entire tapes using minimal JCL. 
Facilities were provided to enable users to determine the amount 
of available free space on the on-line packs at any Instant in 
time. The requirement that all procedures to be catalogued be 
carried to the PAL Unit was eliminated with the announcement 
that such procedures could be submitted via V^YLBUR. 

Users received individual assistance from the Computer Center 
staff on specific problems through written replies to 2,10'* 
Programmer Trouble Reports (PTR) and through thousands of 
telephone calls ind visits to the PAL unit for personal 
assistance. In an effort to minimize paper work for both the 
Center and users, and In an effort to provide more effective 
support to remotely located users, the PTR and Refund Request 
forms were combined Into one and a facility for submitting the 
new form via TSO was offered, The requnement for special 
registration for CPS use was eliminated and CPS users were no 
longer restricted to the use of only one library. 

VJYLBUR was enhanced with the addition of many new and improved 
commands. TSO moved from an experimental test status to a fu!l 
production system providing terminal I/O and Interactive program 
development and debugging In FORTRAN, COBOL, PL/1, and Assembly 
Language. WYLBUR and CPS were then made available under the TSO 
monitor. Although TSO experienced some rather severe 



16 



I 



performance problems when first installed, incremental 
improvements were made as the year progressed and additional 
improvement is planned for next year. 

A major system project was initiated for the redesign of the 
popular conversational text-editor and remote job entry system, 
v;YLBUR. The new design is based on the experience of the past 
five years. It will provide a more efficient system, having the 
ability to handle over 300 terminals simultaneously. flew 
features will be added to the system. Many of these new 
features were based upon suggestions made by users over the past 
few years. New terminal types will be available at higher data 
rates and a powerful new macro-processing capability will be 
available. This will enhance the power of WYLBUR and enable it 
to operate efficiently In many new areas such as transaction 
oriented on-line data collection systems 

The Installation of Release 21.6 In June was the only operating 
system release change made in over a year, and the conversion 
was totally transparent to most of the user community. Those 
users who experienced the traumatic experiences of early release 
changes recognize the significant Improvement in this area. 
Several compilers were replaced with newer versions fixing many 
old problems and adding new features. The PL/1 Optimizing 
Compiler replaced PL/1(F); FORTRAN G was retired In favor of 
FORTRAN Gl and ANS COBOL II gave way to ANS COBOL IV 

One of the more significant accomplishments of the year was the 
design and Implementation of an automatic dataset migration 
facility to both save money and make more on-line suace 
available for users. During the first two months of Its 
operation over 20,000 datasets were migrated to magnetic tape 
saving $30,000 In storage charges and making 80,000 tracks of 
critically needed on-line space available for use. 

As warnings of Impending paper shortages were received, many NIH 
computer users converted programs to produce output on 
microfiche rather than the traditional and more costly printed 
page. Because of an overwhelming increase of over 200?: in the 
use of microfiche during the year, a second unit was Installed 
3t year's end to support the Increasing demand. A new software 
utility was provided to allow a programmer to conveniently 
direct the complete output of a job to microfiche. 

The technical documentation and training activities of the 
Center continued to expand. The training program offered 
thirty-eight different courses and seminars during the Spring 
semester and forty in the Fall. Two new series of courses were 
Included among the new offerings for the first time this year--a 
series on the use of TSO and an expanded DECsystem-10 
programming sequence. Fourteen seminars extended the program 



i 



-^ 



17 



more deeply into the substance of the users problems. Over 
1^9U0 student course applications were received this year from 
candidates of varying backgrounds, an increase of 5-1/2% from 
last year. Unfortunately, due to lack of qualified teaching 
manpower and classroom space, over 1*00 stuJents had to be denied 
admittance. 

As the number of users and functional capability of the NIH 
Computer Utility increased, the demand for current technical 
documentation increased correspondingly. The Technical 
Information Office distributed over 32,000 , pieces of 
documentation, ranging from a one page WYLBUR reference card to 
a kli page Computer Center Users Guide. Documentation profiles 
of 2,700 individual users were maintained by the Automatic 
Documentation Service to Insure that all users received only the 
documentation relevant to their interest or needs. Many 
documents were completely revised and others received only minor 
corrections and enhancements. 

The frequency of INTERFACE decreased slightly this year as only 
seven issues were published. These issues presented over 275 
pages of technical documentation on the organization, policy, 
philosophy and use of the NIH Computer Center as well as basic 
concepts In computer science. Data Line continued to receive a 
number of provocative questions from users and provided 
Informative answers (we hope). Programming Methods appeared 
regularly with discussions of varied programming techniques and 
concepts in computer science. The Bugs, Hints, and Diagnostics 
section continued to provide users the detailed technical 
information necessary to process work on the Utility. With the 
last issue of the year, the Compleat Computer expanded In 
purpose to include tutorials on subjects of general interest. 
The second annual index to INTERFACE covering all issues up 
through the end of 1973 was published. 

The PDP-IQ system, now designated as DECsystem-10, also 
underwent major transformations during the year. Early in the 
year the original KA-10 processor was replaced by a new paged 
dual processor Kl-1077 processor with hardware double precision 
arithmetic, faster memories, triple the amount of on-line disk 
storage, fast swapping drums and addftional peripherals. 

This dual-processor system now provides additional capacity as 
well as processor redundancy permitting the system to remain 
operational even If one of Its processors fails. The dual 
system is controlled by a new operating monitor which is capable 
of dynamically balancing the load between the two CPU's. The 
accessibility to the DECsystem-10 was increased by providing 
ports for both 27'*1 type interactive keyboard terminals and full 
duplex CRTs operating at 1200 baud. 



18 



The excellent Time-Sharing services of this system have been 
recognized by many scientifically oriented users. In 
particular, the constantly improving and evolving OMNIGRAPH 
system has proven to be of great and continuing interest to an 
ever growing group of graphics aficionados. A program named 
"PLOTX" provides the link between pictures seen on a scope and 
the hardcopy desired for research notebooks or formal 
publ icat ion. 



Of particular interest to laboratories with their own smaller 
data acquisition systems was the design and implementation of 
software to permit a remote PDP-11 to be used as a terminal 
concentrator over a high-speed 9600 baud non-conditioned line. 
This system will handle up to 8 teletype devices with speeds up 
to 2*10 characters per second and is connected to a PDP-11 
Synchronous Communications Processor which in turn is interfaced 
to the dual KI-1077 system. 

The already extensive repertoire of available languages and 
programming tools was supplemented this year by 2 major 
additions: APL and SPSS. The former language is particularly 
suited for statisticians dealing with problems involving 
matrices and the latter is of Interest to researchers with 
statistical problems. For those people who have need for 
special pre-prlnted forms or high volume printed output, a new 
facility was developed which permits the transfer of magnetic 
tapes containing upper-lower case text to the 370's for printing 
without the necessity of writing JCL. 

The operating hours of the DECsystem-10 were expanded 
considerably during the year to provide more flexibility In 
working hours for users of the system. The system now has 
operator coverage 16 hours a day from Monday through Friday and 
8 hours each Saturday. Even Sunday is now available by special 
request. 

Me are particularly pleased that the DECsystem-10 helped to save 
the life of a six-year old boy who had Ingested an unknown 
poison. An EPA gas chromatograph-mass spectrometer was used to 
analyze the sample and the sample's spectrum was matched with 
the standard parathion profile using the system. The results of 
this search provided the basis for selecting the proper 
treatment. 

The XRAY modeling system has become a routine part of the 
process of the determination of the structure and function of 
nacro molecules. A number of papers, films, and seminars have 
resulted from the application of this system. Extensions to the 
system during the year included the capability of fitting 
molecular structures to electron density maps, and a means of 
determining the conformation of structure in the active site of 
a macro molecule using NMR data. In conjuncion with modeling. 



Htf ' 



19 



i 



the crystal structure data base continued to develop and grow. 
The structures In the crystal data base can now be searched on 
bibliographic and structural terms. The resulting three 
dimensional coordinates of the structures are then manipulated 
using the XRAY system and displayed on a CRT for immediate 
review by the Investigator, 

The first phase of the Computer Center's planned efforts to 
protect the confidentiality of sensitive data, improve the 
physical security of the computer system, and prevent 
unauthorized use of account numbers became visible. In addition 
to the installation of locks on the machine room doors, two new 
software facilities were installed to provide data security. A 
data encoding system which scrambles sensitive data using a code 
phrase which is defined and known only to the user was made 
operational for all users. Another degree of security was 
achieved by improving the existing keyword facility and 
extending it to make the setting of a keyword effective for both 
batch and terminal systems. A number of additional improvements 
for security and confidentiality within the NIH Computer Utility 
are under development for Installation In the coming year. 

^97^ PI.AN? 

The high standards of performance and the outstanding reputation 
maintained by the NIH research community make It mandatory that 
the Computer Center continue to provide new computational 
capabilities to the NIH research administrative communities. 
New facilities plus the currerst high level of computational 
support are necessary for the success of the NIH mission. In 
the coming year plans have been made to Increase the 
computational capacity of the NIH Computer Utility. This will 
keep the level of service at the desired plateau and provide us 
with virtual hardware, which will enable the Center to employ 
new virtual techniques In overcoming computational restrictions 
currently placed on the NIH research community. A comprehensive 
data base management system will be installed and put into 
general use. This will give users a powerful tool for data base 
management and rapid response to queries for specific 
Information. An entirely new WYLBUR with mary new and povrerfvil 
features wll! be offered. The size of the on-line data storage 
will be Increased significantly to meet the on-line space 
requirements of new applications. New terminal types will be 
investigated and the ones most appropriate for the NIH need will 
be offered to users. Programs for the correlation between 
crystal lographlc structure determination methods and NMR 
structure determinaiion methods will be Investigated. V/ork will 
continue in the fine turning of the NIH Computer Utility to keep 
it responsive to the changing needs of NIH, and In the 
investigation cf new computational techniques that will 
contribute most effectively to the support of the NIH mission. 



20 



July 1, 1973 through June 30, 1974 

NATIONAL INSTITUTES OF HEALTH 
DIVISION OF CCMPUTER RESEARCH AND TECHNOLOGY 

Summary o£ Branch Activities 1. DCRT - 3 

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

Chief 

The Laboratory of Applied Studies engages primarily in cooperative studies with 
NIH scientists, applying mathematics, statistics and computing science to bio- 
medical problems. In addition, the Laboratory undertakes mathematical and 
statistical research with applications to biology. 



D 



D 



During most of this reporting period, the Chief, LAS, has been on research 

assignment to the Medical Research Council of Great Britain, Clinical Research ^ 

Centre, near London. The term of this assignment to the U. K, will conclude 

in August, 1974. Results will be forthcoming during the next reporting year ^ 

and will be described in the next annual report. 

The Head of the Biomathematics and Statistics Section has served as Acting fT 

Chief. 



During this reporting year, the Medical Applications Section has completed 
evaluations of three computer programs for the interpretation of electrocardio- 
grams. These results will appear in the July issue of Circulation . All routine 
adult electrocardiograms collected at the Clinical Center are currently being S 

processed by one of the programs. After review by the cardiologist, the com- 
puter printout becomes the official EGG reading and is entered into the patients ' 
charts . 

Evaluation of EGG programs is continuing, and additional cases with clinical ? 

documentation are being collected by the Medical Cardiology Department of the -v 

Royal Glasgow Infirmary in Scotland. Performance of a program in routine use ]] 
at NIH will be coiT5)ared with that of a program developed in Glasgow. ECG data 

from Scotland, The Netherlands, and Sweden will be used in further testing and « 
evaluation of programs. 

Conputer -based support of diagnostic and research activities of the Nuclear I • 

Medicine Branch of the Clinical Center was continued by the nuclear medicine 

task force consisting of personnel from both LAS and CSL of DCRT and those of 

NM, CC. The most inportant clinical application achieved in FY 74 is the i 

development of ECG-gated scintiphotographic cine angiograms of the heart. ' 

This tool makes possible the non-invasive study of heart function in patients "'' 

about to undergo cardiovascular surgery and in a follow-up period. Because of 

its non- invasive, non-traumatic character, requiring no anaesthesia and less j 

radiation dose to the patient than a single chest X-ray, this study can safely ' 

be repeated frequently. Therefore, it shows considerable promise as a clinical 

tool. 



21 



Several other clinical applications including a scintigraphic evaluation of pul- 
monary function in pre-operative patients at NHLI are being studied. 

Activities in the conputer modeling of neurophysiological phenomena continued. 
These center around tJie LAS MAC- 16 laboratory conpu.er. A neural hardware 
model interfaced with the MAC-16 was used to study a small neural net and give 
insight into the manner in which an action potential can modify the shape and 
duration of post-synaptic potentials and their spatio-temporal interactions. 
The system was also used to model cerebellar function. Study of the reciprocal 
inhibition-excitation behavior of small neural nets continues. 

Development of the MAC-16 laboratory research system continued. It has now 
been interfaced with the Marquette tape drive, used for analog recording of 
ECG's, the Honeywell 7600 analog tape transport, the neural control panel, 
the general purpose switch- filter network, and a real time spectrum analyzer 
with ensemble averager. With this system, the investigator can automatically 
pre-process (filter and/ or digitize) -- his data so that he can get the most 
economic use of a large-scale digital con^juter. 

In FY 74, the advantages of such pre-processing was demonstrated with cardio- 
vascular data recorded on live monkeys, which enabled the investigators to 
study myocardial contractility and ECG reproducibility. 

In collaboration with the National Institute of Occupational Safety and Health 
(NIOSH) analog data from vibratory equipment and the effect of this vibration 
on human electromyograms is being studied using the spectrum analyzer. 

The Applied Mathematics Section has concentrated its efforts in two primary 
areas: (1) the mathematical modeling of biological processes, and (2) methodo- 
logy and techniques for fitting models to data. The various aspects of these 
areas are described in detail in the following paragraphs. 

Preliminary results from Oxygen Transport to Tissue Modeling have been presented 
at conferences and an extensive paper detailing the mathematical model has been 
submitted for publication. A number of simulation programs have been coTnbined 
into a single program with options for a variety of physiological conditions. 
Further work in this area will be concerned with i]T5)roved data on oxygen-hemo- 
globin dissociation reactions, autoregulatory effects of flow aiid tissue meta- 
bolism, and foriiralation of new concepts using time dependent flow fields. 

An extensive investigation of the partition of long-chain fatty acids between 
n- heptane and an aqueous buffer has been conpleted, and the results are in 
press. Related studies continue. 



The curve -fitting routines of MODELAIDE were revised, and a collaborative 
project with CCB and PSL was undertaken to adapt MODEIAIDE for use from a 
Tektronix 4010 graphics terminal under the new Tme Sharing Option (TSO) . 
This system is now operational. 

A number of algorithms offering alternatives to least squares curve-fitting 
have been developed on a trial basis. 



22 



1 



Ongoing mathematical modeling of the passive integrative behavior of single 
neurons has considered the transient response to individual synaptic inputs at 
single branches in the dendritic tree. This work, now in manuscript, has been 
presented at the American Physiological Society's Colloquium on Membranes, Ions, 
and Impulses during the 1974 FASEB Meeting. Present research efforts on active 
nerve conduction continue to exploit a sinple FitzHugh-Nagumo equation to study 
the dynamic stability properties of its traveling pulse solutions and their 
relation to the stimulus -response characteristics of this model axon. 

The activities of the Biomathematics and Statistics Section continued along the 
lines previously established. Study of statistical distribution theory appro- 
priate for multivariable measurements, and particularly for the multivariate 
lognormal model, was continued. These studies extend previous studies of size 
and shape variables and treat covariance properties of the multivariate log- 
normal distribution. Another line of research is that of population models. 
Discrete time models were studied, and a graphic "increment" plot is being 
studied as a practical tool for discrimination among models. These latter 
studies are undertaken in conjunction with a credited research project of a 
STRIDE trainee at American University. Several manuscripts using discrete time 
models in conjunction with conputer simulation have been completed along with 
a manuscript on the lognormal distribution. 

Also inplemented was a conversational computer system which enables non-pro- 
grammers to transfer sequential datasets between computer disk storage and 
private magnetic tapes, while maintaining a directory of the tape contents. 
It is now in use by personnel of the Laboratory of General and Comparative 
Biochemistry, NIMH, for scientific manuscript storage and retrieval. 

Work continued in mathematical studies related to linear algebra, the theory of 
graphs and linguistic analysis, and the theory of computability. Several publi- 
cations resulted from this work. 

Collaborative effort continued on an NCI project for computer analysis of histo- 
logical and cytological bladder cancer pictures. An expandable interactive 
conputer software system has been inplemented and is described in the IMB report, 

Two members of the laboratory were appointed to an adhoc committee for the 
Federal Working Group on Pest Management, an interagency group. System models 
for the transport of DDT and lead through the environment were evaluated. 



Ur 



23 



LAS reports published or "in press" during FY 74 : 

1. Bailey, J. J., Itscoitz, S. B., Hirshfeld, J. W. , Jr., Grauer, L. E,, and 
Horton, M. R. : A method for evaluating computer programs for electrocardio- 
graphic interpretation. I. Application to the experimental IBM program of 
1971. (To appear in Circulation , July 1974). 

2. Bailey, J. J., Itscoitz, S. B., Grauer, L. E., Hirshfeld, J. W. , Jr., and 
Horton, M. R. : A method for evaluating con^juter programs for electrocardio- 
graphic interpretation. II. Application to version D of the PHS program 
and the Mayo Clinic program of 1968. (To appear in Circulation , July 1974). 

3. Bailey, J. J., Horton, M. R. , and Itscoitz, S. B.: A method for evaluating 
coii5)uter programs for electrocardiographic interpretation. III. Reproduci- 
bility testing and the sources of program errors. (To appear in Circulation , 
July 1974) . 

4. Fletcher, J. E.: A mathematical model of the unsteady transport of oxygen 
to tissues in the microcirculation. In Oxygen Transport to Tissue , eds., 
D. F. Bruley and H. I. Bicher, Plenum Press, New York, 1973, pp. fl9-825.* 

5. Fletcher, J. E., Ashbrook, J. D. , and Spector, A. A.: Conputer analysis of 
drug -protein binding data. 7\nnals of the New York Academy of Sciences , 
Vol. 226, November 1973, pp. 69-81.* 

6. Green, M. V., Ostrow, H. G., Douglas, M. A., Scott, R. N., Myers, R. , 
Bailey, J. J., and Johnston, G. S.: ECG -gated scintigraphic imaging tech- 
nique for studying ventricular function. 21st Annual Meeting of the 
Society of Nuclear Medicine, San Diego, June 11-14, 1974. 

7. Green, M. V., Ostrow, H. G., Douglas, M. A., Bailey, J. J., and Johnston, 
G. S.: Scintigraphic cineangiography of the heart. MEDINFO Conference, 
August 5-10, 1974, Stockholm, Sweden. 

8. Harris, E. K.: Comments on statistical methods for analyzing biological 
rhythms. Chronobiology , L. E. Scheving, F. Halberg, and J. E. Pauly, eds., 
IGAKU SHOIN LTD., Tokyo, Japan, 1974, pp. 757-760. 

9. Bitchinson, G.: Recursively unsolvable word problems of modular lattices 
and diagram- chasing. Journal of Algebra 26 1973, pp. 385-399.* 

10. Hutchinson, G.: On classes of lattices represencable by niodules. Proj^ 
ceedings of the University of Housto n Lattice Theory Conference, 197T, 
pp. 69-94.* 



11. Hutchinson, G.: The representation of lattices by modules. Bull. Amer. 
Math. So c, 79, 1973, pp. 172-176. ~ 

12. Kramer, R. J., Roberts, A. J., Gelfand, M. J., Milder, M. S., Hall, C. A., 
Frankel, R. S., and Johnston, G. S.: Ventilation-perfusion scintiphoto - 
graphy in eval.iating the pre-operative cardiac patient. (Abstract), 
Circulation 48: Suppl. IV-187, October 1973. 

2A 



I 



13. Marcus, M. L., Shuette, W. H. , Whitehouse, W. C, Bailey, J. J., Douglas, 
M. A., and Glancy, D. L.: Use of a video system in the study of ventri- 
cular function in man. American Journal of Cardiology 32: 175, August 
1973. 



14. Mirvis, D. M. , Koph, F. S., and Pottala, E. W. : Off-line computer system 
for small laboratories. Proceedings of the Joint Meeting of the Profes- 
sional Association of USPHS , 1973. 

15. Mirvis, D. M. , Koph, G. S., and Pottala, E. W. : The effect of altered 
hemodynamic state on the hannonic content of the left ventricular pressure 
waveform. Proceedings of the 26th ACEMB , Vol. 15, p. 171, Alliance for 
Engineering in Medicine and Biology, Arlington, Virginia, October, 1973, 
(Summary) . 

16. Mortimer, J. A., and Pottala, E. W. : Possible sources of preferred centri- 
petal conduction in dendritic spikes in alligator Purkinje cells: a com- 
partmental neuron model. Proceedings of the Society for Neuroscience 
Annual Meeting (Abstract), November 1973. 



17. 



18. 



19. 



20. 



21. 



Pottala, E. W. : A hybrid neural simulation system. Proceedings of the 
1973 Summer Conputer Simulation Conference , p. 797, Simulations Councils, 
Inc., La Jolla, California, July 1973. 

Prewitt, J. M. S., Reece, D. K. , Hutchinson, G., and Jackson, C. K. : 
DECIDE: An expandable system for medical decision-making. Collogues IRIA , 
Informatique Medical, Le Chesnay, France, 1974, pp. 153-187! 



Rinzel, J. M. : Transients in dendritic trees, 
of the ¥ASm, April 1974) . 



(To appear in Proceedings 



Siji5)son, R. B., Ashbrook, J. D., Santos, E. C, and Specter, A. A.: Parti- 
tion of fatty acids. (To appear in Journal of Lipid Research , July 1974). 

Specter, A. A., Santos, E. C, Ashbrook, J. D., and Fletcher, J. E. : 
Influence of free fatty acid concentration on drug binding to plasma 
albumin. Annals of the New York Academy of Sciences , Vol. 226, November 
1973, pp. 247-258.* 



W 



if 



"=reported as "in press" in FY 73. 



25 



1 



I 



Copputor oystprs Laborritory /'^nnurl Report, in7t| 



Tablp of Tontpnts 



I ntro'^uct i on 



I. Continuinr Cor-'pi.itpr Support for rn-lipp Laboratory 
r^xppr I P'entat i on 

II. Tv^'o ,"pv; l.pl;orrtory Corputer Projpots 

III. Cllnicpl Carr anr* Rpsor-rrh 

IV. nonorrl Resoarch 

V. Gppcial ronsultation 



ti' 



Tatlo of fanpov.'or anr* ExpepfHturp by Project 



L 



27 



I nt roHuct inn 

The prlrpry mission of thr Corputpr Systems Laboratory 
(CSI.) is to ic'entify prohlem rre?s in t> i on^ed i cpI research 
anr' clinical cere in which the corputer offers a potential 
for improved research productivity or improved health Cc<rr. 
The concentration of v/ork is on applications where real-time 
data collection, analysis, display, and experiment control 
are required, where economic considerations favor a small 
computer or where equipment proximity is important. 

The staff of CSL has, in addition to expertise in both 
the enpineerinr and prorrammlnr aspects of laboratory 
computlnr and automation, extensive experience ir v/orHnr on 
problems In the biomedical area. f'any of the laboratory's 
projects require a coordinated effort between enrineers and 
computer scientists from CSI. and researchers from other 
rivisions and Institutes. 



28 



I . Con 1 1 nu i ap- 
Exprr Irpptrt i on 



CorputPr Support for Cn-lirp L?hor?tory 



CSL Is pnrarp^! in a nunhpr of prrjpcts supportirr 
rpsp^rch in thp physic?! pr\<^ lrti?vorI?l scIphcps. Thp 
prinriry poal of this support is ?utor?tion of the collpctiop 
ppH procPssiDF of laboratory r^ata . 



This data, v;h i 
a human pushinr 
analytical instrune 
molpcule/ nust fi 
transnittpd to a co 
Hpvploppd such 1 
appl I cations . CGL 
s y s t pm s in t ! I A f P T a 
structurr of cotrplp 
The analytical in 
corrputers includes 
resonance (NfT) s 
anino acid analyzer 
different physica 
developed by CSL fo 
human subjects 
exper i mentat i on . 
physiological mea 
p:eneral node of ope 
computer control le 
and records the su 
physi olopi ca 1 state 



ch ori<^inates in a variety of forms 
a button in response to a stimuli's 
nt measuring a physical propprty 
rst be converted to a form v/h i rh c 
mputer. The CGL enr i peer I nr staf'P 
nterfacinr equipment for a numbe 
has developed two laboratory com 
pd ope IP niAir v;hich aid research o 
X molecules such as proteips prd 
strumepts which CGL has ipterfac 
spectrophotometers, a puclear mar 
pectrometer, a spectropol ar i me ter , a 
, all of v'hich ^rr used to me 
1 properties of molecules. A s 
r IJIf'!-' collects and processes data 
part ic i pat i pp ip psycholo 
The Information collected i pc 
suremppts and subject respopsps. 
ration is for a subject to respond 
d stimulus while the computer eval 
bjpct's respopses, reactiop time. 



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ts and 
bp| pp' I 
rov i dps 
rl cal r 
eci f I c 



tpms 
casp 
uspd 

he fl 
a pu 

Here 
I nto 

Thp 

lo ppd 

orpto 

ypa 

comp 

two s 

Pterf 

FPn 

csppr 

to 



prr 

\! I t b 

f o r 

I M r 

mbpr 

thp 

thp 

uwv 

to 
r I PS 
r a 
u tpr 
mal 1 

pral 

cher 

b I s 



Kf' 



29 



rxr^^ri rTntrl ('rsir-n. Currmtly oirht st^'tions \'ith slirHtly 
('if^orrrt roD f i ru rp t i OPS prr r>vnilnllr to tt"^ rrsrp r rhrr s . 



V) 



II. Tv/n f'pv; Leborrtory Corptitpr Projects 



C3L has iinc'prt?ken tv/o ppv; laboratory corputpr rf'^jf'fts 

in thp past year, one in support of research on the retina 

anr" another involving a ne\/ instrurent usp'^ in cpncpr 

research for separatinr cells. 



Laboratory of Vision Research 

A research laboratory has been organized in the 
Laboratory of Vision Pvpsearch, Nf"l, for the study of hov.- 
visual pirnents serve to initiate the pho totransc'uc t ion 
process in the retina and how this process is linked to the 
transni ss ion cf si.f^nals from the visual pi rnent-contai ni nr 
photo-excited rerion of the cell to its remote pre-synaptic 
terninal. A variety of physical and chemical experimental 
methods will lie employed and in most cases the data from the 
experimpntal laljoratory instruments will be in the for"^ of 
analor vol tare sip-nals which vary as a function of time. 

A hardwired sirnsl averaper and computer have been 
linked to capturo^ store and analyze data from these 
experiments. Presently software is beinr v;ritten which will 
cause various transfers and manipulations of data to take 
place. A sir-pie keyboard Interrorated by the computer will 
tje useci to communicate the fcjnctions desired by the 
researchpr \;hpn the system is in use in the laboratory. 



D 
R 
G 



FUiorrscencp Activatpd PpII Cpparator 



( F,",C 
v/h i c 
and 
s i mi 
and 
lasp 

the 
Pov/n 
of u 
def 1 
one 
dpte 
f luo 
vo lu 
1 \fU 



Tv7o typ 
G ) ere 
f', v/ere d 

Los 
1 ar i t i PS 
i nco rpor 
r beam. 

f 1 u o r r 
stream o 
nl ■'^orm d 
pcted in 

1 irht s 
rmi np ce 
rpscencp 
me to de 
t scatte 



es of 

nov; 
eve 1 o 
A lamo 
. Ce 
atPf! 

Tel 1 
scent 
f the 
rops . 
to se 
cattp 
11 d 

at 
term I 
r di s 



Fl 
ope 

ped 

s 

lis 

i nto 

s pa 

1 

las 

Th 

para 

r s i 

efle 
two 

ne 

tr il 



uorescen 
rational 
under CO 
Scientlf 
ere rend 

a sma 1 1 
ss spqup 
i r-h t p 
er, the 
ese rVop 
te conta 
rnal are 
ct i on. 

wave Ten 
cell de 
u t i o n is 



ce 

i r 
ntra 
i c 
e rpf^ 

liq 
ntir 
rodu 
f lul 
s er 
i ner 

use 

The 
rths 
flee 

pre 



Acti 
the 

ct 1. 
Lab 
dif 

u i d 

iiy 

ces 
(' is 
p ch 
s . 

d i n 
Lo 
/ 11 
t ion 
sent 



vated 

fir I . 
y Stan 
orator i 
f erent i 
stream 
tb. roiirh 
e 1 pct 

b ro|-en 
prp-ec' a 

One f 

the Gt 
s A lam 
rht sea 
A 
usi n 



Cel 1 
The 
ford 
es, 
ally 
n lu 
th 
r i cr 
int 
prro 
1 uor 
anfo 

OS 

tter 
f luo 

r a 



Separators 

tv/o systems, 

llni vers i ty 

have has ' r 

f 1 uorescent 

mi rated by a 

p I-pan-^ and 

1 s i !^na 1 s . 

o a s p r i p s 

printply and 

cscPrcp and 

rr^ system to 

system uses 

and Coul ter 

rescence or 

convent I onal 



31 



pulr.p liri,"-ht nnnlyzrr (PIIA) ns r nrpns cf rrip 1 y, i <; in l^otl^ 
systoios. r.'itn rollrrtr'' iisinr t\\r PH/^ r.'in Ir forr'Pttr'' to 

slio\y tlir (' i s t r i I II 1 1 on of l-otli Tl un rmrrprr ppf' srrttrr 
vrrsiis niirilrr of rolls. 



CGI lirs propoGTf' n r>t Ti 1 1 rop'ptitor ';ystrt" to rr^llrrt 
('pt''' frop^ F/^CG on- 1 i no ."tk' frori tl'r> Ion AK-t'os svstrn ly 
plnylark of rri nnplop t.'^f^r. TGI vill intrrr,-^rr tho 

instrumrnt to tho ror'putrr .Ti'' v/ill r'pvrlop prorr.T"; vl i rh 
monitor f'ntn rollrrtion pn(' proross tlir ('rlr. '^Pt."' rntrrlnr 
tlir ronipiitrr rrn ritlior hr srnt r'irortly out to ''isl stor.-TP 
for lr>trr rvD 1 iirit i on, or It rpn Ir sortP'' i r ir^rr' i r tr 1 y into p 
r'( X G'l rhpnnrl nptrix of f 1 iiorrsrrnrr pnr' srpttor vrrsiis 
rr 11 counts. This is thr sppt r'-Ptrix whirl' thr P\l^ is 
rpppltlr of Ixiildinr. Ilov-rvrr, tt'r ron[nitrr rpn sort this 

f'ptP on p sprrifir rhprtnrl, i"pl;r ror|>prisons with prrvionsly 
rollrrtrc' dptP pn(' spvr rf^sults - pll of \;hlrl' is not 
possihlp with thr i'lIA plonr. A (!is|-lpy unit will Ir 

provi('r(' to f.irilitPtr th^ ol r.r r vp t i f^n, ron-pprison pnt' 
noi'i f i rpt i on of dptP <' i s t r i hu t i op . fptp ppplysis will 

inrorporptr tlir norp'Pl ron^p 1 nurn t of rop'pu t p t i opp 1 fiiprtiops 
surii PS intrrrptinp ppf' porrp 1 I zp t i on of rurvrs pp'' 
stPtistirpl pvpluptiop of (' i s tr i I'U 1 1 ons . Thp systPP' \'ill hp 
ph 1 p to profUipp P hprc'ropy of ('isplpyp(' rpsiilts rr(^ r^plptplp 
p pprp'PPPnt f i 1p of ('i s tr i hu t i OP"-, for furthor rrrrrrrrr. 



1 1 



Clinical Carr anr' Rrspprrh 





CSl. 


haS/ 


inrrrpsinrly i 


carr 


anr* 


rpspa 


I p cause 


of 


clinicians of 


r'ur 


to 


trrrc 


ana 1 


yzc(' 


rr\(' r 


pati 


rnts 


Th 


aHva 


ncps 


i n re 


havp 


Icr^ 


to th 


of H 


at a 


that i 


anal 


ys i s 


to he 



for the last several years, hecop-e 
nvolveH in the support of rany n^ the clinical 
rch functions at the f.'ll'. This has nrci\rrr(' 

Increasing unHers tanH i nr anr^ a\'rreness l.'y 
the potential of corputers anH autoratlcn anr^ 
n('ous increases in the anount of r'ata that is 
xaninec' for the r^iarnosis anH treatment of 
e increase in Hata lias resulte<' in part fror 
Hical instrumentation anr* techniques vli i ch 
e capal'ility for reneratinr voluminous ar^ounts 
n turn require soph i s t i ca tec' rer^uction anr* 

of any use. 

The primary roals in applyinr autoratior to clinical 
mer^icine are to have computers perform functions vh i ch 
cannot he performed hy manual means and to perfor""' routine 
clerical functions often done l^y ner'Ical personnel so that 
the talents, trainlnr, and experience of tfiese people can he 
more effectively user'. 

The projects descriled here are related to many facets 
of patient carr and clinical research. The technical 
r equ i rer^ents of all of these projects include the 
acquisition, storage, analysis, and display of clinical 
data, and. In most cases, there is a need for these 
functions to he performed on-line anr' in real-time. 

Fu rtlierriore, all require extensive cooppration amon"- 
enrineers, computer scientists, prorrammers, and p-'cdical 
personne 1 . 

nilLI Intensive Carr I'ni t 

The purpose of this activity is the continuous 
monitorin."- of patients in the heart siirrery rerovery area in 
orc^rr to provit'e the earliest possil le ('etection o<" ahnorrvl 
or dprip^erous conc'ltions. For ovrr r year nov, p corpiiter 

systen has heen in operation and perform inr tl'iis fiinctirr 
for a sirrle patient !y collectinr anr' analyzint^ ^cr^ 
temperature, fluid loss, an(' arterial and venous pressures. 
This capatiility Is to hie extent'er' so that the same functions 
can [)P provider' simultaneously for four patients hy 
nid-summer, 1D7I+. Future plans heyonr' tliat tir'e inrlui'e the 
c'evelopment of nethods for the autor\-^tic control of ! lood 
and (irur Infusion, v/i th the control haser' upop the analysis 
of noni torer' clinical signals. 



33 



nilnlcal P^tholory Lni^orritory 

In rY73 CSL hpp-pn ?n pffort to ovprrorr rff^'^lpris of 
rrlirhllity, i ppc'oqurtp flrxilility, pvc^ irsufflcirnt 

cppncity to hpRfilp thr Irhorri tory v/or!< loar' rfpspntpf* to thr 
pxistinr clinic?! l?f-orptory rorputPr systpr. It \v?s 
i rPfM-'i c-i tel y apparrnt that thr only rpplistic Oonr trrr 
solution WPS total rpplacpnpnt of thp rxistinr syst^n. 
'iov'pvpr, cprtain of thp problprs nrrc^pr' innpr^! a to attpntion 
lipforp thr lonrpr tprr pffort roul(^ Iirrin. As a rrsult a 
now tpst rrsult pntry systpn v/as c'rvrloprf^ for thr Chpristry 
anr' I'pnatolop-y servicp. Tpst rrsults ^re nov/ rntprpt' via 
CRT tpminals anr" sppcial Hpvicps fVsI.o-nrd hy CSL for thr 
acquisition of c'ata fron Hcultpr autoratir hloor" rourtprs. 
The tprn^irals ant^ sppcial intrrfarrs pre- control Ipr' by tv/o 
pi n i corputprs, onp in thp Chpnistry srrvirr anr' opp in 
IIppTatolory/ wliich prp in turn ronnrctp'^ to Clinical 
Patliolory's nrc 3200 corputrr systpn for nn-llnr r*ata 
collpctlon. TliPSP subsystpns havp I ppn fully opprational 
sincp latp surrpr, 1973/ providinr significant irprovprpnts 
in lioth pprforrancp and rrlialility ovpr thp systpp that v/as 
usprl prpviously. 

In ar'r'itiop to the al.ovp CSL. also hpran, in nir'-1974/ 
thr autoration of sonp of thr routinr oporations of thr 
f I crof> i ol ory Grrvicp, v/hprp it v/as cons i e'erpc^ npcpssary to 
invpstirate nptliods and procrdurrs hy v/h i ch such data shoi'ld 
he fiandlec' prior to i nco rpora t i n^ thrsp functions into a np\/ 
clinical laboratory systop. This v/or'- is thorpforr 

considered to bp of an intorip nature. Thp roal is to 
prrpit thp rntry and storape of test reaurst and r'^sult i^r^' 
in ^ilrs on thr 300/370 systrn such that thr data can ^^e 
latpr rrtripver' [y inquiries initiatpn fron a typevritrr 
tprp^inal in thp rii crol i o 1 ory laboratory. The systep is nov/ 
oppratinr v/itbi rerard to test request data, but is not fully 
I rp 1 PIT* ntpc" for tfst results, sin-e autop^atic ppans for the 
translation of result f'ata to pachine rppf^p\]p forp has not 
ypt lippn drvispc'. 

C5L l.pran pf forts to'^'ard rpplacenent of the entire 
systep liy dpvelopi n.p-/ in cooperation v/I th the Clinical 
Center, a Rrqupst for Proposals (PFP) for a nev/ Clinical 
Laboratory Inforpation Gysten. There v/rrr no corprrcial 
systrps proposrd v/lilch could prrt thr lonr- trrp rrnt.iirrnrnts 
and foals of thr clinical 1 altera tor i rs ; tbrrrforr, cni. h'S 
undertakon to drvrlop a nrv/ Clinical Lalioratory Copputer 
Systeri, a project estipated to tabe alout threr yrars and 
require 15 to 20 pan-yrars of rffort. In the pean time, the 



34 



Clinicrl CentPr has f^Ptprnirrcl thpt the porforrrncr of tlio 
pxistlnr systpr hps [irconp intolrrpi 1p, ?n<^ p corrrrrlrl 
systrri v/ i 1 1 hp oLtainrf' for use as ? stoprpp n^prsurr v^h i 1 p 
thp rSL dpvplopppnt pffort is in prorrrsi=' . 



''uclp?r f'pr'iclnp Ppr^rtnpnt 

CGI. Iips con 1 1 niJP(! to rortriiutp pnf'i ppor i rr oxpprt 
to r j o i r"" t projprt v/ith \^Z, rcpj anr^ tho fJurlorr f'pfMr 
Ppppr tront, nc to norp fsjily r'rvplop thp pntpnti?! of 
rorp^utor systpn v/hirli hps hppn opprrtionpl for ?lnost 
ypprs. Thp srirntifir oKjpctlvPS pnc' rrrorppl i sbronts 
this prrjrrt aro Hpsrrilpr* in t!ip L.'G rpport. 
partirulrr, CZl li?s pa r t i o i p?tPf' ip thp r'pvpl opmppt of 
tpchnlqup for stuc^inr carrMrr porf orrv->nrp . This tPchni 
pprr^ts visualization of tho hprrt rrvitips throtirh 
non-invpsive procpc'urp. Hotli cjupn t i tp t i vp pnc' qupiitr't 
pnalysis npthor's rrp l-.pinr i nvps t i rn tpd . 



I SP 

i pp 

p 

tv.'o 

of 

ip 



\y 



Phonoro rt' i orrppi Ppspprrh 

For thp p?st tv/o yp?rs CGI. has co 1 1 pl;ora tpr< vi th tho 
ourrical Trnnch of M!'|.. I in thp f'rvpl or?npnt of nptlior's iy 
v/hich ch? rpptpr i 5 1 i rs of thp phonorarr'i orrrr^ ran Ip uspH ns 
r'irrnostic inHIcps nf prostl^ptic liorrt vpIvp pprforrancp. 
Phonorarf' i orrrr-'s nrr rn\i routinoly t?!cpn on pjiout six 
pptionts ppr virrk ppr' rnplyzpf' op tlip hyfrir* rorputor. Thp 
ppfiysis involvps (;pp t- to-l-.pp t rorrplrtion nf thp 

phopocpr f' i or ran rnc' r r'p tP rr'i pr t i on of thp rntio of tho 
pnplituf'p of thp opppinr soimH to thrt of tho rlosinr ^nurr' . 
Thoro is pv'\ ''rrcp that thpsp fnotors can !)p usp'^ to I'ptpct 
pnr' iHfntify crrtain prosthetic heart valvp ra 1 f unc t i ops . 



Pulr-Tpary Piiyslolory I.ahcratory 



th 
PI I 
of 
rp 
rr 
th 

pr 
CO 



Pu r 
p c 1 
y s i o 1 r) 
rout 
spo rch 
5 i s t a n 
p npP'' 
ni J a 1 
copor'a 
r rcspo 



i n i 
f^y 
i pp 

a c 
cr^ . 

fn 
cal 
tp 
Pf' i 



FY 
ca 1 
Lab 

n 

ti V 

r 

cu 1 
a s 
nr 



71^ C 
an^' 
or a to 
u Irion 
i t i PS 

Til is 
nr(' i c 
a t i o n 
i rni f 
i ncrp 



r 
ry, 
ary 
rr 
pff 
al 
s 

i rr 
asp 



rnr 
PSP 

r'M 
f 

qu i 

ort 
tP 

anf' 

nt 
i n 



1-1 pt 

arch 

I. I . 

u p c t 

r i nr 

has 

cli pp 

i n 

i rr 

sta 



the autoration of sono of 
protocols oF tho Pulrioppry 
!ipsp irvnlvp'^ thp atitoratiop 
p pvaliiatiops anr' of clinical 
he rpasnrpnpnt of rospiratory 
ppp successful ip ''linipatipr 
rists to pprforr pxtpnsivp 
allov;inr t!ip lal oratory to 
asp in v.'or I' lopf' v/ithout 



35 



IV. Gpppral Rpsparch 

U'hilp thp [)ul!c of thp v/orl' in CSI Is ronnpcted v.'i th 
laliorptory autonrtlon pnc* cllnirrl cere thprp Is 
COPS I r'prablp pffort r^pvotpf' to othpr ?rp?s o^ rorputpr 
rrspcTch rplPtPt' to biorpdical ?pp1 I cat ions . Currontly 
thprp ?rp two major arpas of o-pnprrl rpsparrh, tbp usp of 
conputpr pattprn rrrornition ppthods in I, i oppr! i ra 1 prol iprs 
and thp dpvpiopnent of a ripHical tp 1 pcorruni rat ions systpn. 



PattPrn Rprornition Studios 



techn 
and c 
163 
dpscr 
of ch 
havp 
al i Up 
acti V 
o thpr 
thei r 
mptho 
wh i ch 
appli 
now I) 



l.'ork 
iqup 
hpmi 
anti 
i bpd 
pni c 
thp 

i n 
ity, 

dr 

str 

ds 

ma 
cat'l 
pri n 



cont i nupd 
s to study 
cal structur 
-tunor drup" 
mathpnat i c? 
al suhtructu 
samp kind of 

s tructurp 
thpy ?re al 
ufs of relat 
ucturp. Pr 
hold promi s 
y havp ant 
e to other 
ni nr v/i th ot 



I n 

th 

p of 

s, t 

iiy 

ral 

su 
and, 
i l<p 

PC^ s 

el in 

p f 

i-tu 

str 

hpr 



appl 
p rp 1 at 

druFS . 
hp ch en 
by coun 
unit it 
b s t r u c t 

ass urn i 
in ac t i 
t r u c t u r 
i nary 
or scrp 
por PC 
ucturp- 
data. 



y I n.p- pp 
i o n s !i i p b 
Thp pa i 
ical stru 
tinr thp 

CO n t a i n p 
ur a 1 UP i 
nr that s 
vi ty also 
p can thp 
rpsu 1 ts 
pni nr lar 
ti vi ty. 
act i vi ty 



ttprr 
ptv/prn t 
n projpc 
cturp of 
nupbpr o 
d . Two 
ts pro 
tructurp 
. Thp a 
n I'P prp 
i nd i catp 
rp nupbp 
Thp pp 

S tudi PS 



rrror 

hp ?c 

t In 

wh I r 

f PPC 

drurs 

cons 

rpl a 

rti vi 

di r tP 

tha 

rs of 

thods 

anr* v; 



ni 1 1 op 
t i vi ty 

VO 1 VP(^ 

h v:prp 
h typp 

v/h i rh 
i d p r p r' 
tPS to 
ty of 
d f rop 
t thp 

drurs 

rrr 

or I' is 



in othpr rplatpd work boinr flonp, cfippical roppoiinds 
arp charactpr izpd by thplr pass spectra. f'pthods are bpinr 
devploppd to obtain thp rirht copblnatiop of passps to 
dcscrllp the coppoupds ip order to improve classification of 
upknown ccppounds from their mass spectra. 



f'edical Tr i ercrmun I cat i ons Systpm 

For sevaral years C5L has lippn en^^ared in thp 
development of a technology ly which computer services can 
he made available to thp ppdical coppuni ty usinr only a 
convpntional touchtone tplephcne as a copruter ter'^inal. 
The plan has been to make such services readily available so 
that^ the power o^ th'= copputpr can hp appl lad in assisting 
physicians in such arnas as diarnosls, traatrent, anr' 
therapy plannirr. 



36 



A 
use of 
provi <^l 
i n vo 
appl i cp 
i nHI cat 
Thp np(' 
exprpss 
app 1 i CO 
a pro 
col 1 abo 
vppturp 
eval uat 
projpct 



pro 
t 
nr 

I CP 

tio 
i ve 
i ca 
pd 
tio 
up 
rat 
i s 
i on 



toty 
hp 

i npu 

o 

n pr 

of 
1 s 

i nt 
ns i 

of 
e v;i 

pxp 

v;i 1 



pp sy 
pushb 
t to 

op- ran 
the t 
chool 
pres t 
n thp 
corr 
th th 
pcted 
1 hp 



stpn has !'P 
uttons on 
the conputP 
the telep 
s have als 
ypes of app 
of the 
in us i nr 
Uni vers i ty 
uni ty phys 
F L'nivprsi 
to con t i nu 
npr^p as 



er corplp 
thp tPl 


tpr^ V/h 
pphorp 


i ch perri ts 
as a rrans 


the 


r , v/h i 1 p 

hone. A 


the computer 
nurhrr of 


rrspopr^s 
rpc' i CP 1 


bppn 

1 i cations 


r^FVP lo 

v/h i ch 


pec^ v/h i ch prp 
ripht hp uspr*. 


University of 


I .' i s CO n s i p 


has 


thp systpn 


f cr a 


set 


of 


hospi ta 1 


, anr* 


poss i t 


y anonp 


i c i ans . 
ty for 
p throuph 


CCI. 
this 
FY75, 


has prrrrd to 

purposp. Th i s 

after v/h i ch an 


to the 


(""i spos i t i on 


of 


thp 



D 
R 
G 



H?t 



2 



37 



V. Sppclrl CnnsultPtion 



I n ?c'c' i t i on 
rPSPrTchers in 
consultPtion c?n 
mr\ result In 



to the work Hpsrrihpcl, C5L ronsults vi th 

need of corputer rxpprtisp. This 

bp sirply edvire on ? spprifir proMpn or 

tlip (Ipsirn of p pi POP of sppci?'! purposo 



hprr'\.'arp or in tho '..Titinr of sppcinl softwrrp. 



occiirr 
for v.'ii 
v.'h i cl") 
th?t c^ 
C5L 

cornun 
to til 
prrcps 
shovn 
othpr 
to trc 



typi 
pd \J 
ich n 

Hp tp 
^t^, 
pnri n 
i cat i 
p P^ 
s i nr. 

tiTP f 

snail 
nsni t 



CPl 

ith 

GL's 

rr-i n 

i n (' 

par 

on i 

P-10 

Th 

p?s i 

lab 

d?t 



pxanplo of 

a fiata col 1 

afVi cp v;as 

pd thp siZP 

i ri ta 1 forr, 

r^odi f i pc! 
ntprfacp so 
conpijtpr, 
e nodi f i cat i 
hi 1 i ty of th 
oratory data 
a for procps 



th i s 
pct i o 
soup-h 

on a 

this 
th a t 

vi a 
ons b 
i s pp 

col 1 
s i nr 



typp 
n proh 
t. A 

trur o 
ra^np 
pqu 
di pi ta 
tp 1 pph 
ui 1 t ^ 
p roach 
pct i on 
on thp 



o^ 
Ipr 
n I 

f pp 

tic 

i pnp 

1 r^p 

onp 

or 
and 
sys 
cen 



Sll 

ar i s 
ns tr 
rti c 
tapp 
nt 

ta c 
1 i OP 
thi s 
can 
tpns 
tral 



pport I 

i np- in 

uppnt 

iPS an 

cassp 

and 

an nov 

5, for 

syst 

bp ?(' 

to al 

faci 1 



vp v.'orlc 

pxi S tPd 
d stored 
ttp. A 
p(^(^p(i a 
I ) p s p n t 
further 
pr havp 
aptpd to 
lov/ ther 
ity. 



38 



If 



\ f)ject Name 


Project Leader 


jBldg. 2 516 


Shapiro 


jNMR 


Col burn 


NIMH 


Syed 


;NIAID -Waxdal 


Shapiro 


INEI 


Schultz 


NCI 


SchuHz 



Summary of 

LEVEL OF EFFORT AND EXPENDITURE 
BY PROJECT 



DCRT Man-Power (M-Y/Year ! 
FY-73 FY-74 



ledical Tele- 
communications 


'attern 
Recognition 


Pulmonary Lab, 



Shapiro 



.5 
.5 
.5 



2 

2 

2 

3 

1.5 

1 

7 

4 
.5 
.5 

1 



DCRT ^Capital Invested 
($X1000)includinq maint. 
FY-73 FY-74 



6K 
20. 7K 



5K 




80 K 

5K 

5K 
.5K 
14. 5K 



2K 



2K 
24. 8K 



9K 

IK 


80. 6K 


40K 
.5K 

3K 






39 



I 



I 



< 



»]W. 



July 1, 1973 through June 30, 1974 
PUBLIC HEALTH SERVICE - NATIONAL INSTITUTES OF HEALTH 
DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY 



Summary of Branch Activities 
2. PHYSICAL SCIENCES LABORATORY 

I . OBJECTIVES 



1. DCRT - 5 

3. Dr. G. H. Weiss 



The Physical Sciences Laboratory is devoted to the study o£ problems in 
physics and chemistry that relate to the biological sciences. Several 
disciplines are represented in the membership o£ 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. CURRENT LABORATORY PROGRAMS 

1. Research in. the general area of biochemical separation techniques has 
been carried forth with three objectives in mind: the elucidation of physical 
and chemical effects that bear on separation techniques; development of 
methods of processing data from analytical techniques, and development of 
new methodology in the separation methods. In this past year Dr. George 
Weiss has, in collaboration with Professor N. Catsimpoolas of M.I.T. and 
Dr. David Rodbard of NICHD, given a theoretical analysis of transient iso- 
electric focussing, a separation technique currently in use in the equilib- 
rium regime only. Data from the transient phase can be used to furnish 
niore detailed molecular parameters than has so far been possible. Experi- 
mental work on transient isoelectric focussing is being carried out by 
Professor Catsiinpoolas and his collaborators at MIT. Another project in 
this area is the elucidation of the effects of molecular heterogeneity on 
resolution in chromatography and electrophoresis. We have shown that hetero- 
geneity sets practical limits on the ability of systems tc resolve molecular 
species. Further work is being carried out in the area of resolution in 
chromatographic systems. The classical definition of resolution is inadequate 
for the design of systems with a gradient of properties. We are presently 
developing alternative methods for specifying the resolving power of a system 
that can be used for the more general systems now in use, such as two di- 
mensional electrophoresis or pore gradient electrophoresis. 



41 



2. Another area of investigation is that of elucidating physical forces in 
biological entities in order to interpret the phenomenon of biological 
assembly (cell membrane formation, protein association, cellular aggregation 
into tissues) in physical terms. Progress during the past year has been in 
the development of new expressions for interaction energies and the success- 
ful design of experimental systems to measure physical forces. The theory 
of van der Waals forces between large bodies has been developed to include 
the influence of spatially varying distributions of material at their sur- 
face. Drs. Parsegian and Weiss have also succeeded in formulating the 
attraction between parallel curved spherical and cylindrical bodies. A 
physical method has been found that facilitates conputation of electrostatic 
forces between rodlike particles, in collaboration with Professor S. Brenner 
of the University of Kentucky. The results have been applied to the pheno- 
menon of gel formation by Tobacco Mosaic Virus. A successful combination of 
experimental measurements by Dr. A. Shih at the National Bureau of Standards 
and theory developed by Dr. Parsegian has been used to analyze the attraction 
of single atoms or molecules passing in a beam near a solid substrate. This 
is an extremely sensitive technique for the measurement of forces on the 
molecular level. A second experimental method, for the measurement of 
forces between lipid membranes has been developed in collaboration with 
Professor P. Rand of Brock University, Ontario. It was found that the 
attraction forces between membranes vary with the presence of solute particles 
in the water as theoretically predicted by Dr. Parsegian. A method was de- 
veloped to exert forces on the membranes themselves to measure repulsive 
forces between them. 

3. Techniques of intensity fluctuation spectroscopy for measuring hydro- 
dynamic coefficients of biological macromolecules , swimming speed distribu- 
tions of motile microorganisms, and the electrophoretic mobilities of blood 
cells and platelets are being jointly developed by Dr. Ralph Nossal, Professor 
S.H. Chen of MIT, and Professor B. Berne of Columbia. Recent work on this 
project concerns the effects of optical heterogeneity on the inelastic light 
scattering spectra of large particles. The presence of chromatin rich regions 
within a cell leads to a reduction of the effective size of a microorganism 

as measured by its light scattering spectrum. 

4. Dr. Ralph Nossal in collaboration with Dr. L. Kohn, NIAMDD and Dr. B. 
Nisula, NICHD have developed refined Leukocyte Migration Inhiba.tion (.MIF) 
tests for detecting tissue antigens. The assay can be adapted to test for 
cellular autoimmune bensitivity to thyroid tissues of patients having various 
manifestations of thyroid disease. For exc'ui^jle, it has been found that an a- 
granulocytic patient having Grau's disease shows a positive MIF response 
despite the absence of PMN leukocytes in their peripheral blood. 

5. Dr. James Ferretti in collaboration with Dr. E. Becker, NIAMDD, V. Colburn 
of DCRT, and T. Clem of DRS, has developed a fast scan technique to obtain 
NMR spectra. Two working NMR spectrom.eters have been modifj.ed to permit 
spectra to be scanned in very short times (often less than two seconds) . The 
responses are digitized, time averaged, and stored in a Raytheon 704 jonputer. 
The conputer is then used to crosscorrelate the data either with a suitable 
reference response or with an analytical function. The rapid scan technique 



42 



I 



conpares favorably with pulse methods in sensitivity and in some instances 
has distinct advantages over the pulse techniques. An important advantage 
is the simplicity of the additional instrumentation required. 

6. Dr. George Weiss, together with Dr. D. Hoel, NIEHS, and Dr. R. Simon, 
NCI have continued development of adaptive sampling techniques to be applied 
to the design and analysis of clinical trials. Several methods were compared 
for choosing the better of two treatments in which success is measured in 
terms of survival time. One technique, suggested by Flehinger and Louis was 
found to be obviously superior and quite robust. This method was modified 

to give a stopping rule and adaptive sajipling procedure for choosing the 

better of two dichotomous treatments (i-e., results are given either as 

success or failure) . The resulting technique was found to be considerably 

more efficient than all others given in the literature. A further applica- 
tion was made to the problem of deciding whether a new treatment is better 

than a control treatment. Here too, the likelihood method proved to be the 
method of choice. 

7. Drs. Robert Jernigan and James Ferretti are studying the kinetics of the 
helix-coil transitions of polypeptides in solution. Relaxation times and 
time correlation functions have been calculated on the basis of a single 
helical region in the chain, as is usually the case for short polypeptide 
chains. The calculated values of these parameters can be conpared with ex- 
perimental results to obtain kinetic parameters. The results so obtained 
are in disagreement with values derived from the current theoretical inter- 
pretation, the differences being several orders of magnitude for short chains. 
Although the newer theory has not been validated experimentally (nor has the 
older one) it takes into account dependence on chain size, and so might be 
expected to be more accurate. 

8. Dr. James Ferretti, collaborating with Dr. N. Sharpless, NIAMDD, have 
been measuring WIR spectra at 220 MHz and analyzing the results using the 
coiiputer program UEAITR written for the PDP-10. In this way they have found 
that the spin-coupling constants are not simply related to the electron density 
but that the chemical shift and electron densities are linearly related. 

9. Drs. Robert Jernigan and George Weiss have begun a study of the validity 
of the rotational isomeric approximation for calculating configurational 
properties of macromolecules . For short chains it is possible to obtain, 
essentially by enumeration, effects of details of the energy contour on 
configxirational properties. The distribution functions that are being calcu- 
lated allow one to check various approximations that are presently in wide use. 
Present results suggest that these approximations may lead to erroneous results. 
In connection with this project an international symposium was held at NIH in 
February on Configurational Properties of Biopolymers. 

10. In addition to the individual research projects enumerated in the pre- 
ceding paragraphs, members of the Physical Sciences Laboratory engage in a 
large number of consulting activities in collaboration with other scientists 
at NIH as well as in the broader biomedical community. Specifically, Richard 
Shrager has made extensive use of curve fitting techniques on collaborative 



J-u 



A3 



problems. He has applied these techniques to fitting potent iometric and 
thermometric data for the titration of proteins supplied by Drs. R. Berger, 
NHLI and M. Marini, Northwestern U.. He has furnished technical assistance 
on the problem of the digestion of fibrogen by trypsin, with data from Drs. 
E; Mihalyi and D. Towne, NHLI, as well as on the determination of rate para- 
meters for fumarase kinetics with Dr. L. Kohn, MLAMDD and Dr. I. Darvey, 
IMiversity of Sydney. Mr. Shrager, D. Ashbrook, and G. Knott of DCRT have 
inproved and iQjdated Modelaide and MAB programs. Modelaide has been re- 
vised extensively and now runs on TSO. Mrs. Mildred McNeel has worked ex- 
tensively with Dr. W. Caveness, NINDS, and Dr. B. Rish, Naval Medical Center, 
on data relating to head injuries to veterans of the Korean and Vietnam wars. 
She and Dr. George Weiss have also worked with Dr. E. Fishmann of Freedmen's 
Hospital on the use of EKG surface maps as a diagnostic aid in left ventricu- 
lar hypertrophy and acute myocardial infarction. Mrs. McNeel has also help- 
ed Drs. Jack Cohen, NICHD and M. Hayes, NIAMDD to conpile a review on nuclear 
magnetic resonance of amino acids, peptides and proteins. Dr. Adrian Parsegian 
has led a tutorial seminar on The Physical Approach to Cell Membranes and Dr. 
George Weiss has given a series of lectures on Numerical Analysis for DCRT. 

11. Dr. Adrian Parsegian has been elected a member of the Council of the 
Biophysical Society. 

Dr. George Weiss has been appointed a member of the NIH Medical Board. 

PSL PUBLICATIONS 

Weiss, G. H., Dishon, M. : Approximate solutions of chemical separation 
equations with diffusion. Advances in Chemistry 125 , 207-215 (1973). 

Rodbard, D., Weiss, G. H.: Mathematical theory of imnunoradiometric 
assays. Analytical Biochemistry 52, 10-44 (1973). 

Johnson, M. , Yphantis, D. A., Weiss, G. H. : Instability in pressure - 
dependent sedimentation in monomer -polymer systems. Biopolymers 12, 2477- 
2490 (1973). — 

Weiss, G. H., Dishon. M. : Elation properties of inhomogeneous systems. 
Biopolymers 12_, 2631-2637 (1973). 

Weiss, G. H., Ackers, G. K. : Effects of nonumiform gel properties in 
analytical gel chromatography. Analytical Biochemistry 57_, 569-577 (1974). 

Rodbard, D. , Chrambach, A., Weiss, G. H.: Optiiiazation of resolution in 
analytical and preparative polyacrylamide gel electrophoresis . Electro- 
phoresis and Isoelectric Focussing in Polyacrylamide Gel Elect rophoresis, 
(to appear) . " 

Weiss, G. H. , Rodbard, D.: Resolution of species showing microheteroger.eity 
by zone electrophoresis and chromatographic systems. Separation Science 
(to appear) . 



44 



Weiss, G, H., Catsiqpoolas, N., Rodbard, D.: Transient state isoelectric 
focussing. Archives of Biophysics and Biochemistry (to appear). 

Parsegian, V. A., Gingell, D.: A physical force model of biological 
interactions. Recent Advances in Adhesion (Gordon and Breach) 153-192 (1973). 

Parsegian, V. A.: Long-range forces in the biological milieux. Annual 
Review of Biophysics and Bioengineering, 2^, 220-255 (1973). 

Gingell, D., Parsegian, V. A.: Prediction of van der Waals interactions 
between plastics in water using the Lifshitz theory. Journal of Colloid and 
Interface Science 44, 456-463 (1973). 

Weiss, G. H., Kiefer, J. E., Parsegian, V. A.: Effects of dielectric 
inhomogeneity on the magnitude of van der Waals interactions, Journal of 
Colloid and Interface Science 45_, 615-625 (1973). 

Parsegian, V. A.: Possible modiiLation of reactions on the cell surface 
by changes in electrostatic potential acconpanying contact. Annals of the 
New York Acaden^ of Science (to appear) . 

Nossal, R. J., Weiss, G. H.: Analysis of a densitometry assay for 
bacterial chemotaxis. Journal of Theoretical Biology 41, 143-148 (1973). 

Parsegian, V. A.: Formulae for the electrodynamic interaction of point 
particles with a substrate. Molecular Physics (to appear). 

Brenner, S. L., Parsegian, V. A.: A physical method for deriving the 
electrostatic interaction between rod-like polyions at all mutual angles. 
Biophysical Journal (to appear) . 

Parsegian, V. A., Weiss, G. H.: Electrodynamic interactions between 
curved parallel surfaces. Journal of Chemical Physics (to appear). 

Nossal, R. J., Chen, S.H.: Effects of chemoattractants on the motility 
of E. Coli bacteria. Nature, 244_, 253 (1973). 

Nossal, R. J., Weiss, G. H.: A generalized Pearson random walk allowing 
for bias. Joiomal of Statistical Physics (to appear). 

Nossal, R. J., Weiss, G. H.: A descriptive theory of cell migration on 
Surfaces . Journal of Theoretical Biology (to appear) . 

Nossal, R. J., Berne, B. J.: Inelastic light scattering by large structur- 
al particles. Biophysical Journal (to appear). 

Jemigan, R. L., Ferretti, J. A., Weiss, G. H.: Helix lifetimes within 
the conformational transition region. A random walk model. Macromolecules 
6, 684-687 (1973). 



45 



Ferretti, J, A., Jemigan, R. L.: Conformational lifetimes in the helix- 
random coil transition region by NMR. Macromolecules 6^, 687-69C (1973). 

Milstein, J. B., Ferretti, J. A.: The effect c-p polydispersity on the 
nuclear magnetic resonance of polypeptides. Biopolymers 12^, 2335-2345 (1973). 

Gupta, R. J., Ferretti, J. A., Becker, E. D. ; Rapid scan Fourier trans- 
form NMR spectroscopy. Journal of Magnetic Resonance (to appear). 

Sharpless, N. E., Bradley, R. B., Ferretti, J. A.: The nuclear magnetic 
resonance of heterocyclic compounds related to anthracene. Journal of 
Organic Magnetic Resonance 6^, 115-120 (1974). 

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

Hoel, D. G., Sobel, M., Weiss, G . H,: Comparison of methods for choosing 
the best binomial population with delayed observations. Journal of Statis- 
tical Confutation and Simulation (to appear) . 

Kiefer, J. E., Weiss, G. H.: Truncated version of a play-the -winner rule 
for choosing the better of two binomial populations , Journal of the American 
Statistical Association (to appear) . 

Simon, R., Weiss, G. H., Hoel, D. G.: Sequential analysis of binomial 
clinical trials . Biometrika (to appear) . 

Hoel, D. G., Weiss, G. H.: Conparison of methods for choosing the better 
of two negative exponential lifetime distributions in Reliabil ity and 
Biometry (SIAM, Philadelphia) 563-583 (1974). 

Dresser, A. Meirowsky, A. M., Weiss, G. H., McNeel, M. L., Simon, G. A., 
Caveness, W. F.: Gainful employment following head injury, prognostic factors. 
Archives of Neurology 29, 111-116 (1973). 

Cohen, J., Hayes, M., McNeel, M, L.: Nuclear magnetic resonance of 
amino acids, peptides, and proteins. Magnetic Resonance Reviev (to appear). 

Weiss, G. H.: The diffusion constant for two-state brownons. Journal of 
Statistical Physics 8, 221-224 (1973). 

McNeil, D. R., Weiss, G. H.: Merging from an isolated intersection. 
A dvances in Traffic Science (to appear). 

Blumenfeld, D. E., Shrager, R. I., Weiss, G. H.: Spatial distributions 
of homes for journeys to work by different modes of transport. Transportation 
Research (to appear) . 



46 



July 1, 1973 throueh June 30, iy7U 

PLuLll. lidALTh SERVICE - MATIONAL I UST IT UTff.S CF HEALTfl 
DIVlolON OF L-OMPUTF.l-> REliLAPXti ANP. TECHNOLOGY 



1. riLuRISllCJ LALiOPwrrORY 



1. PORT 6 

Serial iJuriiber 

3 • Jafnf;s R. Slagle 
Chief 



Heur i s C i cs Labo 
Lhan twenty paper ;i 
three papers per non 
stafi or the Labor 
o i" computers to .jIoi.i 
lerA;e anJ cirri cult, 
neeccc to solve t 
Laboratory are creat 
app 1 icat i on, and 
i np 1 er^.en t i ni, exist in 
worked upon uy the 
year are sumnarlsed 
the Laucratory inv 
parcfithes is.) 



ratory 


riad 


are e i 


ttie 


-yea r . 


no 


atcry are 


edicGl 


fie 


ef t i c ient 


heni. 


The 


ivc anc 


a 


Bx-yt 


dif 


Z Tiett'ic 


ds 


Heur i St ic 


as fol 1 


OW5 


o 1 V e d 


i n 



a very truit 
r '.i l; o 1 i 5; h e d r. 
s t prcol ens u 
concerned wit 
1 ■ i s . Since t 
and heur is 
refcsrc, the 
t the r'ront 
ferent fron 

and systems 
s Laboratory 
: (The names 

each projec 



1 yea 
accept 
e rtake 
the ap 
se pro 
c niet 
t i V i t i 
r of 
hose 

The 
ring t 
of Pie 



r. More 
ed, aoC'Ut 
n by the 
pi i cat I on 
blerns are 
hoc;s are 
es of the 

compute r 
rout i nel y 

proj eccs 
he fiscal 
mbers of 
1 i s t p c! In 



A iltW DESIGN FOk CIIEMILAL STPUCTURt SFAnCM (I'cies): 



we are cc 1 1 e bo ra t i ng 
InstitJLt-. of Pescarch (u'l'AI 
suustructure syster.i in conj unc 
the obsolete »,i.Aii-; system 
ttiirc .-.eneraticr! copiputf r. 
searciin-; c.i.-line for botfi str 
vill =i'::com'nodatp» s file \'hr 
.lil liens. There are tv/o ossic 
First is the establ i sht^en t of 
screens. Le 'ue^o: cevelrped a 
Jeteninins a ccnplete set of 
c-fUite lar,,<^ tragr'ients. Second 
whict. vor tiie first ti;.;e br 
rancc.i access on substructure 
nave oeen intet.rated into a ra 
theoretical v/ork on the discri 
have outained an elegant 
perfonr:ance is versatile, precj 
imprcvenient over other chenica 
results on estaul i sh, i n:^ sc 
2, r a t i V y i n ^ . 



ith tlie Walter 
?.) on the desi&n 
ticn with the c 
from a second i^e 

The nev/ systen-! 
ucture and sui.<st 
se coi^riounds can 

ne'.; ffloT'ents in 
a sy-te;! f^f struc 

uniforn, iterati 
screens fron sin;=^ 
, i :; a nev; use C'f 
in^s to Lear tiio 
searching. These 
t ions 1 f raii'cv/ork 
"^.i net ion power of 

and practical 
ictable and efiic 
1 search systen,s, 
reen i n'^ f r3.>-Tien t 



Reed 


Army 


of a clien^ 


ical 


onvers ion 


of 


nerat i on 


t'^ a 


will a 


1 1 ow 


ructure. 


a n d 


nuTifier in 


the 


cur des i .,n . 


ti, re fra? 


nent 


ve rnethod 


for 


le atons 


tr 


hash cod 


in?. 


f ul 1 spec 


r! o f 


two elements 


based on 


new 


sc reens . 


We 


design v- 


hose 


ient, and 


an 


Prel imi 


nary 


s have 


been 



47 



^^A. 



,PECT«AL SEARCH (Heller) 



As of i^epcenber i, l'J73 the N I H Mass Spec Search System 
(i'lSS-j) was officially put on the international IF conputer 
netv/ork by the Unite-i Kinsdon Spec Data Centre. M 1 1-! ' s rcW^ 
in the future v/ill be that of a con?;ultant for the syste--. 
A copy of the system rernalns at N' I H for interr.al u'-.e an-i 
further research and development. 



Irn'EHHR^TATICH OF f:> 
and Mel 1 er) : 



;PECTPOr:ETr;Y OATA (Slagle, Chan. 



A proi;ran was developed to reorganize a lare;e -f" i 1 e of 
mass spectral oata. From the dis-ilay of the reorf^anized 
data, we were able to define new dirouus of conpounds by the 
presences and the absences of certain mass snectral neaKs. 
3o far, we have good results for four croups:- thiolesters, 
sulfoxides, aromatic caroamates, and amino esters. The 
definition rules for these grouos have been tested 
intensively, and found to be able to discriminate a compound 
in the groups from other compounds not in the croups. 

MLAB - AiJ ON-LINE ;-;ODPLIiiG LABORATORY (Knott): 

riLAB has been further developed. We have spent 
considerable time promoting MLAB and cnllaborat Ins: with 
users in setting up models and applying then. The third 
edition of the MLAB manual has ueen prepared. Usins MLAB 
jointly V J t h Jean-Marie Ketelslager, vie have obtained some 
results on hormone binding. 

MICROCIOLOGY DmTA BA.'iK (Morton): 

Collaborating vnth Dr. Krichevsky of NIDR, we revised 
the program for inputting data to the mi c rob i ol o-ry data bank 
to give consi deraol y more extensive diapinostic nessa2;es in 
cases of deviations from the specified input format v^hich it 
will not forg i ve. 

TISSUE TrpING COMPUTER AIDS (LMxon and rorton): 

We are col 1 aborat inji with Dr. Kayhoe of i^l I A I D on the 
evaluation of the 1330 trays usin>^ the t i ssue- typi ns; 
program. The results demonstrated nev. patterns nf 
serun-anti4;en specificity on the IJIH tray. That Is the 
programenabled many "false pointers" previously interpreceu 
as noise or laboratory error to be 'nteroreted 
systematicully in terms of (sometimes weak) serum reactions 
to antii\ens determinants. 



48 



COI'IPIJTER MODEL OF THE flUMAN MEj.'STRUAL CYCLE (Dixon): 



mod 

wr I 

ova 

men 

s irn 

atr 

the 

wer 

eab 

cal 

i n 

was 

sta 

eye 

wr i 

t im 

A s 

mod 

Hod 

the 



el I 
tte 
lat 
str 
ul a 
es i 

mo 
e 

ier 
led 
Ma il 
a 
1 1 s 
le 
tte 
e I 
et 
el 
i f i 

re 



e ar 

n^; o 
n i 
ion 
ual 
t i n « 
a v; 
del 
stre 
to 

Ha 
\<k. 
1 so 
t ics 
can 
n . 

nter 
of a 

pa 
eat i 
St o 



e col laborat ini? with Dr. Carp:ill<j of rjICHD on the 

f the human menstrual cycle. A con^puter m-^ciel 

n the DYNAtiO lanrua>?,e simulates the prf-icess of 

and the variation of hormones durin<^ the hunan 

cycle. Last year the model did a -:r-od j o^j of 

the normal cycle and a dynamic mechanism for 

as postulated and put Into the model. This year 

',vas completely rewritten. Many av/fnard equations 

amlined and the whole model v.as r.-.Tie simpler and 

understand. This nev; version of the model v/as 

.'?K't. .\ simulation of pregnancy wa,^ also include 'I 

A statistical version of the model called ''APK5 

written. ilARKS can be run for many cycles an>J 

of hormone levels at various times during the 

be collected automatically. MARKb -was also 

This is a version of i-1ARK5 which uses a larger 

val (DT) so long runs can be made at less exoense. 

bout 10 validity tests v;as then prepared. The 

ssed half the validity tests witiiout chansie. 

ons were then made to the model to .^et it to pass 

f the tests. This v^or^ is still in prof;ress. 



CO/:PUT£R IMFcRENCE mND LEARNING (Dixon): 



The &oal of this projec 
aiscover relationships in n 
this proi^ram will be of prac 
all fields for automatic ana 
basic idea is to improve 
multiple re:.^ression analysis 
as if they were nev; pred 
technique non-linear re.F,rc 
necessary to reduce the v 
cofiib i nat i ons to a reasonable 
r\ C I D 2 '.va s w r i 1 1 en . ACID 
analysis on a given data set 
products of predictors are 
are then tested on a portion 
roferessirn analysis. This 
the name or the program. A 
have oeen V/ritten to col lee 
sets vcr this pror.ran;. Ther 
to test tnis prosi'<"H:-i. T 
tissue tyoine data, stock 
simulated vehicle/ a compute 
random numbers/ as well as 
a pri.iiitive condition. No h 
It is hoped that the mod 
heuristics. fJut prelimi 
non-linear regression v^orks 



t is to develop a program to 

umerical data. It is hope i tliat 

tical use to research workers in 

lysis of experimental data. The 

the standard technique '-'r linear 

oy usins; products of predictors 

ictors. One mijht call tins 

ssion analysis. Heuristics are 

ery larr^e n ur ib e r c f on s s i ';> 1 e 

nu'iber. A basic orrgra- called 

2 does a multiple regression 

by the steowise method. All 

used. The ^c'els thus oL^tained 

of the data nc^t used in the 

is called tne acid te'^t - hence 

numuer of auxilliary orr^-rans 

t/ fajricntp and r lan i pul ate :.iata 

e crp noi iJ dat? '='.ets on which 

[iey incli'de hlood oressuiro data, 

market averagps, a oof'^mtor 

r sii'Tulated radi-T/ tables '"d" 

othiers. The ACir2 pro^rar-' is in 

euristics are usf^d at n resent. 

el will be sole to learn its own 

nary results indicate that 

better than linear re k re;? s ion. 



49 



AuTOliATlCJ PROGtMM-VERI F ICATIOH (Sla.a:le, Chanc: and Lee): 

The application of theoren proving tpchniques to 
program verification uos consiJere.i. A new and direct 
technique for proving pronrans correct was optaineu. 
Progress in this field h^ay eventually enable us to test 
whiether software is reliable or not. 

AUiCi-iATIC PkYTER'' FECOGfilTIOil (Slagle, Chanff an^i Lee): 

An algorithii for findin."; prototypes for a nearest 
nei^fioor classifier was developai. The al ^or i thr,i ;;as 
applied tc bi4 cases of liver disease, anj only 31+ 
prototypes were found necesc^ary tc achieve luU % of correct 
d iagnos i s . 

In adaition, nany clusterin>; a 1 ^,or i tiiris were tested. 
The short spanning, path al.?;orithrT was found to be simpler 
ana coriiparaDle v-itii the inininiur.i spanning tree inethod. 

PROFES5IOi>iAL ACTIVITIES: 

J. F\. Slagle participated in the National Institute 
of Education Plannin;^ Conference on Produc i t i v i ty and 
Efficiency in Education in the United States. !!e ?iave a 
computer science ser.inar at IBf' Research Center at Yorkt^wn 
l-ieishtS/ tne State University of New York at Albany, and the 
University of Texas at Austin. 

C. L. Chsn.j, ^ave sen-,inars at the Rut?;ers University, 
iL-ill Kesearch Center at Yor-ktf''wn iieit^hts, and IBM Research 
Laocratory at San Jose. He taught v.itli Sla!-:le a DCRT course 
on pattern recoup iton. 

J. ;<. DixC'H taught two DCPT course^ on heuristic 

pro'^raiijp.ii n^. 

S. K. iieller .jave a lecture at the HMO AS 1 on 

'-Cor/ipuLer kepresentat ion and N'an i p.il at i on of Chemical 

Infortnat ion" in riolland, and a talk in the CODATA meetitig in 

Freiourg, Geriiia.iy. 



L. HoJes j^ave a seminar at the University -^f Maryland. 



50 



b . C. Kiioct tau^^ht fiLAi-' and the ■, r^iphics courses in 
D^J^',T. i:e tias vvritten w r.cnch.-; '.'orth ,-f I-JTErsFACF, articles 
en various copies. Also, he lau;ht the computer science 
couiprinent or the Computers in Clinical Medicine prosra-n 
sponsored oy DCRT. 




L. 

on L)i;D 
systen. 



.jorton participated in a 
systei'5, giving a 1/Z 



.:?,ovc rnp'en t-Vi i de b r i e f i ng 
hour talk -".n his inctexine; 



PuiiLICATIul-lo: 



lu 
11 



C ii a n s , C 
!"! i scr ii ii 
IJo. ij, p 
C h £ n f, , C 
CI ass i f i 
!iel I'jr, 
::ipect ra . 
Hel ler, 
of f''.ass 
Anal vt ic 



nan t 
p. '6 5 
. L., 
ers." 
S. R. 
" To 
i. R. 
opect 
al Ch 



"P 
Fun 

9-6 

"F 

T 
II 

app 

/ C 
ron 
emi 



dellcr, i 



I no ilvol 
iie 1 lor/ 
cf No rep 
!lel ler, 
"A Conve 
ot ipecc 
tiouts, L 
[•:ao i a c i o 
:..p. 1--1- 
KnutL, ij 

LrAJ_/ Vc 

Knctt, U 
Cor:putfc r 



I ' i 1 n 
ut ion 
S. R. 
hr 1 ne 

;s. R. 

rsat i 

ra an 

"s 
• f >j 

n T r e 

1 y b / 

. D., 

1 . 17 

. L'., 
Jour 



/ R 

6/ 

of 
/ R 

an 
, D 
ona 
d D 
em i 
atm 
Jan 

"A 

/ iJ 

"H 

nel 



Co 
£y 
at 

op 
on 

S 
i m 

CM 
P 
/ 

i n 



n R 
s/' 

ept 

f, P 
ear 
ter 
n A 
Cha 
Dat 

Fel 

nvp 
ste 

ami 
i ve 
Sea 
ila 
ati 
1 an 



eco^;nition by Piecev/ise Linear 
IEEE Trans. Computer , Vol. C-22, 

. 1^)73. 

rot 
i n 
Te 

;\T0 



tyocs I'-'-r Near 
lEEF. Tranj-. . on 



est .'Neighbor 
CoiTinuters . 



I ques 
I Proc 



for Interpreting^ Mass 
eedirvi. 



a Ui 

V/ : 

dnar 
rsal 

and 
ne/ 
r, ^ 
rch 
r i ti 
c 
n i n 



d K. C 
r, C 1 u s 

H. ,'■;. 

nal f'S 
Chen. 



hu, "The Interpretation 
ter Anal ys i s, " 



Fal es 
Sea re 
Doc . , 



r.ol 



Ja 
Ph 



COD5'>n 

a rrn . , 



i>y 

y C 
pti 



t!. Fal 

s ter.i. 
or:pa r ! 
mi zat i 
Radio 



PS/ an 
I I I . D 

sr,n." 

n f; f 

1 o r. y , 



/ and 

h Syster-. IV. 
13/ 130 (1973). 
"A no Study 
■J/ hiib-k'dC, (1973) 
d G. {■'!. A Milne, 
isplay anc: Plotting 
In press . 
External Beam 
7ol . 110/ IJo. 1/ 



erin-.; Systei'. inr Cor.ib ina t ionS/ " 

pp. '»h-'tO/ Jan. l.:7'i-. 
?■ Functions." To appear in the 



Dritlsh 



i. r 1 chevs 
I'ata ^y 
To aopea 



ky an 

Uoi.ipu 
r i n 



u L 
ter 
Int 



. 'lorton/ "ltora:',t: anu Manipulation ot 
s for Deterni nat i ve f'acter lol o.ey . " 
. J. of Syster:iatic Sacter i ol o;?:v. 



51 



Pro.erar f c r 
First 




Id. 

17. 
18. 

IJ. 
20. 

21. 



Au.d:. 1 
Lee, \{ 
Improv 
CAL'M > 
Slagle 
o i m p 1 i 
i n JAL 
iilagle 
lincvc] 



a73. 

. C. T., 

ed Pro&r 

Vol. 17, 

, J. R., 

fiers, CoMi.iUtat I V i ty , and Associativity." To aopear 

f'i. 



C. L. Chang, and R. J. V'aldin>:-er, "An 
•an-Synthes i z in)": Algcritnm and its Correctne 
No. h, pp. 211-217, April 197U. 
"Automatic Theorem Proving, for Theories wi 



ss; 

th 



It 



, J. R,, 
oped i a o 



Slagl e 
with S 
Patter 



, J. R., 
ome CI us 
n Reco^:;n 



"Theorem Proving, Autonat 
f Computer Science . 

C . T . 



C. L. Chan; 



and R. 



ter Analysis Algorithms 
i t i on . 

D i xon. 



ed." To appear in 

Lee, "Experiment: 
To appear in 



"List Process i ri.e. 



Slagle, J. R., J. Dixon, and T. Jones 

To appear in Encyclopedia of Computer Science . 

Slagle, J. R., and L. Norton, "Experiments with an automa 

Theorem Prover having Partial Ordering; inference Rules," 

CACii/ 1D/ pp. b82-6S8, Nov. 1973. 

Slagle, J. R,, and L. Norton, "Automated Theorem-Proving?; 

for the Theories of Partial and Total Ordering,," To 

appear in Computer Journal . 



tic 



52 



July 1, 1973 through June 30, myit 
PHS-MIH 
Division o^^ Computer Research and Technology 
Sumnary of Branch Activities PCRT 



Data Management Branch 



J. Fmmett Ward 
Branch Chief 



I . SUMMARY 



New computer software capabilities had a significant impact 
on systems developed by the Data flanagement Branch during fiscal 
year 197it. Although the new ARMS system v/as not the most 
complex system developed in the branch during the fiscal year, 
it certainly was the one which best demonstrates the advances 
made over the past year. Virtually every personnel office at 
the NIH is entering Its data at a communications terminal and 
each of these offices can retrieve information at the same 
terminal only minutes after a request Is entered. 



This sane approac 
techniques, has been 
trieval system for cl 
In prior years were h 
justify an expensive 
weeks of delay In obt 
it Is possible for a 
one day and receive t 
The most significant 
cost of obtaining thi 
mately $500.00 to $20 
year It is expected t 
Interface other cllni 
it more useful for an 
pointed out that this 
the Office of Clinica 
Center by enabling te 
users. 



h, using much more complex programming 
used In developing a retrospective re- 
inlcal pathology laboratory data. Requests 
eld until there was enough volume to 
computer run. This often meant several 
aining valuable research information. f^ow 
research investigator to enter a request 
he appropriate laboratory data the next, 
aspect of the new approach Is that the 
s information has dropped from approxl- 
-$30 per request. During the next fiscal 
hat this same technique can be used to 
cal data with the laboratory data to render 
alysis by investigators. It should also be 
methodology facilitates data security for 
1 and Management systems In the Cllnlcai 
rmtnal control over laboratory data 



In the highly dynamic world of software support, the branch 
has embarked on an effort which will combine each of its 
generative systems into a completely Integrated data management 
system. These systems are extremely useful as individual 
entities, but require several refinements and much more inte- 
gration to keep pace with the latest facilities available at 
the DCRT. As part of this effort, the Recursive f-lacro Actuated 
Generator (RMAG) is also being completely modified to improve 
its input and output capabilities. 



D 

R 
R 

/ 

D 
R 
S 



53 



The Biological Abstracts biweekly BlOSiS service was sub- 
scribed to by the DMB this year as a supplement to the existing 
Chenical Biological Activities Service. Both services are pro- 
vided free of charge to the NIH community. During this fiscal 
year we have also negotiated with the NIH library to advertise 
both services and to provide assistance to prospective users in 
preparing profiles of search requests. This relationship seems 
to be working out quite well. 

The Harwell mathematical subroutine library v/as added to the 
nCRT Mathematical and Statistical Program Library during the 
year. These subroutines represent several years of ' programmi ng 
effort by personnel at England's Atomic Energy Commission and they 
should add significantly to the flexibility of the DCRT library. 
A joint effort has also begun with library users to determine 
what nev/ facilities should be made available and what old pro- 
grams and subroutines should be eliminated from the existing 
library. It is planned that better communications terminal 
facilities will be added during the next fiscal year. 

Under the direction of firs. Prewi tt and with the continued 
support of the National Bladder Cancer Project^ the PEEP/DECIDE/ 
GRAPH general purpose conversational programming system for syn- 
tactic and semantic information processing on structured data 
bases has matured materially and lead to positive research 
results. This general purpose system is being used to solve the 
fundamental problem of classifying patients for treatment and 
tumor type; localization/ extent and progression constitute 
Indlspens i bl e information for indicating the modality of choice 
and the scheduling of therapy. Our role Is to develop a hither- 
to unattempted objective and quantlatlve basis for bladder 
hi stopathologV/ which Is currently regarded as the "penultimate 
truth", clinical Information, cystoscopy, and exfoliative 
cytology notwithstanding. The data bases consist of stained 
clinical biopsy specimens, r^canned and digitized at high photo- 
metric and spatial resolution and magnification at JPL wit^ 
several visible wavelengths and white light, and analyzed at 
DCRT with the PEEP/DEC! DE/PiRAPH systems. 

Dcrlng the past fiscal year, PEEP has acquired new built-in 
picture operators for global dynamic thresholding based on 
several prlncloles; spatial derivatives; Laplaclans; fast and 
ultra-fast Fourier and Hadamard tranforms and Inverses; sub- 
picture creation automatically, by explicit sampling and Inter- 
actively via displays; masking; convolution; connectivity 
determination; medial axis construction, and shape, size, 
brightness. Integrated density, and orientation descriptions. 
171 th these capabilities we have been able to perform picture 
segmentation optimally In the presence of artifacts and Inter- 
cellular debris, to extract cell nuclei, describe nuclear 
features quantitatively, and assemble attribute lists for 
pattern recognition and mul t i-dlmenslonal scaling purposes. We 



54 



plan to process 100-220 cells automatically by June, covering 
the range of Grades I, II and III papillomas and papi 1 larycar- 
cinomas. DECIDE facilitates decision-making and pattern recog- 
nition by addition for facilities for defining sub-sets, com- 
plexes and syndromes, for statistical decision theory (Bayesian, 
maximum likelihood, other; linear and quadratic), and for 
tracking error rates. GRAPH, a new system component, provides 
soft- and hard-copy two and three dimensional displays of curves, 
graphs and surfaces. Commands are rel at i vi st i c; that is, they 
can be issued from the vantage of the viewer or the viewed. 
Several publications and public addresses on the system and its 
results for bladder cancer h i stopathol ogy have been' issued. 



During the coming fiscal year, we plan to unify the three 
subsystems, PEEP/DEC I DE/HRAPH, into one system on the PDP-10 
dual processor, '-ie plan to process and scale or classify cells 
and tissues in several dozen scans (amounting to several 
thousand cells). We vyi 1 1 attempt to optimize staining by 
further experimentation with Harris hematoxylin, Feulgen, and 
gal locyani n-chromal um, and to optimize mul ti spectral scanning 
wavelengths for resolution of contrast and characterizing 
morphological detail. 

In a highly developmental effort the Data 'lanagement Branch 
is collaborating with Dr. Pinesh Sharma, NHL I , to facilitate the 
planning and forecasting mechanisms within the OD, fJHLI, The 
basic objectives of this system are to support both strategic 
and operational planning, to assist in the budget staging and 
monitoring process, to develop future projections based on past 
trends and to provide a better method for evaluating manpower 
and other resource allocations. 

The methodology for establishing such a facility will be to 
combine much of the existing NIH grants, financial and budgeting 
data with information endemic to the MHL I and to provide this 
information in summary fashion to the Office of the Director. 
Facilities such as a flexible terminal based interactive system 
v/ill be made available to enable quick modification and retrieval 
of data in formats dictated by the user at the time of access. 
'7e have high hopes that, through the efforts of Dr. Sharma and 
the programming expertise of DMB personnel, the system will be 
highly useful to the .NHL I. 

The follovnng is a summary of those systems which 
were developed by the various sections in the branch and, 
where appropriate, an abstract of those projects which 
demand a more detailed explanation. These projects can 
be summarized best by organization structure. 



55 



Documentation and Systems Support Section 

1. Clinical Center Data Processing Support 

Provided reports to Clinical Center Investigators from the 
Laboratory Data Files (BETA) at their request and according to 
their specifications. 

2. Case 1973 Reports 

These annual fiscal year reports will contain 135 different 
listings, tabulations and ranking tables to be published in 
five volumes by the OD/ADPPF/ORA. For Fiscal Year 1972 we began 
to standardize the approach to producing output tables. We 
achieved only partial success In that 1/3 of the 120 case reports 
were produced without programming. By using these program gener- 
tlon techniques it Is expected that we will avoid reprogrammi ng in 
several new areas this year. Eventually it is hoped that program 
generation will significantly reduce the time and resources 
necessary to support this annual requirement. 

3. Trends in Graduate Enrollment and Ph.D. Output In Selected 
Science and Health Professional Fields. (1962-19S3 thru 
197(M971). 

U. Redesign of ARMS Personnel System 

All Institutes without appointing authority are currently 
using a new terminal based personnel data collection and re- 
porting system. The new system Is being Integrated with the 
departmental Terminal Data Collection System and it Is antici- 
pated that all of the personnel offices at NIH will have the 
full power of the new ARMS facility by the end of FY 197U. 

5. Vitamin C Study, C.C. 

Additional relationship tables were provided at the request 
of Dr. Chalmers, t!ie former Clinical Center Director. 

6„ Clinical Center Census Reports 

Institute, Ward and Bed complements were changed effeotIv3 
10/01/73 and the system was modified uo reflsct these chsnges. 
An additional program has been written to provide <) recurring 
monthly Geographic report. 

7. Diagnostic Radiology Department Case File, C.C. 

This computer system was developed to replace a manual 
radiology record keeping system. Neither the old manual nor 
the new automated system records diagnostic Information, but 
provision for doing so is possible. 



56 



8. Physician Authority List Syste 



m, C.C. 



Additional programs were v/ritten during the year to provide 
Index cards of physicians involved in patient care. These 
programs are capable of terminal communication. 

9. Fogarty International Center 

Data on Russian Scientists, Doctors and Institutions 
was collected by Library of Congress personnel using prompt 
programs written by DflB. A "Directory of Institutions" and a 
"Directory of Personnel" has been produced from this data. 

10. NHLI Information System Phase II 

System established for collecting, editing and updating 
of all NHLI extramural programs using data from both the 
Division of Research Grants (DRG) and the NHLI. 

11. Study of Baltimore Cancer Research Center (BCRC) Time 
Sharing Requirements 



At the request of BCRC, the Data Management Branc 
a study of the possible alternatives to BCRC's presen 
Tymshare's computer system. A GSA requirement preclu 
use of the Tymshare service after October, I'ilh. Res 
study indicate that some use of the Tymshare computer 
necessary until a table making facility can be duplic 
in-house or by another time sharing service. It is a 
however that Cal 1 -a-Computer will provide much of the 
sharing support for BCRC and that two of the larger s 
namely Census and Microbiology, will be supported on 
computer system. Work is in process now to accomplis 



h conducted 
t use of 
des BCRC's 
ul ts of the 

system is 
ated ei ther 
nt ici pated 

new time- 
ystems, 
the DCRT 
h this. 



Ul 



12. NCI Contractor Data System 

An automated NCI contractor data base was created using data 
fron the DRG Impac system supplemented by additional elements 
entered by the UC\ . The Research Contracts Branch now has a 
facility for automatic reporting of both open and pending 
contract information. 

13. NCI/DMB Contract Involvement 

Personnel of the section are acting as consultants to 
various NCI personnel and contractors. These Include contracts 
with Tracor/Ji tec, JRB Associates and TRW. 

1I+. Opportunity Skills System, ODA, P 



57 



15. Results of Questionnaire on Housing, Transportation and 
Child Care Needs of NIH Personnel, ODA, P 

16. Case 1973 Data Preparation for NSF, OD/ORA 

17. NICHD Grants System 

18. Blood Assay Test Results, NIMH 

19. Lupus Data, NIAMDD 

20. Computer-assisted Electron Microscopy, NHL I 

21. KWIC Indexes for the NIH Central Library, DRS/L 



58 



Applied Systems Programming Section 

1. Type II Intervention Study. 

The system supplies all of the data storage, validation, 
purification, monitoring, and reporting capabilities required 
in support of the Type II Invervention Study being conducted 
by the Lipid Metabolism Branch, NHLI. The reporting capabilities 
were added this year and the nMB is maintaining the present 
system. Analysis of the data is partially defined and will 
continue thru FY 75. 

This system makes it possible for Lipid Metabolism Branch 
personnel to store and to subsequently do reporting and analyses 
on their patients with blood lipid disorders and to relate these 
analyses to other family members. It also provides them with 
listings used as an aid to the doctors for patient handling in 
the clinic. Of particular current interest is the development 
of reporting capabilities to serve the Patient Safety flonitoring 
Committee. Support for the system and training of NHLI personnel 
in its use is supplied by the DMB. 



2. Carcinogenesis Bioassay Data System 



This 
for the 
genesis, 
tion, re 
to the s 
detormln 
includes 
contract 
report, 
graph, 
for al 1 , 
study, 
complete 
Branch s 
their st 



compu 
Office 

MCI t 
port in 
tudy a 
e thei 

many 
s awar 
pathol 
Output 

sel ec 
The CO 

data 
uppl ie 
udles 



ter ized 
of the 
o contro 
g and an 
nd ident 
r carcln 
thousand 
ded by t 
ogy repo 

can be 
ted cont 
ntractor 
base sub 
s ass ist 
are incl 



data 

Asso 

1 th 

al ys 

iftc 

ogen 

s of 

he U 

rt, 

prod 

ract 

s ca 

set 

ance 

uded 



process ing 
ciate Scien 
e data acqu 
is of anima 
atlon of va 
ic effect o 

animals be 
C I . Exampl 
survival cu 
uced in har 
s, or selec 
n, upon req 
of thei r da 

to contrac 

in the sys 



system makes 
tific Directo 
is i tion, inpu 
1 research da 
rious agents 
r capacity, 
ing tested un 
es of output 
rve graph, an 
d copy or on 
ted experimen 
uest, be prov 
ta. In addi t 
tors before a 
tern. 



it possible 
r for Carcino- 
t, purifica- 
ta related 
in order to 
The Study 
der various 
are a summary 
d weight curve 
Mi cro-f I che 
ts in a 
ided with a 
ion, the 
nd after 



The major data management system developmental effort has 
subsided, however, the DMB continues its support. The 
attention has now shifted to the analysis phase and the DMf?. 
Is actively involved in this. 



59 



3. Autopsy Data System. 

This system makes It possible for Dr. Young of the Compara- 
tive Pathology Section, Division of Cancer Treatment, NCI to 
store and maintain his data and to subsequently do logical 
retrieval from a data base consisting of the extremely variable 
Clinical and Pathological diagnosis data In autopsies of cancer 
patients. The primary purpose of this study is to determine 
what. If any, relationships exist between the use of specific 
agents and the occurrence of designated lesions. The computer 
assistance provided by the DMB Includes CPS data acquisition, 
automatic SNOP encoding of clinical and pathological diagnosis, 
error correction, edit/update, a fixed format report, and a 
completely generated COBOL retrieval program executed via TSO, 
which provides almost complete flexibility in composing quick 
queries. 

k. Computerized Distribution List. 

This system will provide the Grant and Contract Guide 
Distribution Center, DRG, with the capability to create, main- 
tain, and selectively produce labels to be used In the distri- 
bution of the Grant and Contract Guide and/or any of the 
various supplements. The data base will eventually be augmented 
to Include other NIH mailing list requirements. 

5. NIH Appropriations and Obligations Information System. 

This computerized data processing system provides the Office 
of Legislative Analysis, OD, NIH, with the facility to maintain 
a data base of NIH Appropriations and Obligations by total NIH, 
total NIH minus programs transferred out, by activity within NIH 
and by activity within program. 

6. NIH Personnel Accident Reporting System. 

This system utilizes the computer to monitor and retain a 
complete history or NIH employee accidents, fol low-up-ac i-ions, 
and corrective meaaures taken. It communicates with the DHEW 
computer system via magnetic tape. 

7. NIH Space Management System. 

The Space Management System helps the Space Management 
Office manage NIH space utilization and allocation. It also 
assists other offices by maintaining information relating to 
areas containing biological or radiation hazards. 



60 



R. Iledlcal Records Discharge Diagnosis System. 

The system provides the Clinical Center Medical Records 
Department with the ability to maintain a current, accurate data 
file of all Clinical Center in-patients' discharge diagnoses. 
It also supplies various useful reports and listings in the 
form of indexed MICROFICHE. 

9. NIH International Activities and Personnel Monitoring System 
for the Fogarty International Center. 

10. Type V Intervention Study. 

This system provides Dr. Creenberg of the Lipid Metabolism 
Branch, NHLI v/Ith the capability of storing and purifying for 
analysis data collected by UHLI on patients with TYPE V lipid 
disorders and their first degree relatives. 

11. NIH Central Registry of Biological Agents and Materials. 

This system is designed to aid the Environmental Services 
Branch, DRS, in its administration of the Registry. The primary 
purpose of the Registry is to make feasible the monitoring of 
hazardous and potentially hazardous materials and agents in use 
at IHH. 

12. Pharmacy Computer File System. 

The Clinical Center Pharmacy maintains a complete, accurate 
file of relevant Information on all drug products which It has 
available. From this file we produce a variety of reports of 
use to the Pharmacy itself and to doctors and nurses who pre- 
scribe and use Pharmacy drug products. At the same time, the 
file serves as a centralized, computer readable file of drug 
information about drugs used in the Clinical Center. 

13. Dental Clinic Report. 

This is a very basic system that aids the Clinical Investi- 
gations and Research Services Branch, NIDR, in maintaining a 
computerized data base which reflects all dental services 
rendered by this Branch for all Institutes. 

lU. Fgytian Autopsy Data Analysis. 

Dr. Cheever of the Laboratory of Parasitic Diseases, NIAID, 
performed approximately 250 autopsies on subjects In i^gypt. He 
now wishes to computerize the data In order that an analysis can 
be nade relating to a specific parasite/parasite egg resident In 
various organs of the subject's bodies. 



J 



61 



15. HL-A Data Maintenance System. 

The nature of Dr. Rogentine's study for the Immunology 
Branch of NCI Is to try to determine if there Is any connection 
between specific HL-A types and disease. Now that the system 
is operational, our role is supportive. 

16. DCRT Personnel and Training System. 

17. Leukocyte Infusion Update and Reporting System. 

The system collects data and reports on Leukocyte Infusion 
Information for the Medicine Branch's Leukemia Service in rJC I . 
The information collected includes specific infusion information, 
laboratory follow-up information, and infusion series summary 
information. Data 5s extracted from two related systems, the 
Cell Collection and the Donor Recipient Information System. 
These data are then combined with the Leukocyte Information 
for other reports. 

18. Lipid Protein Study - Lipid Metabolism Branch, NHL I 

19. Hypertension Study Data Processing System. 

The purpose of the study is to try to find correlations 
betv/een hypertension and other variables such as the kidney's 
secretion of different levels of Renin. This effort supports 
the Reproduction Research Branch, NICHD. 

20. CI in/Path Test Result Extraction for the Immunology Branch, 
NC I 

21. FVIF Medical Records Information System. 

The Emergency Virus Isolation Facility, MCI, has requested 
that its data collection and reporting system be made con 
versational. The effort essentially is a redesign of the existing 
system to provide total data control within the corriTes of the 
Building il facility. It is hoped that when !:he system is com- 
pletely operational, the loss risk relating to sensitive employee 
data will virtually be eliminated. 

22. Animals for Research. 

At the request of the NCI, DMR is developing a completely 
automated system for the Institute of Laboratory Animal 
Resources, (ILAR). The intent of the system is to improve the 
publishing and referencing facilities available from ILAR, which 
publishes data relating to sources of animal stocks, fluids, 
tissues End organs. 



I 



23. Cigarette Condensate Study System. 

The study being conducted by the Etiolgy Branch, MCI and 
executed by Hazel ton Laboratories is an attempt to determine the 
possible alternatives for people who must smoke and to establish 
pathways of minimum risk. Df^B provided programming support for 
the data collection and reporting segment of the project. 
Analysis will be handled by flC I personnel. 

2k. Computerized Grant Supported Literature Index. 

At the request of the Program Analysis and Evaluation Branch, 
MCI, the DMB is providing a computerized capability to 1) create 
and maintain, 2) index on keyword, and 3) print for publishing 
the Grant Supported Literature Index. 

25. Computerized Patient f1enu Labels. 

This system vylll search the Admission file for active In- 
patients and produce three labels for each. The labels will 
be placed on each of the 3 segments of the patient's daily 
menu for Identification of the meal selection by patient. This 
will save the Nutrition Department In the Clinical Center from 
having to hand prepare approximately 9nn labels per day. 



D 
R 
G 



63 



Scientific Application Section. 

1. Psychophysiological Measures 

In support of the Laboratory of Socio and Environmental 
Studies, NIMH, the Data Management Branch has developed a 
generalized data management and statistical analysis system for 
psychological and physiological measurers. During this fiscal 
year, an artifact detection and removal module for heart rate 
data was developed, the system was completely documented and 
the user/system interface using live data was started. 

Future efforts will concentrate on the integration of 
laboratory processing data with the computer and on the possible 
development of a file maintenance capability. 

2. Data Base for Surgery Branch 

The Surgery Branch of the NCI had a need for a data 
collection and reporting system. This included the 
editing, storing and retrieving of all data related to re- 
search projects of the Surgery Branch, NCI. 

During the past year two new protocols were Incorporated 
Into the system. To date, the DMB has provided CPS data collec- 
tion/edit prompt programs as well as an update, retrieval and 
reporting system for nine NCI protocols. Data files have been 
developed to include one file of common data and an associated 
auxiliary file. This represents a file of all Surgery Branch 
Operations Including those which have not been expanded Into 
separate protocols. Nine additional protocols for which only 
core data will be entered are currently being Implemented. 
Analysis of the data may lead to more complete protocols for 
operations not under special investigation at present. 

3. Cancer Survival System 
NCI 

The Survival System was origlnaKly developed to 
support the End Results in Cancer Studies. Maintenance 
and Improvemenv: of the system is the primary goal. 

During the year several more requests were made for copies 
of the system. In addition there has been Increased use 
of the system by elements outside the Cancer End Results 
Group. A number of minor problems have been solved. 

A new submission of cancer data took place this year and 
the CER personnel ran their own edit and analysis programs 
with some consultation with us. The next submission of data 
will involve substantial changes in format, making it necessary 
to make changes to the Survival System to reflect format and 
coding changes. 

64 



1 



If. Current Awareness Search of Clinical Biological Activities 
(CBAC) 



The biweekly Issue of the CBAC data is received from 

the Chemical Abstracts Service (CAS) in Columbus, Ohio. 

These Issues are used to supply the NIH community with 

information on current articles related to the chemical- 
biological area. 

Retrospective searches are also run monthly or on demand 
In special cases. 

The major non-routine effort in this area during the year 
was conversion of all PL/1 programs in the system to the new 
PL/1 compiler. At the same time, the print program was 
streamlined In order to realize additional savings. 

5. Current Awareness Search of Biological Abstracts (BIOSIS) 

This Is a new service, offered for the first time at NIH 
In 1974. Twice a month tapes v/Ill be received from the Biological 
Abstracts Service and Information will be disseminated to the 
NIH Community thru the same vehicle as CBAC. 

The major effort went Into the development, programming, and 
testing of the reformat program for this new data base. The 
original CBAC search program Is used for BIOSIS data after 
reformat. 

6. Aortic Valvular Disease 

In collaboration with Dr. Walter Henry, NHL I , the DMB 
Is providing programming support for a study which will 
attempt to define prospective pre-operati ve rlsl< for heart 
valve replacement patients. 

DMB's main Involvement with this project during the past 
year has been to respond to questions concerning the use of 
the data collection and file maintenance programs we provided. 



65 



7. Cutting on 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 morbld'ty of cutting oil 
workers. A data base has been established, and a survival 
analysis program simlllar to that developed for the Steel- 
workers Project will be written. 

During the latter half of 1973 a number of frequency tables 
were produced as a preliminary aid to the development of sped- ^ 
ficatlons for the analysis. 

8. Federal liomen's Program Statistics 

The Department of HEW supplies the Federal Somen's program 
with tables reflecting NIH employment and promotions by race, 
sex, and employment level. Data is extracted from these tables and 
used to create some graphs. A Calcomp program was set up which 
allows the production of several different graphs and bar charts 
as desired. Complete documentation for running the programs 
was given to Ms. Adele Nusbaum, 0, FED. 

9. Gastroenterology Training Rtvlew 

A coding technique for recording the training, education, 
and experience information on questionnaires sent out to training 
grants recipients was devised. After the data was keytaped, i| 
frequency counts were computed and sent to Dr. Kitzes, NIAMD. 

10. Multiphasic Zone Electrophoresis Programs 

The output from these programs (2000 recipes for Gel Electro- 
phoresis Systems) Is being distributed thru NTIS. Our only real 
effort in the past year has been in replacing 3 tapes damaged at 
NTIS and In supplying JCL procedures to the University of 
Colorado to enable them to run the retrieval program, 

11. Radioimmunoassay Programs 

This system of programs which evaluates the Scintillation 
Counter output of radioimmunoassays Is In dally use by NICHD. 
in collaboration with Dr. Rodbard several revisions have been 
made to the system to keep pace with changing theory and . 

methodology. ' 

Future plans include the replacement of the ploc portion of 
the system with a new printer plot capability. 



66 



12. CBAC/Microf Iche Project 



The entire CRAC retrospective file was put onto microfiche 
and the file Inverted with respect to keywords, molecular 
formulae, and CAS registry numbers for Dr. Fales. 

During the coming fiscal year we plan to create an on-line 
disk file on the PDP-IO and to develop a search program which 
will operate In conjunction with a computer-driven microfiche 
reader. 

13. X-Ray Crystal 1 os;raDhy 

A set of computer programs for implementing direct methods 
In ;(-Ray Crystallography was developed at the Medical Foundation 
of Buffalo. DfIB personnel converted, stored and tested these 
programs for use by Dr. James Sllverton, MHLI. 

Ik. Gastroenterology Data Base - Dr. Krueger, MIAMD 

This will be a data base of journal abstracts from the 
literature of Gastroenterology. During fiscal year 197U, re- 
format and print programs were written. The CBAC system v/Ill 
be utilized for searching the text. 

This will be set up on a recurring production basis with 
a new data tape arriving from the Franklin Institute, Phila- 
delphia, once a month. Volume is expected to be about 3,000 
abstracts/year. The researchers In NIAMD will eventually 
develop and run their own profiles or search requests. 

15. Computerize Data from Scintillation Counter 



In collaboration with Dr. Stephenson of the Viral Carcino- 
genesis Branch, NCI, data from a Packard Scintillation Counter 
Is being transmitted over telephone lines from Hazel ton Labs In 
Virginia to the PDP-10 at NIH. Programs for calculating con- 
centrations of proteins being measured by radioimmunoassay and 
for comparing reactivities of different proteins based on the 
relative slopes of their titration curves were provided. 
Currently the option of plotting up to 7 distributions on the 
same graph Is being Implemented. Future plans Include a test 
for determining the amount of variation between different assays. 



67 



# 



16. Computerize Data from Coulter Counter 
Biology^ NIAMD. Dr. Shehata, Dr. Kempner % 

Coulter Counter data is supplied to the PDP-10 via paper 
tape from the Laboratory of Physical Biology. Dr. Shehata and 
Dr. Kempner were provided with a program which computes mean, 
mode, standard deviation, and coefficient of variation for 
bacteria counts and displays them at the terminal. Future plans 
include provision of teletype graphs and line-printer graphs. 
Also being discussed are graphic displays, perhaps using the 
Omni graph. " 

17. Serum Bank - Inventory and Retrieval System 

Dr. Alexander, Surgery Branch, NCI has data for about 2500 
patients and anticipates up to 10,000 with up to 15 blood 
samples per patient. An Inventory system must be set up to 
keep track of the freezer location of the serum vials and to 
store test results for undefined numbers and types of tests on 
the sera. Also desired are updating and reporting facilities as 
well as a quick retrieval capability. 

Specifications for the system have been developed and 
implementation has begun. 

18. Mass Spectral Search System 

During FY 197U, the DMB assumed responsibility for the main- i 
tenance of an Interactive mass spectral retrieval system. In 
collaboration with Dr. Fales, Laboratory of Chemistry, NHLI, the 
DMB revised all programs In the system to accommodate new file 
formats. A new data file, which increased the number of spectra 
from 12,000 to 30,000 arrived during the year. This new addition 
plus Interface problems between the system's two computers re- 
quired expert maintenance support. The dynamic nature of this 
system will cause many complex problems for the forseeable 
future. These problems in turn will require thoughtful and 
experienced computer support for solution. 

19. On-Line Table Creation Facility 

At the request of the Chief, DMB, a procosal for an o.T-l!ne 
table-creation facility has been written. A system of programs 
Is to be developed to do frequency counts and elementary statis- t 
tical calculations. It Is to be operated in either a time- 
sharing or batch mode and will permit a user to specify para- 
meters for his job ir. a problem-oriented notation. 



68 



Math/Stat Section 

1. Analysis of Data of Inbred Mice and Nutritional Treatments. 

In support of DRS programs DMB evaluated data involving 
rations containing two levels of crude protein and three levels 
of fat which were fed to four strains of mice. Split plot de- 
sign and least square analysis programs have been run to evaluate 
the effects of open formula rations on reproductive performance 
and reproductive performance with different physical characteris- 
tics. Evaluation has also Included data on reproductive perfor- 
mance and growth of mice fed rations varying in crude protein 
and crude fat. 



2. Interview Scheduling. 

The Clinical Center requested major modifications to 
the original specifications of the Clinical Associate 
Interview Scheduling System. Systems modifications to 
make programs compatible with the new FORTRAN-Gl compiler 
and I/O packages have also been completed. This system Is 
continuously being updated to take advantage of new computer 
systems. The original documentation is being modified to 
reflect new changes In the program and run Instructions. The 
system Is used each year around April. 

3. Evaluation of CO Heart Data. 

The Initial objective of providing a massive storage 
and retrieval capability for chemistry data of the 
Endocrinology Branch, NHLI has been accomplished. Statis- 
tical programs have been prepared to evaluate chemical data 
combined with patient demographic Information and fourier 
analysis on blood pressure data at 2t* hour Intervals. The 
final objective of this study will be to develop a capability 
to produce recurring statistical output and evaluations that 
would aid scientists In studying the data. 



k. Retrospective Study of Aortic Valve replacement. 

A set of programs have been completed to edit data on 
700 patients who underwent open heart operations. Simple 
statistical parameters have also been computed In addition to 
survival analyses. 



69 



5. Lipid Protein Study. 

In support of NHLI, this study involves evaluation of ^ 

data on Type li kindreds whose propositi were the first 
120 individuals found to have Type II hyp'^rl i poproteinemia 
at the Clinical Center. To date data description statis- 
tics and multivariate variance analyses have been provided. 
Future plans include the addition of sex and age factors to the 
analys is. 

6. Probit and Logit. , |^ 

This DBS project involves evaluation of different com- 
putational methods in an effort to refine the assessment 
of biologies products. The programming has undergone major 
modifications; it computes probits and logits with options to 
compute individual or pooled slopes, with or without con- 
version of Input data. Additional options in the programs 
Include tests for parallelism and relative potency. 

7. Evaluation of Pertussis Potency Tests. 

This project involves the evaluation of Pertussis 
vaccine potency as performed at DBS. Programs performing 
probit analysis have been extensively utilized in this 
study. However, additional programming Is underway to 
determine if there are seasonal variations in the test as 
evidenced by cyclic changes in standard vaccines or changes M 
in the Immunity of animals receiving standard vaccines. The ■ 
findings so far have led to two major Innovations in procedure, 
an increase in the number of animals per dose and careful 
randomization of mice to vaccines and dose levels. 

8. Multiple Family Group Study. 

The basic unit of this study Is a group therapy sesslcr in 
which several families with disturbed adolescents meet with 
personnel from the NIMH Adult Psychiatry Branch and the Psychiatic 
Institute. There have been approximately 100 of these sessions, 
each ibsssion yielding five types of data: 

a. Cohesi/eness Questionnaire Data. 

b. "Who-to-V/hom" Speech Data. 

c. V^ard Value Questionnaire Data. 

d. Soclometry Data. % 

e. Seating Position Data. 

The first three sets of data have reached the analysts stage. 
The soclometry data Is still in the process of being validated 
and nothing has been attempted with the seating position data. 



i 



70 



9. Type II Intervention Study 



This effort is part of the analysis phase of the Type II 
Study being conducted by the NHLI. In collaboration with Dr. 
Brensike and the MHLI Biometrics Branch, four PL/1 data retrieval 
pronrams, initially begun by user, have been implemented. Upon 
execution, these programs retrieve data pairs for each patient; 
eliminating missing or inadmissible data and input these data to 
a program that computes paired-t tests. 

A program has been developed to retrieve and edit different 
sets of data and to access the SPSS (Statistical Programs for 
Social Studies) package. One of the features of this package 
will provide Dr. Brensike with the flexibility to obtain what- 
ever cross-tabulations he wishes. 

Future plans include the implementation of the Duncan- 
Vialker probability package for analyzing independent variables. 

10. Treatment of Massive Obesity: Changes in Cardiovascular 
Risk Factors 



This study involves analysis of changes in cardiovascular 
risk factors (i.e. blood pressure, glucose tolerance, blood 
lipid levels, uric acid, heart size on chest X-ray, electro- 
cardiographic findings) associated with weight loss in patients 
with massive obesity. One hundred six patients who lost at 
least one hundred pounds constitute the study population. 

The degree of weight loss and the changes In the above risk 
factors assessed by seventeen parameters measured before and 
after weight loss are being subjected to systematic analyses In 
terns of incidence of and degree of abnormality. Changes are 
correlated with degree of weight loss. Correlations among and 
betv/een parameters are being derived and analyzed. 

11. Carcinogenesis Information Evaluation 

The analysis phase of this study involves data from ongoing 
bloassay experiments In mice. The Immediate aim Is to detect 
previously unidentified carcinogens. 

A major programming effort has begun on this project. Data 
for the statistical analysis will be drawn from two files: one, 
a file containing complete background data for each animal 
group; the second, a file containing complete individual animal 
records. Call these the 'Control File' and the 'Individual 
File' respectively. Initial analysis programs Include simple 
data descriptions, such as counts of animals within a sample 
and counts of animals with certain pathologies. Survival 
statistics are also being developed. 



71 



12. Radioimmunoassay of GS Antigens 

Project involves development of a system to calculate the 
degree of antigen bound in radioimmunoassay data using one^ two 
or three isotopes. In this procedure the amount of antigen Is 
measured by inhibition of the precipitation of standard labelled 
antigen and specific antibody. The purpose of the second and 
third Isotopes is to determine non-specific contributions to 
the precipitate. 

Programs have been completed to perform calculations using 
one and two Isotopes and the investigator has received numerous 
outputs. Programming for three Isotopes has just begun. 

13. Analysis of Data in Occupational Medicine 

Project Involves analysis of medical examination data and 
dynamic ECG records of NASA Headquarters personnel. The Initial 
phase of this project involving regression analysis Is complete. 
No future assistance is planned for this effort. 

Ik. Rvaluatlon of Long Lines models 

This project involved the conversion and evaluation of three 
separate systems that compute econometric models used to derive 
AT&T long lines rates. All of the programs were written by AT&T. 
DMB's objective in this project was to assist FCC In evaluating 
these models. The system Is now operating on the DCRT computer 
and has been turned over to FCC personnel. 



72 



HOW TO USE 

THESE SEPARATORS 

Use one page for 
each separation. 

Select appropriate 
tab, add further 
identification if 
desired, and cover 
it with scatch 
tape. 

Cut of f and discard 
all tabs except the 
one covered by tape. 




TABBED SEPARATOR SHEET 

Form HEW-69 

(3-se) 



t.|^ 



^ 



O/V/S/OA/ 






^AfA/UJ^l J^£PGJir 



FflsoaH T®a3P 3L®'^4 



r 



CONTENTS 



Page 
Highlights 

Office of the Director ..... i 

Grants Associates Program 5 

Grants Inquiries Section 7 

Office of Research Manpower 9 

Adniinistrative Branch -i-i 

Institutional Relations Branch 13 

Research Analysis and Evaluation Branch 17 

Research Grants Review Branch 19 

Statistics and Analysis Branch 25 



c 



HIGHLIGHTS 

An unprecefdented volume of applications was processed and reviewed-- 
25,448, including 2,976 individual research fellowship and research career 
development awards. Of these, 16,400 competing applications were assigned for 
technical merit review. 

The new research fellowship award program became operative with the 
February 1, 1974, deadline. Approximataly 3,300 individual fellowship applica- 
tions were received for both the NIH and ADAMHA., and 210 institutional 
applications. 

The Research Career Development Award program was reinstated with June 1, 
1974, the initial deadline for receipt of applications. 

The number of workshops held by the study sections this fiscal year was 
five only. 

A new computer method for streamlining the monitoring of scientific 
evaluation grant expenditures has been in operation since July 1973. 

Much interest was generated by the report on the project, "Support of 
Principal Investigators by the NIH: 1966 to 1973," published in Science , 
July 20, 1973. The project and similar studies are therefore continuing. 

Classification codes for research contracts were devised to assist in the 
effort to estimate NIH support of applied research projects and development 
projects. 

A low-cost system of automatically retrieving Notices of Research Projects 
from a computer tape was devised to provide substantive information about the 
content of research proposals. 

Estimates of available minority and women manpower in the sub-specialties 
of internal medicine were prepared and documented for a coordinated NIH response 
to a request from the Department of Internal Medicine, Yale University 
addressed to all NIH institutes. 



A new system for the preparation of the Research Grants Index was 
completed and the publication was printed by means of the GPO Linotron process 
utilizing magnetic tapes. 

Twenty grantee institutions received audit visits from DRG staff to 
determine the adequacy with which grantee and contractor institutions are 
carrying out their responsibilities within the terms of the DHEW policy on 
protection of human subjects and to initiate negotiations for revision of 
written assurances to reflect improved performances by these institutions in 
the protection of human subjects. 

New or revised assurances of compliance with the new DHEW policy on the 
use of warm-blooded animals in research were negotiated with over 600 institu- 
tions. 



DRG continues to assist DREW in the application of policy requirements 
to specific prcgrams and projects involving animals. 

A computerized data base of the Report of Expenditures for Fiscal Year 
1973 NIH research grants was established. 



r^ 



The establishment of central control offices in grantee institutions for 
the distributicn of grant application Icits became operative xn aunuary 1974. 



c 



OFFICE OF THE DIRECTOR 

The Director was present at several scientific meetings during the year 
under review. 



Among the meetings in which he participated were the Council of Graduate 
Schools Workshop for New Deans held in Seattle, Washington, July 22-27, 1973, 
at which he spoke on the "Washington Climate"; a Workshop-Conference on 
Grantsmanship held at Purdue University, Purdue, Indiana, on September 11, 1973, 
a^ which he spoke on "Preparing Formal Proposals"; the annual meeting of the 
Association of Independent Research Institutes held at Bar Harbor, Maine, on 
October 4-5, 1973, at which he spoke on "Hews in the Grants Area"; a workshop 
at the University of Oklahoma, Oklahoma City, Oklahoma, on November 13-14, 1973, 
at which he spoke on the "NIH Granting Mechanism-Overview"; and a symposium at 
the Health Science Center at Dallas, University of Texas, Dallas, on March 11, 
1974, at which he spoke on "The Grant and Award Mechanisms." 

The Director also attended the annual meetings of the Council of Graduate 
Schools in Williamsburg, Va., on December 12-14, 1973; the Western Association 
of Graduate Schools in Victoria, B.C., on March 3-5, 1974; the Midwestern 
Association of Graduate Schools in Chicago, Illinois, on March 24-26, 1974, and 
the AAMC Northeastern Business Officers Meeting in Philadelphia, Pa., on May 
29-31, 1974. 



On January 16, 1974, the Director was host to a group of officials from 
the Instituto Nacional de Investigaciones Agrarias (I. N.I .A.), Madrid, Spain, 
who were visiting the United States under the sponsorship of the U.S. Department 
of Agriculture, and representatives of the research agencies of USDA and the 
Land-Grant universities. Presentations were given by the Director and senior 
DRG staff members on the mission of the National Institutes of Health, the 
functions of the Division of Research Grants, and the NIH dual review system for 
evaluating research proposals. 



The Deputy Director spoke at the Biomedical Research Manpower Conference 
held at the Battelle Seattle Research Center, Seattle, Washington, October 1-3, 
1973. He also participated in the NIH Senior Staff Seminar on Management by 
Objectives, held at Belmont, Md. , September 17-19, 1973; the session entitled, 
"1973 Continuing Education Program," held by the Group on Business Affairs of 
the Association of American Medical Colleges, New Orleans, La., September 19-21, 
1973; the Annual Meeting of the Association of American Medical Colleges, 
Washington, D.C., November 6-10, 1973; a seminar entitled, "Executive 
Development Days," held at the National 4-H Foundation Center, Chevy Chase, 
Md., December 3-4, 1973; the ECEA Seminar on Peer Review, held in Reston, Va., 
February 26-27, 1974, and the Fourth Advanced Leadership Laboratory for FEI 
Executives in Ojai, California, June 16-21, 1974. 

The Deputy Director is a member of the NIH Executive Committee for Extra- 
mural Affairs; the ECEA Subcommittee on Training; the NIH Public Advisory 
System Coordinating Committee; the Working Group on Projects: Recommendation 2 
of the NIH Program Mechanisms Committee Report (Cooper Report); the Study Group 
on the Protection of Human Subjects in Biomedical and Behavioral Research, and 
Chairman of the Subgroup on Safeguarding Sensitive Statistical Data. 



The Deputy Director organized three DRG staff seminars during the year 
under review: On July 16, 1973, Mr. Louis Voegler, acting chief, Executive and^ 
Management Development Branch, spoke on "Executive Development at NIH"; on V— 
October 2, 1973, Dr. Albert Pawlowski, chief. Extramural Research Branch, 
National Institute on Alcohol Abuse and Alcoholism, ADAMHA, spoke on the 
"Alcoholism Research Program of the National Institute on Alcohol Abuse and 
Alcoholism," and on Fftbruary 22, 1974, Dr. Theodore Cooper, then director NHLI, 
spoke on "Receni, Developments in NHLI." 

The Deputy Director authored with the Chief, Research Analysis and 
Evaluation Branch, a report entitled, "Support of New Principal Investigators 
by NIH: 1966 to 1972," published in Science^ Vol. 181, pp. 241-244, July 20, 
1973. 

A member of the OD staff has been serving on the NIH Grants Management 
Advisory Committee and its Operations Sub-Committee; the Program-Project and 
Center Task Force; the ADERT Unfunded Applications Committee, and as NIH 
Alternate on the Interagency Standard Application Task Force. 

Several staff members continue to work with the Office of the Associate 
Director for Extramural Research and Training, NIH, in preparing materials for 
use in the grants program, for example, revising instructions to adapt current 
application forms to new policies or revising forms to conform with new policies; 
and developing manual issuances to implement new PHS policies. 

On May 15, 1974, a reorganization of the Research Grants Review Branch was 
put into effect to enable the Division to effectively handle a material increase 
in DRG's responsibilities for processing and reviewing applications for grants 
and awards for research and training. ^^ 

The reorganization abolished the Research Grants Review Branch and 
established two new branches: (1) the Scientific Review Branch, with responsi- 
bility for day-to-day management of review and evaluation activities, and 
(2) the Referral Branch, with responsibility for day-to-day activities involving 
receipt, assignment, and processing of all centrally received applications. 

The Division's formal employee training program continues to cover both 
short-term needs and long-range career plans. Fourteen employees are attend- 
ing Federal City College under the Upward Mobility Program; 16 employees have 
attended or are planning to attend the Staff Training Extramural Program (STEP); 
one employee was accepted as an NIH Management Intern, and two employees are 
participating in the STRIDE Program. Other training included participation in 
the Employee Executive Training and the NIH Development of Potential Executives 
Program. 

Of the 598 training courses requested during the year, 334 were approved, 
260 were completed, 21 are in progress, and 43 are pending. The slight down- 
ward trend from last year reflects the lower DRG employment ceiling for this 
fiscal year. 

Members of the Opportunity Program (TOP) Committee formed part of an ad 
hoc committee appointed by the Director to review and prepare comments and 
recommendations on proposed revisions of both the Division and NIH Merit 



Promotion Flans. 

Committee members also attended NIH EEO Council meetings and a seminar 
held by the NIH EEO Office for supervisors and EEO functionaries, and at the 
request of the Division's Equal Employment Opportunity Counselor, TOP 
submitted recommendations for inclusion in a DRG Equal Opportunity Report to 
employees. 

Two members of the Committee were invited by the Employee Relations and 
Recognition Branch, 0PM, to speak to employees on transportation, housing, 
employee insurance, and other topics of interest. 

Most members of the Committee attended a 2-day orientation program held 
by members of the DRG Personnel Office on the functions of the Personnel Office 
as they relate to anployees and to management. 

A film showing, "Prejudice," was sponsored by the Committee for Westwood ■ 
employees in the belief that films such as this help to stimulate an awareness 
of prejudices and how to cope with them. 



TV 



> 



GRANTS ASSOCIATES PROGRAM 



The Grants Associates Program is completing its 12th year as a source of new scien- 
tific administrative talent for the National Institutes of Health. Fiscal Year 1974 has been 
a year of self-examination and evaluation for the Program. 

In Fiscal Year 1974 the Grants Associates Board began discussions on ways in which 
the Program could be strengthened and made more relevant to the present, and possible 
fu^'ure, extramural environment of the NIH. A need for better utilization of B/l/D 
Coordinators was recognized and as a result a plan was developed and submitted to the 
Associate Director for Extramural Research and Training for comment. In the same vein a 
"Contingency Plan" was formulated, and approved by ADERT, for the placement of GA 
graduates during periods of economic stress. A general planning committee has been 
formed to make an assessment of the extramural activities of the NIH, both grants and 
contracts, and to make recommendations to the Board as to how the Program cnn best 
serve the extramural needs of the B/l/Ds. 

An advertisement concerning the Program was placed in the February 15, 1974, 
issue of Science magazine. Nearly 400 inquiries were received within 60 days as a direct 
result. Also, the Executive Secretary attended the Federation of American Societies of 
Experimental Biology meetings in Atlantic City, N.J., in April to recruit for the Program. 
Forty-four people were interviewed, 14 of whom were given application kits. Approxi- 
mately 100 job seekers asked to discuss the possibilities of employment at the NIH. The 
National Institute of General Medical Sciences was assisted in its quest for employees by 
making the resumes of those seeking positions available to them. 

By April 30, 1974, the Grants Associates Program had processed 516 inquiries 
regarding the Program. Two hundred and thirty-two applications were received, part of 
which went directly to the Civil Service Commission for processing. Twenty-seven 
applicants were reviewed by the Grants Associates Board. Eight accepted invitations to 
join the Program. Later, for various reasons, two of these had to decline the appointment. 



GRANTS XNQUIRIES SECTION 



The name of the DRG Information Section was officially changed to the DRG 
Grants Inquiries Section (December 18, 1973), with the approval of the Director, 
NIH, and in compliance with the Secretary's directive to reorganize the public 
affairs function into a central organization in each bureau of the Department. 

As a service component of the former NIH information organization, the 
functions of the Grants Inquiries Section were not compatible with those 
functions established for public affairs personnel. This was the major 
reason for management's decision to make the Section a non-public affairs 
component . 

The reorganization and subsequent reduction in the niunber of public 
affairs personnel also led to a reduction in the number of internal and 
external periodicals and newsletters. The Division of Research Grants was ordered 
to cease publication of the NIH/DRG Newsletter , a monthly publication designed 
to keep grantees informed on changes in policy, procedure, and management, and 
also the DRG Personnel Items , a monthly publication distributed internally to 
keep DRG staff Informed. 

When application control centers were established January 1, 1974, the 
supply and control of application forms for research project support was 
transferred from the NIH to its grantee institutions. The Grants Inquiries 
Section was designated as the responsible NIH unit for maintaining and updating 
the listing of central control offices in the grantee institutions and for 
supplying the offices with the appropriate forms (398 and 2006-1). 

In March 1974, the Director designated the Grants Inquiries Section as the 
responsible DRG unit for mailing and billing inquirers for fees involved in 
searching, reproducing, certifying, and forwarding the materials requested under 
the provisions of the Freedom of Information Act. 



OFFICE OF RESEARCH MANPOWER 



At the beginning of FY 1974, the Office of Research Manpower was engaged in 
operations involving the phaseout of the NIH training programs. During that year all three 
programs (training grants, fellowships, and research career development awards) were 
reinstated as a result of the release of Fiscal Year 1973 impounded training funds, but no 
new applications were accepted in these programs. In addition, two training programs were 
initiated under the direction of Secretary Weinberger in a new DHEW research manpower 
pogrom. Also, as a result of the transfer of the Research Career Development Program to 
research grant funding, applications were solicited for submission by June 1 , 1974. In all 
of these areas, the Office of Research Manpower has been directly involved in developing 
program policy and announcements, modifying and preparing applications materials, 
providing information and application kits, contacting previous applicants, and processing 
applications for these programs. 

The details of the new DHEW research manpower program were released in November 
1973. Approximately $30 million was made available for Fiscal Year 1974 to the National 
Institutes of Health (NIH) and the Alcohol, Drug Abuse, and Mental Health Administration 
(ADAMHA) to support two programs, the Individual Research Fellowship and the Institutional 
Research Fellowship Awards. 

The first deadline for these two programs was January 15, 1974, but this was later 
extended to February 1 , 1974. Approximately 3,300 applications were received for both 
the NIH and ADAMHA under the Individual Research Fellowship Program and 210 under 
the Institutional Research Fellowship Program. These figures include applications reactivated 
from the January 1973 and February 1973 deadlines. 

The processing of applications was directed by the Office of Research Manpower. 
Because of the number of applications and the short time to process them, ORM staff was 
supplemented by other DRG personnel as well as some institute personnel . When the 
February 1 deadline was over, the ORM processing personnel were transferred to the Project 
Control Section, Research Grants Review Branch, DRG. In the future, all training appli- 
cation processing will be handled in that Branch. 

Regardless of the resurgence of the training programs, the receipt and processing of 
all types of applications during the 12-month period from April 1973 through March 1974 
declined 29 percent from 1 1 ,087 applications to 7,833 applications. The competing 
applications during this period decreased 35 percent from 5,791 to 3,771 . The noncom- 
peting applications decreased 23 percent from 5,296 to 4,062 applications. There was an 
overall decline in the number of training grant and research career development award 
applications received of 38 percent (4,937 to 3,069) and 39 percent (1 ,796 to 1 ,097) 
respectively. This was mainly because of the decline in competing applications, although 
noncompeting applications also declined. There was a decline of 13 percent (4,354 to 
3,767) in the number of research fellowship applications received. The decline was 
smaller because of the 3,000 competing applications received in the February deadline. 



Of the total applications received in the Office of Research Manpower, 25 percent 
(1 ,941) were directed to the Alcohol, Drug Abuse, and Mental Health Administration. 

Now that the programs have been reinstated, one of the immediate concerns of the 
Office of Resea7ch Manpower will be the revision of application and program material. 
The Chief of the Office is the chairman of a drafting committee for the revision of the 
fellowship applicaficn, H\n 1975-1 (formerly PHS 416-1). The comm^ I It-;*- !. working for 
a June 1 target date for completion of a revised form. Application forms for the other 
programs will also be reviewed for possible revision. In addition, the numerous policy 
booklets and award processing forms will have to be reviewed and reissued in the light of 
the changes in the programs. 

The Chief of the Office chaired a committee to develop a manpower report form to 
obtain annual information about the NIH research grant and contract supported manpower 
pool. Early in December forms weresent to principal investigators of NIH research grants ■ 
requesting them to complete the form at the appropriate time so that this information could 
be available for assessing the country's biomedical manpower needs. Contractors and 
grantees will be required to submit these forms annually on the award anniversary dates. 



C 



1 



10 



ADMENISTRATIVE BRANCH 

The study to streamline the previous method of monitoring the scientific 
evaluation grant expenditures was completed and a new computer method has been 
operational since July 1973. A monthly cost analysis is produced for manage- 
ment and evaluation purposes, which provides DRG staff with a detailed cost 
analysis of each study section and committee on a timely basis. Additional 
management repcrts are provided by the computer for purposes oi administering 
these funds. 

Following the recommendation of the Reference Room Committee, the 
Reference Room recently acquired more than 50 new texts covering a wide range 
of scientific subjects, and significantly increased the number of its new 
journal subscriptions. In addition, the card catalog is being completely 
reorganized so that all DRG-owned books, including those scattered in various 
offices in the Westwood Building, will be classified by subject, author, and 
title. It is expected that the usefulness of the Reference Room will thereby 
continue to increase. 

The Special Services Section provides clerical and automatic typing 
assistance for DRG and NIH institute/division staff. Three new automatic 
typewriters using magnetic tape and magnetic cards are in use in the Section. 
Use of these machines has enabled personnel to complete more than 2,000 letters, 
8,000 mailing labels and 300 Summary Statements. In addition to numerous other 
small jobs, the Section staff has assisted extensively in other offices. The 
staff has also given individual typing instruction to DRG employees, excluding 
Section staff, under the Upward Mobility Program. 

The Travel Section provides information and assistance for DRG personnel 
and outside consultants traveling for the Government. During the past fiscal 
year, they processed and forwarded for payment approximately 4,000 travel 
vouchers for consultants who serve on the various study sections. These 
vouchers total over $2 million. Another $250,000 was spent to pay travel costs 
on approximately 700 vouchers for DRG travelers and other Government employees. 

The DRG Mail Room received and processed approximately 25,000 research 
grant applications; 300 NLM grant applications; and 11 construction grant 
applications; and a large volume of supporting docimients, letters, and 
publications. In addition, the Mail Room assumed the responsibility for 
handling training grant and fellowship applications. 

The Office Services Section compiled and handled an average of 9,000 
grant application kits of all types and mailed 9,500 miscellaneous packages a 
month during the period under review. The Section also provided planning and 
assistance in accomplishing several major moves within the Division; acquired 
and maintained equipment, furniture and supplies, and provided duplicating 
services for Division personnel. 



--< 



11 



INSTITUTIONAL RELATIONS BRANCH 

The Institutional Relations Branch administers the Department of Health, 
Education, and Welfare policy on the protection of human subjects and the 
DHEW policy on animal welfare. Other responsibilities of the Branch include 
establishment of eligibility to serve as a grantee; establishment of 
eligibility for waiver of equipment accountability under PL 85-934; negotia- 
tion of successor in interest agreements; and liaison with OS-DHEW with 
regard to responsibilities under Title VI of the Civil Rights Act. 

The Branch prepared the NIH/DRG Newsletter until its discontinuance in 
December 1973. The Branch continues to disseminate information on NIH- 
supported conferences. 



Protection of Human Subjects 

The Branch has negotiated general assurances with about 700 institutions 
as required by DHEW policy on the protection of human subjects. In addition, 
the Branch has negotiated approximately 1,000 single project special assurances 
with institutions having few active projects involving human subjects. 

The Branch has been the focal point for revision of the present policy. 
This has involved receiving, collating, and evaluating comments from some 200 
private institutions and agencies and redrafting the issuance in the form of 
final rule-making. It is expected that the regulations will be issued before 
the end of this fiscal year. 

The Branch has acted in an advisory and administrative capacity to the 
special study group appointed by the Director, NIH, and charged with reviewing 
and recommending policies and special procedures for the protection of 
children, prisoners, and the institutionalized mentally infirm in research, 
development and demonstration activities. The report of this study group was 
published in draft form in the Federal RegisterMuring the fiscal year. Some 
500 public comments were received and analyzed, and about 150 controlled 
correspondence letters were requested by congressmen and senior HEW officials. 
Presently, the Branch is providing continued staff back-up to the members of 
the special study committee in their efforts to formulate a Notice of Proposed 
Rule-Making which is expected to be issued this calendar year. 

At the request of the Assistant Secretary of Health, the Branch has 
prepared a revision of a draft Federal policy applicable to activities involving 
human subjects supported by all or any Federal agencies. This has involved 
conferences with representatives of other Federal agencies at the policy- 
making level, and has aimed at producing uniform Federal administrative 
practices by the end of 1974. 

During this fiscal year, staff members organized and participated in 
systemsaudit visits to 20 grantee institutions. These visits are designed to 
determine the adequacy with which grantee and contractor institutions are 
carrying out their responsibilities within the terms of the DHEW policy and to 
initiate negotiations for revision of the written assurances to reflect 
improved performances by these institutions in the protection of human subjects. 



■-1 



13 



Flans are underway to increase the number of these visits during the balance 
of this year aad in the future. 

Tuskegee Syphilis Study 

Two members of the staff were detailed for 8 months to the Office of the 
Assistant Secretary for Health, DREW, to serve as staff to the Tuskegee 
Syphilis Study Ad Hoc Advisory Panel. 

Welfare of Laboratory Animals 

The Branch collaborated with Department of Health, Education and Welfare 
components in publication of a policy statement on animal welfare, and with 
the National Institutes of Health on revision of policy and establishment of 
rules to implement departmental requirements. This policy now applies to all 
warm-blooded animals used under DHEW supported grants and contracts, and 
enhances the Branch's ability to carry out its assigned responsibilities. 

New or revised assurances of compliance with the new policy have been 
negotiated with over 600 institutions, essentially all those using animals in 
research supported by NIH grants. Institutions receiving support from other 
DHEW components and through contracts are submitting assurances as required. 
NIH contracts now contain a clause requiring compliance with the policy. The 
Branch will continue to assist DHEW programs in the application of policy 
requirements to specific programs and projects. 

Citizen's complaints and congressional inquiries concerning several 
grants have been answered. No grantees or contractors have refused to submit 
or revise assurances or to answer questions concerning their laboratory 
animals procedures. 

Successor in Interest and Name Change Agreements 

During the year, the Branch has written the NIH policy and procedure for 
the negotiation of "Successor in Int'^rest and Name Change Agreements" pertain- 
ing to all grant programs. These agreements are necessitated as a result of 
legislative or other legal action affecting the status of a grantee institu- 
tion,, such as mergers, divestitures, or other corporate changes. 

Three agreements are pending at the present time. When these have 
been concluded, each institute and(or) division will be notified of action 
taken. 

Institutional Control of Research Grant Application Forms 

During the past 3 years, 36 major institutions have participated in a 
study to consider the recommendation that all renewal and continuation 
application kits be routed through one control point. Follow-up studies from 
time-to-time indicated that the project was being well received by administra- 
tors and that specific internal benefits were being realized, i.e., lines of 
communication were established which never existed before, better control of 
budgetary requests was effected, checks for accuracy and timely submissions 

14 



1 



were facilitated. 

In view of the willingness of grantees to assume more responsibility in 
the management of grant programs, the Branch developed the policy and 
procedures to include all grantees under the system of application control. 
This was effected on January 1, 1974. In addition, it is expected that NIH 
will realize considerable savings in the cost of applications since the 
distribution ot kits can be confined to one source in the Division. 

Equipment Accountability 

The Branch continues to serve as the focal point in NIH for carrying out 
the provisions of PL 85-934, which consist of determining institutional 
eligibility under the law for "waiver of equipment accountability." 



Part 11, Volume 38, No. 221, November 16, 1973 



■- -A 



J 



\ 



15 



c 



RESEARCH ANALYSIS AND EVALUATION BRANCH 

The project, "Support of New Principal Investigators by NIH: 1966 to 
1972" was completed and published in the July 20, 1973 issue of Science . 
Requests for reprints (4,000) and the interest in this publication has led to 
a continuation of the project and similar studies, especially those having to 
do with flux in the population of principal investigators. 

Analyses of NIH approval and award rates and key factors affecting award rates 
in certain biomedical disciplines were the subject of several briefings for 
OD-NIH staff. Other analyses of the competing research grant programs focused 
on budget trends over the past decade. A report charting the survival 
characteristics of grants in selected research programs has been completed and 
will be available in the near future. 

The Research Analysis and Evaluation Branch contributed to the effort to 
estimate the NIH support of applied research projects and development projects 
by devising classification purpose codes for research contracts. Another 
result of this effort was the identification of contracts which provide support 
for research resources and others which identify the NIH information dissemina- 
tion system through the contract mechanism. RAEB continues to code all 
research contracts according to the CSCS code. 

Dr. Julio Cesar, an official of the Mexican Government, spent 3 days 
studying the DRG's information systems and the operation of the Research 
Analysis and Evaluation Branch to obtain information that would assist the 
Mexican biomedical research establishment in their classification and 
organization of research support programs, especially with respect to record 
keeping, analyses and evaluation. 

The Branch continued furnishing information requested by several inter- 
agency groups or committees. This year NIH was host for the Spring meeting of 
the Federal Interagency Chemistry Representatives for which arrangements were 
made by the RAEB staff. Broad questions, especially those that are scientific 
discipline oriented or those that concern various issues or problems spanning 
several or all of the institutes and divisions are typical of those that fall 
within the purview of the Branch. 

A staff member devised a low-cost system of automatically retrieving 
Notices of Research Projects from a computer tape to provide substantive 
information about the content of research proposals. Documentation of this kind 
has been found to be a valuable supplement in various analytical studies. 
Similarly, the system has proved to be useful to the Research Documentation 
Section of the Statistics and Analysis Branch, which has similar needs. 

In response to a request to all of the NIH institutes from the Department 
of Internal Medicine, Yale University, the Branch prepared and documented an 
NIH coordinated response on estimates of available minority and women manpower 
pools in the sub-specialties of internal medicine. 

Other specific non-routine requests for information were as follows: 



■■^ -1 



17 



Acupuncture research 

Arctic research (principally adaptation to harsh environment and behavior j 

problems) 
Care of animals in biomedical research; response to criticism of 

experiments described in the scientific literature 
Diagnostic nuclear medicine 

Identification of projects involving marin? manmals 
Marine research 

Research involving the plant sciences 
Support of research in schools of pharmacy 
Research grants related to rehabilitation 
Research in advanced computer technology 
PHS projects (principally having to do with alcoholism, drugs, and driving) 

related to highway transportation research 
Nutrition 
Hematology 

In compiling the above reports, the Branch made extensive use of the DRG 
information systems, including CRISP, IMPAC and the CSCS codes. 

One senior staff member attended a health-scientist management training 
course in Atlanta; another attended the STEP module on science and public 
policy in Reston, and in February the Branch Chief attended the Brookings 
Institution "Policy Conference for Science Executive" held in Williamsburg, Va. 
Two staff members are attending the Upward Mobility College, and one received 
the Ph.D. frcn- Catholic University. Nimierous individual training courses were 
taken by other staff members, especially in the area of computer science 
techniques. 



18 



RESEARCH GRANTS REVIEW BRANCH 

During Fiscal Year 1974, the Research Grants Review Branch processed and 
reviewed an unprecedented volume of applications. In February, March, and 
April 1974, the Branch received, referred, and reviewed a near-record number 
of applications for research grants and, in the same period, assigned and 
reviewed approximately 3,000 applications for fellowships. Competing and non- 
competing applications processed by the Branch during this lisc&i year totaled 
25,448, including 2,976 applications for individual fellowships and career 
development awards and 157 for institutional fellowships. Of the total, about 
16,400 were competing applications assigned for technical merit review. 
Approximately 80 percent of the research applications were assigned to NIH. 
The Branch provided the initial scientific review for about 90 percent of the 
NIH competing applications for research grants and for all of the NIH applica- 
tions for individual fellowships and career development awards. 

A table showing the distribution of applications processed in fiscal year ' 
1974 is appended to this report. 

February 1, 1974, was the first deadline for two new DHEW research 
manpower programs: the Individual Research Fellowship and the Institutional 
Research Fellowship Awards. In the assignment, processing and review, within 
a short time-frame, of the approximately 3,000 applications received, difficult 
administrative problems were encountered. Problems involved personnel shortages, 
overcrowded offices, overloaded equipment and facilities, overtaxed services, 
and so on. Efforts are being made to deal with these problems before the fall 
review cycle begins. 

In September 1973, a revision of the National Institutes of Health 
Referral Handbook was issued. It is designed as an internal working guide for 
the Referral Office, DRG, in the assignment of grant applications to awarding 
agencies of the Public Health Service. 

A report from the Radiation Study Section's April 1972 workshop, 
"Ultrasonics in Medicine," was published in December: "Ultrasound in 
Diagnostic Medicine," Radiology , Vol. 109, No. 3, pages 737-742, December 1973. 

Several articles written by a staff member of the Branch, Dr. Rob S. 
McCutcheon, have been published in Pharmlndex : (1) "Drugs of the autonomic 
nervous systesa* Part I — Cholinergic drugs and related blocking agents," 
Pharmlndex 15:11A, 1973; (2) "Drugs of the autonomic nervous system. Part II — 
Adrenergic drugs and related blocking agents," Pharmlndex 15:12A, 1973; 
(3) "Drugs used in diagnosis," PharmEndex 16:2A, 1974; and (4) "Oral contra- 
ceptives," Pharmlndex 16:5A, 1974. 

Dr. Bemice S. Lipkin presented a paper entitled, "Textured Parameters 
Related to Nuclear Maturation in the Granulocytic Leukocytic Series, "at the 
Engineering Foundation Conference on Automated Cytology at Asilomar, 
California, December 2-7, 1973. The paper, co-authored with Lewis E. Lipkin, 
has been accepted by the Journal of Histochemistry and Cytochemistry , Williams 
and Wilkins Company, publisher. 



19 



Affected by budgetary and personnel limitations, the study sections 
sponsored only five workshops this year. Study sections conduct workshops and \ 
conferences to survey the status of research in their areas, enhance reviewer 
competence, and stimulate research in neglected areas. Two workshops were held 
in January 1974, and three in April. 

On January 9 and 10, the Endocrinology Study Section conducted a workshop 
in Silver Spring on "Molecular Processes in Secretory Cells." This workshop 
was organized to summarize recent advances in molecular biology that might 
relate to hormonal control of the function in secretory cells. The workshop 
vias organized into six subsections: (1) Cell Membrane; Structure and Function, 
(2) Biology of Steroid-Hormone Receptors, (3) Protein Synthesis-Transcription, 
(4) Protein Synthesis-Translation, (5) Protein Kinase: Isolation and Function, 
and (6) Stimulus Secretion Coupling: Molecular Relationships. 

The workshop was of extreme interest to the participants and observers and 
generated a great deal of discussion on new concepts emerging from this field. 
The plasma cell membrane was discussed in terms of its components and its 
tremendous fluidity. The point was well made that the plasma membrane is 
actually in a dynamic state. Recent studies on intracellular membranes, also 
presented, concluded that membrane segregation is maintained during communica- 
tion betweein cellular compartments. The hormone receptors were discussed in 
some detail in terms of their physical-chemical characteristics, their 
nuclear binding sites, and their biology as related to hormone induction of 
specific new processes. Effects of hormones on gene transcription were noted 
and new techniques emerging from this field were emphasized. It was evident 
that future work in this field should be coupled with that of hormone receptors 
and it should eventually be learned how a hormone receptor directs changes in (^ 
readout of certain gene elements. Whether the hormone receptor complex affects 
polymerase activation, polymerase binding to DNA, polymerase initiation of 
transcription, polymerase propagation of transcription, or RNA chain release 
chain processing, or chain transport will probably be determined in the next 2 
years. The mechanisms relating to translation of messenger RNA were discussed 
in detail and the new systems available for studying endocrine relationships 
in terms of specific mRNA were reviewed. The translational assay systems are 
now of sufficient sensitivity to detect the presence of only a few molecules 
of mRNA. Major progress is being made towards purification of the regulatory 
and catalytic subunits of protein kinase. Much work is currently in progress 
to determine the substrates for phosphorylation during hormone action — a key 
area on which investigators should focus in the next 2 years. The role of a 
stimulus secretion coupling and its relation to ions, temperature and pH were 
reviewed. Mechanisms to explain cellular secretion and export were presented. 
This is also ah exciting area of endocrine research, and methodologies now 
exist to answer a number of long standing questions. 

The other January workshop took place in Bethesda on January 16, 1974, 
when the Nutrition Study Section and invited speakers reviewed the topic, 
"Carbohydrates." The influence of dietary carbohydrate on health is receiving 
considerable attention. This interest is fairly recent and the significance 
of implications which have been made is not currently known. Refined sugar 
has been implicated as contributing to the development of cardiovascular 
disease and hyperlipemia. Preliminary evidence suggests that intakes of fiber 

20 



influence the development of diverticulosis and colonic cancer. There is 
considerable interest in the role of trace elements in carbohydrate metabolism. 
This workshop considered primarily the metabolic consequences of altered 
intakes of refined sugar and of fiber. The following topics were discussed: 
(1) sucrose in health and disease; (2) interrelationships of trace elements 
and dietary carbohydrates; and (3) the role of complex carbohydrates. 

After taking inventory of some of the effects of feeding sucrose or 
*^ructose to experimental animals and man, discussion of the first topic was 
directed to the findings of some investigators that there is a strong 
correlation between fat intake and sugar intake. In certain patients given 
sucrose when on a diet high in polyunsaturated fats and low in cholesterol, 
investigators found no induction of hypertriglyceridemia, but they showed a 
striking hypertriglyceridemia following sucrose when they were eating a 
saturated fat, high cholesterol diet. These experiments illustrate the 
importance of studying not only what effects individual diet constituents 
have, but how they can interact to produce different results. 

Presentation and discussion of the second topic emphasized the role of 
manganese, zinc, and chromium in carbohydrate metabolism. Manganese is not 
only involved in the synthesis of mucopolysaccharides, but it has a function 
in glucose metabolism as well. Manganese-deficient guinea pigs have an im- 
paired glucose tolerance test which can be normalized by manganese supplemen- 
tation, and manganese was shown to have strong hypoglycemic activity in one 
diabetic subject. Zinc deficiency also results in deterioration of glucose 
tolerance in rats, as compared to pair-fed controls. These changes are in 
part due to a reduced secretion of insulin in response to the glucose load, 
but, in addition, due to a decreased response of the zinc-deficient rats to 
insulin, as shown by a slower decline of serum glucose levels after insulin 
injections. That zinc may be a part of endogenous insulin has been postu- 
lated by several investigators, but, if there is such a relationship, it is 
probably restricted to the storage form of the hormone within the pancreas. 
Chromivmi is closely related to the peripheral action of insulin; this element 
has been shown to potentiate the action of insulin in vivo and in vitro . 
Consequently, chromium deficiency results in a decreased response of the 
organism to its own and to exogenous insulin, and in impaired glucose 
tolerance. It is suspected that the consumption of excessive amounts of 
sucrose that furnish no appreciable chromium can result in substantial 
chromium losses, but these effects cannot yet be quantified. 

In the third presentation problems relating to definition and analysis 
of complex carbohydrates were described. Crude fiber has been defined by 
international agreement of the Association of Official Agricultural Chemists 
as the portion of food that resists extraction first with sulphuric acid and 
subsequently with sodium hydroxide. The human alimentary enzymes divide the 
carbohydrates differently. Man can hydrolyse by his digestive enzymes the 
vegetable cell contents, carbohydrates, fat and protein; but the structural 
polysaccharides and lignin present in the cell-wall resist hydrolysis. 
These remnants have been defined as dietary fiber. This complex group of 
substances surrounds the starch, fat, and protein of all natural plant foods 
while digestion occurs in the small intestine; then these remnants are 
hydrolysed in varying degrees by bacteria in the large bowel. Hypotheses and 



1 



y 



21 



evidence as to protection against diseases of the large bowel, diabetes, 
ischeniLc heart dlL.ease, and gallstones, which relatively high intakes of fiber 
may afford, were discussed. 

On April 16 and 17 in Bethesda, the first spring conference was held. 
Entitled, "Developmental Hutian Behavior Genetics," it was sponsored by the 
Developmental Behavioral Sciences Study Section and the National Institute of 
Child Health and Iluiaan Development. Human behavioral genetici^sca <swd 
developmental behavioral scientists met to discuss methods and strategies for 
the improvement of research in developmental human behavior genetics. The 
following subjects were presented and discussed: (1) state of the art in 
developmental himian behavior genetics and implications; (2) genetic mechanisms 
in human behavior development; (3) quantitative genetic perspectives: 
implications for human development; (4) gene -environment interaction in human 
behavioral development; (5) empirical methods in quantitative human behavior 
genetics; (6) populations for the study of behavior traits; (7) use and 
misuses of behavior genetics: ethics of civil rights and informed consent; 
and (8) behavior genetic counseling. Several publications from this conference 
are planned. 

"Immune Reactions in Invertebrates" was the subject of a workshop convened 
by the Tropical Medicine and Parasitology Study Section on April 17 and 18, 
1974, in Bethesda. The workshop explored in depth several of the mechanisms 
in invertebrate immunity which are real and potential determinants of 
successful parasite transmission by vectors. Equivalent phenomena were compared 
in different vectors and reservoirs (insects, ticks, snails) and comparisons 
made of similar mechanisms operative in vertebrate immunity. 

The first session, on the invertebrate gut as a barrier to invading 
parasites, included the following topics: (1) barrier structures of the gut 
wall; (2) infectious process of insect pathogenic viruses in arthropod gut; 
(3) interactions of vector with vertebrate pathogenic viruses; (4) bio- 
chemical aspects of virus infection in insect gut wall; (5) parasite 
penetration of peritrophic membranes in vectors; and (6) evidence of genetical 
control of invertebrate immunity and if.s field significance. 

A second session, on analysis of invertebrate immunity, examined cellular 
components and hemolymph components in invertebrate immunity. In the final 
session on vector destruction of parasites, encapsulation, melanization, and 
host hormones were discussed. Following these topics, vertebrate and inver- 
tebrate immune mechanisms were compared. Information gathered during the work- 
shop is being prepared for publication in book form. 

The third spring workshop, sponsored by the Reproductive Biology Study 
Section and the Center for Population Research, NICHD, was held in Bethesda, 
April 27 and 28. The uterus is the all important organ for conception and 
pregnancy. A growing number of applications deal with its physiology. It is 
involved in sperm transport and probable capacitation in some manner. It is 
the organ involved in implantation, after which it serves as the "home" for 
the developing fetus until parturition. The cyclic phenomena of the uterus 
relate to the physiological and psychological well-being of the human 
female. 



2,2 



I 



At this "Workshop on the Uterus" presentations and discussion were focused 
on: (1) the structure of the uterus,, including epithelium, stroma, and 
decidualization; (2) the uterus as a model of hormone action, including 
physiology of estrogen receptors, receptor structure, carbohydrate metabolism, 
and synthesis of specific RNA and protein as a result of hormones; (3) the 
uterus as a muscle, in':luding hormonal control of Ca transport in myometrial 
sarcoplasmic reticulum and the adenyl cyclase system, and (4) other aspects, 
including uterine fluid proteins and clinical status of prastr-^landins as 
effectors in the uterus. 



J 



23 



APPKLCATIONS PROCESSED BY REFERRAL OFFICE, RGRB 
Fiscal Year 1974: March 16, 1973 - March 15, 1974 



APPENDIX 



COUNCIL Nov. 


1973 


March 1974 


June 1974 




CCMPETING 






Types 1, 2, 3 NIH 

HSMHA 
FDA 


- 3,324 

713 

25 


3,358 

641 

28 


3,925 

1,230 

26 


TOTAL 


4,062 


4,027 


5,181 


PL 480 

Institutional Fellowships 
Career Development 
Individual Fellowships 


6 


3 


3 

157 

51 

2,925 



Subtotal 



Type 5 

Interim-Regular 
& Cross Fiscal 



Subtotal 



4,068 4,030 

NON -COMPETING 
(All 3 PHS components) 
3,708 2,199 

429 251 

4,137 2,450 

TOTALS 
(All 3 PHS components) 



Competing 
Non-Competing 



TOTAL 



4,068 
4,137 

8,205 



4,030 
2,450 

6,480 



Grand Total for FY 1974 (Competing and Non-Competing) 



8,317 



2,121 

325 

2,446 



8,317 
2,446 

10,763 



May 3, 1974 
RGRB 



24 



STATISTICS AND ANALYSIS BRANCH 

In Fiscal Year 1974, the Statistics and Analysis Branch placed increased emphasis 
on the "wholesale" dissemination of infonnation and reports. The practice of providing 
selected data from the Information for Management Planning Analysis and Coordination 
(IMPAC) and Computer Retrieval of Information on Scientific Projects (CRISP) Systems on 
magnetic tapes to BIDs was continued with all but one institute availing themselves of this 
service. To expand the BIDs' understanding of the Central Data System and permit them to 
fu.Jy utilize the magnetic tapes provided, the Branch increased its efforts toward the 
orientation of BID personnel by expanding its formal training programs on the IMPAC 
system. These courses highlight and describe the data content and format of information 
recorded in the IMPAC system and develop proficiency in the use of the Inquiry and 
Reporting System. In addition, a system was developed to generate special subsets of 
infonnation contained in the CRISP files describing the scientific content of research 
grants and contracts. These tapes can be utilized by the BIDs to meet their individual D 

scientific reporting requirements. 



Efforts were continued to respond to requests from institutions for development of 
their information systems in the grants and contracts programs. By providing such assistance, 
SAB seeks to interact with these institutions in a manner that will: 



^ 



R 

R 

/ 

-A 



1 . promote the possibility that reductions in future data-capture workload can be 
effected through the development of data interchange conventions and systems q 
that will be compatible with the IMPAC and CRISP systems, and 

R 

2. improve the data integrity of the DRG information systems through the transmittal 
of information to, and subsequent feedback from, these institutions. ^ 

In line with the Branch's service concept, it continued its attempts to be more 
responsive to user needs in spite of reduced personnel availability. 

The Branch continued its support of the NIH Affirmative Action Plan for Equal • 

Employment Opportunity through an active employee training and development plan. T 

Sixty-nine Branch employees participated in 53 different training courses and seminars. 
Special training programs in which Branch employees were involved included the Upward « 

Mobility College, the attendant Special Career Development Proposal Workshop, and the 
STEP Continuing Education Program. The three student trainees recruited under the Federal 
Junior Fellowship Program in 1973 continued their second year of training. Other special ' 

programs in which employees participated included the Consumer Education Course and ' > 

the Retirement Planning Course. i 

■' 

Significant activities and major accomplishments are discussed below. ' f< 

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 implementation of new applications. Design of | 

25 



ihe manpower reporting system and expansion of the Committee Management Information 
System were two m«jor areas of Involvement. These areas are detailed in the reports of 
the Data Processing Section and the Special Projects and Services Section. A new com- 
puterized system for the preparation of the R esearch Grants Index Volume 11 was completed 
and the publication was printed by means of the GPO Linotron process utilizing magnetic 
tapes. Additionally, efforts were expended in implementing the new counter-signature 
system for awards, revarT'oirj ttte assigiiment system for Fiscol Year 197,'l C^^nrion Account 
Numbers by program areas, initiating the centralized mailing of continuation application 
kits for research programs, introducing a new budget category identifying costs for third- 
party contracts under consortium grants, incorporating P„L. 480 (Foreign Currency) Programs 
into the overall information system, and establishing a computer system for reporting 
contract summaries to the Science Information Exchange. A major project was also 
initiated by the Section to study the feasibility of establishing a terminal system to be 
utilized by the BIDs in producing a Notice of Grant Award at their work sites. 

2. Data Processing Section . The Data Processing Section is responsible for (1) planning 
and directing a data processing program for the collection, compilation, interpretation, 
presentation and publication of statistical data pertaining to the extramural programs of 
the PHS; (2) developing, operating, and maintaining the NIH IMPAC system for the storage 
and retrieval of information of PHS extramural grant and contract programs; and (3) develop- 
inging, preparing and issuing various reports to theinitial review groups and institutes/ 
divisions necessary for or related to the review and award process. The following items 
highlight significant projects relating to the overall Section responsibilities: 

Impounded Fiscal Year 1973 Funds . Special procedures were developed in the 
Section to process awards issued from the released Fiscal Year 1973 impounded funds. The 
IMPAC System's update program edit criteria were modified to accommodate to the various 
ways the institutes are awarding these grants. New Common Accounting Numbers for the 
impounded funds were added to the IMPAC central table look-up system. A new data item 
called "impounded funds" was added to the IMPAC Open/t*ending file to identify grants 
issued from the Fiscal Year 1973 impounded f jnds. The new item is to be used in responding 
to inquiries about these funds. 

Resumfe of Transactions . A new system for distributing the Research and Training 
Grant Resumes of Transactions (ROT's) has been installed by the Data Processing Section. 
This new system employs the use of a computer-based address file and the Cheshire labelling 
method. The labels are prepared by computer on special paper and mechanically affixed 
to the cover sheets. The resumes are prepared in the Section and sent to the print shop for 
duplication along with the labelled cover sheets. After duplication, the ROT's are 
collated with the cover sheets and sent directly to the mail room for distribution. Prior to 
the advent of this system, thermofax labels, which were manually affixed, were used for 
ROT distribution . This method required approximately 44 hours of DPS employee effort 
each month, whereas the Cheshire method requires only 2 or 3 hours. 

IBM 3330 Direct Access Storage Facility . The Section converted its computer files 
from an IBM 231 Direct Access Storage Facility to the larger capacity IBM 3330 Direct 

26 



1^ 



Access Storage Facility. As a result of this conversion, the on-line storage capacity of 
the IMPAC System's files has increased from around 466 million bytes to over 800 million 
\ bytes. This increase in storage capacity enables additional IMPAC files to reside on-line 
and greatly facilitates processing. 

Manpower Repcrt Sya^m . A computer file was established for recording data con- 
toined in the new Mcnprv^sr Report Form (NIH-1749). These data ore to nid NIH in 
annually accessing the input of its research support on the Nation's biomedical and health 
related manpower. Two files will be maintained: (1) IMPAC-Open file to establish and 
maintain internal processing control (mailing, receipt, follow-up, and so on) and (2) 
Manpower Report file to store and report data on personnel who performed salaried and 
unsalaried work on research projects. Information stored includes such items as number of 
persons; manweeks of effort; and dollars. Personnel working on the project are also grouped 
by levels such as Professional - Non-Faculty; Pnafessional - in Training; Clinical Supporting 
Staff; Technical; and so on. 

Committee Management Infonmation System . A new Committee Management Infor- 
mation System containing information on NIH public advisory groups became operational 
in Fiscal Year 1974. The System maintains complete and up-to-date records on all NIH 
Advisory Councils and Committees and their members. It includes the processing of all 
documents concerned with the establishment, appointment of members, utilization, 
operation, and termination of NIH Committees; editing completed file for the semi-annual 
"NIH Public Advisory Groups" and other publications; and consulting with the Committee 
Management Office, OD, NIH, in developing procedures and handbooks. The computer 
system consists of two files. The Committee File contains information on the establishing 
y authority, statute number, number of positions authorized, number of scientific positions 
authorized, budget, date established, and other information of the Committee itself. The 
Appointment File contains biographical information on each of the committee members. 

Combined Research/Contract Narrative File . The Section is gathering detailed 
information and creating specifications t) allow the combining of narrative data from 
contracts and research projects into a single file. This file is ultimately expected to be 
incorporated into the routine query processes of the Research Documentation Section 
providing added reference to scope and objectives of projects in addition to general grant 
and key term information . 



Modifications made to IMPAC System during the year . 
(a) The Abbreviated File, a reduced version of the Per 



The Abbreviated File, a reduced version of the Pending/Open File, was 
established on line. The file is mode up of items that have a high probability 
of being used in reports. The principal advantage of this file is that it can be 
queried through the "B" Initiators by all users and provides them with faster 
turn-around at computer cost savings. The savings ore realized because the file 
size has been reduced, which results in a reduction of search time. 



27 



(b) Department codes were established in the IMPAC System for schools of higher 
education to provide consistency in reports using department names. 

(c) Other items of data added to the system were sex code of investigators, 1 1 
awarded budget categories, manpower control code, and impounded funds signal. 

3. Research Documentation Section (RDS) . The Section maintains a computerized disk 
storage and retrieval system, CRISP (Computer Retrieval of Jnformation on Scientific 
Projet-.s) 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 informa- 
tion 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 medi- 
cal research. 

The Research Documentation Section publishes annually as a "spin off of the CRISP 
file: 

(a) The Research Grants Index, which is 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 (2) research contract 
identification data and (3) project investigator information . 

(b) 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 (subproject) number of investigator, and individual institute listing of 
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. 

In addition, perfonning subject searches and producing Scientific Profiles or investi- 
gator listings on subprojects of program projects, center and other large grants is a unique 
feature of the CRISP system. 

A number of innovative features added to the CRISP System that have expanded its 
capabilities and streamlined operations include: (1) computer printout of individual 
project Scientific Profiles, immediately after indexing, on all type 1 (new) projects for 
mailing to the Principal Investigators. This has eliminated the laborious task of manually 

28 



typing the same information; (2) a new grant query format designed to print the term number 
to the left of each indexing term, for streamlining editing operations; (3) improved query 
logic, which provides greater ease and versatility of query formulations and output on 
subject searches; (4) inclusion of IPF Codes in the CRISP System, which allows for pro- 
duction of Institution Scientific Profiles by a single query rather than the cumbersome 
method used previously; and (5) computer preparation of Volume II of the Research Grants 
Index. (The Section is indebted to the Data Processing and Systems Planning Groups of 
SAB for providing the program and query logic, which made these cost reducing procedures 
posoible.) Other improved operations in the Section include a fully automated mailing 
list file for the Research Grants Index. 

Research Grants Index. For the first time the preparation of the Research Grants 
Index has been fully automated. Linotron tapes of both Volume I and Volume II were 
submitted to the Goverment Printing Office in December for publication (DHEW Publication 
No. (NIH) 74-200) in April 1974. 

Medical and Health Related Sciences Thesaurus . A revised edition of the Thesaurus 
was published and distributed on a request basis. Since the demand far exceeded the R 

number of copies available last year, additional numbers of the current edition were pro- 
duced. 



CRISP Services. The dramatic increase in both the number and variety of inquiries 



■-i 



for CRISP services is noteworthy. In addition to responding to hundreds of routine inquiries, 

the Section: (1) prepared Linotron tapes used in the creation of "miniature" Indexes for 

three institutes; (2) produced Institute Scientific Profile data reports for two institutes; 

and (3) furnished NIH-wide scientific program area data to responsible institutes. S 

An inexpensive method developed by the Research Analysis and Evaluation Branch 

links CRISP data with project narrative tapes, and substantially increases the options ! 

available to the users of the CRISP System by providing project summaries (upon request) ^ 

on demand searches. Further refinements of this capability are planned, which will 2 

incorporate narrative data directly into the CRISP System in a unified format. 2 

1 
4. Reports and Data Evaluation Section . The primary function of the Reports and Data 
Evaluation Section is the collection, storage, computer retrieval, presentation, and 

analysis of data on the extramural programs of the NIH and PHS for use in policy consider- \<\ 

ation, program planning, program analysis, and program management. In addition, the j; 

Section is responsible for the coordination of responses to inquiries about the extramural i ji 

programs received from the Executive and Legislative Branches of the Government and , 

non -Government sources. , 

K 
Publications. The following volumes of the annual multi-volume series on PHS 

Grants and Awards were issued: 

(1) PHS Grants and Awards: NIH Health Manpower Education, Port IV, and Food 
and Drug Administration, Part V, Fiscal Year 1972 Funds. 

29 



J 



(2) PHS Grants and Awards: NIH State and Organization Summary Tables, Part VI, 
Fiscal Year 1972 Funds. ^ 

(3) PUS Grants and Awards: Health Services and Mental Health Administration, 
Part VII, Fiscal Year 1972 Funds. 

(4) PHS Gra nts and Awards : NIH Research Grants, Part I, Fiscol Yeo- 1973 Funds. 

(5) PH S Grants and Awards: NIH Training, Construction, Medical Libraries, 
Part II, Fiscal Year 1973 Funds, 

(6) PHS Grants and Awards: NIH Research Contracts, Part III, Fiscal Year 1973 Funds. 

(7) PHS Grants and Awards: NIH Health Manpower Education, Part IV, and Food 
and Drug Administration, Part V, Fiscal Year 1973 Funds. 

(8) PHS Grants and Awards: Health Services and Mental Health Administration, 
Part VI, Fiscal Year 1973 Funds. 

The timely publication of the complete Fiscal Year 1973 series during the current 
year was an unprecedented accomplishment which greatly relieved the pressure for special 
reports and tabulations to answer inquiries on support to particular individuals, areas, 
and institutions. 

Data for the pocket reference book, Basic Data Relating to the NIH— 1974, were 
compiled In cooperation with the NIH Office of Program Planning. 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 Years 1967-1973, and participated with 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 July 1973, and subsequently to various additional audiences. The data were 
also issued, with an accompanying analysis, in a chart-book entitled, NIH Extramural 
Trends, Fiscal Years 1967-1973 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 Infonmation Activities." 



I» 



30 



< 



The CASE Report is an annual survey on 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 are 
also requested for institutions of higher education by program. 

The HSMHA portion of this survey was also prepared by this Section 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, by field of science, 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, by institution, by field of science and by 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 Office of 
Financial Management, the institutes/divisions, and the Office of Research Manpower, DRG. 

Inquiries. The Section responds to hundreds of requests for information each month 
from Federal agencies, NIH officials, other Government and non -Governmental organiza- 
tions. These requests are primarily for statistical and analytical information concerning the 
NIH grants and award programs and characteristics of grantee institutions contained in the 
IMPAC system. 

The inquiries range in complexity, as measured by man-hours, from several hundred 
to less than one per project. The Section has devoted considerable effort to the develop- 
ment of shelf, or reference listings, unpublished reports, and microfiche, to answer such 
inquiries. The Inquiry and Reporting System (a computer software facility) is the primary 
method for data extraction, manipulation, and hard-copy presentation of the information 
requested. About 8,000 queries were processed through the Inquiry and Reporting System 
for this purpose during fiscal year 1974. 

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 
infomiation 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 1,500 



-■-I' 



J 



31 



new institutions were added to the IPF. The IPF now contains about 20,500 records on 
institutions participating in NIH programs, as well as the programs of the Food and Drug ^] 
Administration and other agencies of the Public Health Service. 

During the year, a system for coding academic departments became fully operational, 
enabling consistent and accurate presentation of department names in academic institutions. 
The system was also used to select and tabulate records for specific kinds of departments, 
such as "surgery." 

Retrieval Methodology . Three IMPAC Inquiry and Reporting System (IRS) courses 
were offered by the Section. A total of 35 persons attended two basic courses, and an 
additional 6 attended a course in advanced applications. IRS is the primary instrument for 
extracting and reporting IMPAC data . 

About 8 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) has been developed as an informal, 
technical handbook 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 are distributed to DRG and institute/division personnel responsible for 
compiling IMPAC data. 

Graphic Arts . Approximately 1 , 100 pieces of graphic art work were completed by % 
the Illustrator in Fiscal Year 1974. The bulk of this work included: cover designs, charts, 
certificates, slides, signs, visuals, special exhibits, and illustrations for flyers and hand- 
books. 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 1967-1973 . 

5. Special Projects and Surveys Section . Fiscal Year 1974 was the Section's second year 
of existence as a formally established part of the Statistics and Analysis Branch. Its work 
focused on the collection and analysis of data concerning NIH extramural programs as aids 
to program operation and management. Performance of this function involved conducting 
surveys, designing and preparing special evaluation studies, making analytical reports, 
and developing appropriate computer systems. 

Research Grant Expenditures . A computerized data base of the Report of 
Expenditures (ROEs) for Fiscal Year 1971 NIH research grants was established. 
This is the first comprehensive collection of expenditure data from these forms 
undertaken for all of the NIH. The data base combines the information reported 
on the ROE form that is submitted to the NIH by grantees with pertinent data 
from the IMPAC file. Data input and table programming were performed by a 
contractor funded under the NIH Health Evaluation Program. 



32 



The computer file is maintained by the Section and data from it can be made available 
to those having an interest in this aspect of the extramural program. Special computer 
systems have been developed for ready access to the file. The Section is developing 
similar data bases, with the assistance of contract funds available under the NIH Health 
Evaluation Program, for Fiscal Year 1972 and Fiscal Year 1973 expenditure data. 
Information for several years will permit analyses of trends in the spending patterns of NIH 
research grant recipients. 

Two analytical reports on the Fiscal Year 1971 expenditure data were prepared and 
distributed to those concerned with extramural management. In addition, a presentation 
utilizing graphic slides was designed and given before groups of key personnel . These 
briefings not only provided those attending with information on expenditure patterns but 
informed them of the varied data available from the computer file. As a result there have 
been continuing requests for special studies to meet individual needs. In addition, the 
data from the Fiscal Year 1971 expenditure study are being used in the development of a 
manpower allocation model sponsored by the National Science Foundation for federally- 
funded research. 

Biomedical Research Price Deflator. Analysis of the expenditure data called for 
use of a specialized statistical tool to provide a measure of the purchasing power of current 
dollars in relation to dollars of an earlier period. Comparison was made with expenditures 
for Fiscal Year 1966 for which data from a sample survey were available. Extensive 
investigation was made of the various price deflators available for this purpose. The 
deflators were applied to the expenditures and an analysis made of the results. 

The Office of the Director, NIH, has contracted for the development of a price 
index to meet NIH needs. The Fiscal Year 1971 expenditure data are being used by the 
contractor to develop such a biomedical research price deflator. 

Annual Manpower Report. The staff of the Section performed the major part in 
planning and designing the new annual report form for personnel working on NIH research 
grants and contracts. 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's staff has been the focal point for correspondence and 
telephone calls from grantees related to completion of the form. The staff also served as 
advisors on processing problems and on the design of future report forms. 

Manpower Analysis . The analysis and preparation of special reports covering the 
data from the 1970 NIH Research Grant Manpower Survey continues. The survey planned 
and conducted by the Section's staff has proven a valuable data base, unique among the 
infomiation resources of NIH. The work completed has been continuously used by institute 
and OD staff. The National Science Foundation impact and allocation model of federally- 
funded research by academic institutions is using the 1970 survey data as the basis for 
extrapolating biomedical research costs and manpower and developing FY 1972 estimates. 

33 



The development of the annual manpower report has increased the need for 1970 
manpower d^La to serve as a basis for comparison. There are four 1970 baselir^ i 
analyses that are presently at varying levels of completion. Two of these wc^e 
prepared under contract funded by the Fiscal Year 1974 Health Evaluation Program 

Publications 

NIH Research Grant Expenditures Fiscal Year 1971 - Part 1 . Special 
Project Report No. 1, January 1974. 

NIH Research Grant Expenditures Fiscal Year 1971 - Part II . Special 
Project Report No. 2, June 1974. 



34 



HOW TO USE 

THESE SEPARATORS 

Use one page for 
each separation. 

Select appropriate 
tab, add further 
Identification If 
desired, and cover 
It with sc CTt c h 
tape. 

Cut of f and discard 
all tabs except the 
one covered by tape. 




TABBED SEPARATOR SHEET 

Form HEW-69 

(3-66) 




ANNUAL REPORT 

FISCAL YEAR 1974 
(July 1, 1973-June 30, 1974) 

DIVISION OF RESEARCH RESOURCES 



* 



National Institutes of Health 
Bethesda, Maryland 20014 



l!t 



TABLE OF CONTENTS 

Report of the Mrector 1 

Animal Resources Branch 7 

Biotechnology Resources Branch 2 5 

Chemical/Biological Information Handling Program 53 

General Clinical Research Centers Branch 67 

Genera 1 Research Support Branch 89 

Program Analysis Branch 99 

Office of Science and Health Reports 103 



REPORT OF THE DIRECTOR 
Dr. Thomas G. Bowery 



1 



Report of the Division Director 



Fiscal Year 1974 has been one of further refinement and additional development 
of the multi-categorical biomedical research resources supported by the 
Division. This activity is reported on by the major program areas in the 
accompanying pages of this annual report. 

This continued program development has taken place concurrently with, and 
against a backdrop of an internally initiated self-analysis of the objective, 
function, and structure of the Division of Research Resources. 

In 1961, the Division of Research Resources (nee the Division of Research 
Facilities and Resources) was established with the objective to — 

"support general purpose facilities and resources 
and strengthen the general health research 
capabilities of institutions." 

During the period of 1968-1970, the DRR (while within the Bureau of Health 
Manpower) was assigned a status quo objective to — 

"provide a focal point for the administration and 
management of broad NIH programs intended to supply 
a wide institutional base of support for health- 
related research." 

During the last half of Fiscal Year 1973, an internal DRR Task Force was 
established by my office to deal with a single question — "Can DRR broaden and 
strengthen the interrelationships among its variety of research resource 
programs in such a way that their individual and corporate actions will be 
even more effective in the future than they have been in the past?" 

The Task Force developed and presented to the Division for debate, four 
candidate contemporary objectives (actions)* with accompanying assumptions 
and tentative derivative actions. During the first part of Fiscal Year 1974, 
the Division decided to select a single contemporary objective, i.e.: 



1. Make research resources exclusively "merit-driven." 

2. Abet the sponsored activities of NIH's categorical programs, 

3. Assist non-profit institutions in the development of their 
biomedical research capabilities. 

4. Facilitate the acquisition of new knowledge. 



TO IDENTIFY AND MEET THE RESEARCH RESOURCE NEEDS 
AND OPPORTUNITIES OF THE NIH INSTITUTES 

by 

conceiving, creating, developing, and insuring 
the availability of those resources that are 
essential for the efficient and effective conduct 
of human health research. 

During the latter part of Fiscal Year 197A, the Division's top management team 
and subteams were actively engaged in examining the needs of the contemporary 
objective as regards — 

• the type of resource development system and organization; 

• the type of grants management and processing system and 
organization; 

• the type of technical merit review system and organization. 

As we move into Fiscal Year 1975, we plan to continue to test our assumptions 
regarding the selected objective, i.e. — 

• DRR can best sei-ve the NIH by selectively concentrating its 
resource activities on the clientele of the categorical programs; 

• DRR can set up machinery for program planning, analysis, and 
evaluation that is adequate to make DRR — and its clientele — 
highly responsive to the pace and direction of categorical 
programs, and to the resource needs of those categorical programs; 

• DRR can get continuously up-to-date profiles of where and how the 
categorical Institutes commit their appropriated funds and an 
understanding of the rationale for these commitments; 

• the Institutes and the OD, NIH would actively support such a 
contemporary objective. 



DRR BRANCH REPORTS 



i 



Fiscal Year 1974 Annual Report 

Animal Resources Programs 
Division of Research Rv^sources 



INTRODUCTION 



The overall objective of the Animal Resources Branch 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 RESEARC H CENTERS PROGRAM 

The Primate Research Centers, established with Federal funds in the early 
1960's, continue to provide national and international leadership in the 
rapidly expanding field of biomedical primatology. The Centers, operated 
by grant funds , provide unique research environments where biomedical 
research in many important areas is being conducted. During this year, 
numerous contributions were made in the areas of metabolic and degenerative 
diseases, cardiovascular diseases, reproductive biology, infectious diseases, 
and neurological disorders. 

The core support provided by this program permitted the 141 core staff 
scientists to conduct research on a total of 134 grants and contracts 
totaling $7.4 million. As a result, 677 scientific papers and 53 books 
were published during the year. Some 484 collaborative scientists from a 
number of universities utilized these facilities to conduct research on 191 
NIH supported grants and contracts totaling $14.0 million. The Centers were 
active in both research and professional training with 127 graduate students 
participating in the research activities. Three veterinarians and two 
veterinary pathologists received special training in primate medicine and 
pathology. The program provided salary support for 162 doctoral level staff 
and 680 technical and administrative personnel. 

The Centers, realizing that primates are difficult to obtain from their 
native habitats, are taking steps to breed the animals required for their 
research programs. During the past year, a total of 1,110 infant monkeys 
were produced in the Centers for use in the research programs. It is 
estimated that the Centers are now producing 50% of their annual requirements. 
The Centers are also maintaining small nuclear breeding colonies of some 
^j24 less commonly used primate species in order to assure their survival for 
future biomedical research purposes. 

The missions and selected research activities of the Centers are as follows: 

OREGON PRIMATE RESEARCH CENTER 



D 
R 

S 



I The missions of this Center are reproductive biology, cardiovascular and 
metabolic diseases, and immune diseases. The following are examples of 
•their research accomplishments : 

7 



1. Triggering the Onset of Labor ^j 

It is not known whether the full-term fetus is a self-starter or if some 

maternal or placental mechanism precipitates labor. An answer to this 

question will greatly help clinicians in dealing with the medical 

problems of premature labor and postterm retarded onset. It is 

known that anencephalic Infants often have long gestation periods, 

suggesting the pituitary gland is an essential factor in the 

regulation of the onset of labor. A technique has been devised for 

functionally removing the pituitary of fetal rhesus monkeys at Q|' 

midpregnancy and thereby in effect, inducing anencephy. The overall 

growth of the fetuses is markedly retarded, and the endocrine 

glands are only one-tenth normal size. These results show 

that the fetal pituitary is essential for normal development 

and that the hormones of the maternal pituitary do not cross 

the placenta. This new way of exploring the role of the 

primate fetal pituitary during gestation may lead to the 

development of endocrine therapy for human fetuses before birth. 

2. Cholesterol Gallstones and Atherosclerosis in Squirrel Monkeys 

Cholesterol gallstones involve more than 5 percent of the total U.S. 

population and a much higher percentage of certain groups. This 

affliction has a high dietary cholesterol intake as a common feature with 

atherosclerosis, a disease responsible for over half of the deaths in the 

U.S. However, the populations with the highest incidence rates for each . 

of these diseases is different. Studies on the cuase of gallstones in v 

experimental animals are intrinsically valuable per se , but may 

be even more valuable in elucidating the much more important 

problem of atherosclerosis. It is particularly important to 

know the treatment of each disease affects the development of 

the other. An animal model for studying gallstones has not been 

available; however, recent investigations have shown that gallstones 

consistently form in the squirrel monkey. The composition of diet 

determined the prevalence of gallstones. These studies on the 

squirrel monkey were the first to describe a consistent nonhuman 

primate model for induced gallstones and to systematically 

investigate the nutritional and individual factors that influence 

stone formation. Monkeys fed diets containing cholesterol in 

proportions similar to those in an opulent human diet develop a 

level of cholesterol in their blood plasma similar to that of 

people. They also have a 50 percent chance of developing 

cholesterol gallstones after one year on the diet. Studies on /^ 

squirrel monkeys may prove helpful in devising nutritional methods ^ 

or drugs for preventing or dissolving cholesterol gallstones without 

accelerating the process of atherosclerosis or any other unfavorable 

side effect. 

DELTA PRIMATE RESEARCH CENTER 

The primary mission of this Center is infectious diseases, and examples of 
their research activities are as follows: 



1. Cancer Virology 

The virus complexes that have been isolated from lymphomas of monkeys 
are being studied, and methods to grow and detect these viruses in 
cell cultures have been developed. Attempts are being made to 
reproduce the disease by inoculating young monkeys. This Center is 
also studying a monkey virus that closely resembles the virus causing 
infectious mononucleosis. In some monkeys, this virus causes tumors, 
while in the squirrel monkey it produces a benign infection. The 
defenses in the squirrel monkey that prevent tumors are being investigated. 

2. The Chimpanzee as a Model for Serum Hepatitis 

Serum hepatitis has been an increasing health problem over the past 
decade, especially for patients requiring frequent blood transfusions. 
Research has been hampered as no laboratory animal was available to 
study this disease. Recently, it has been shown that the chimpanzee 
is an excellent animal model for serum hepatitis. Experimental 
inoculations with human serum from hepatitis patients have been made in 
order to determine the relative virulence of the various subtypes of 
serum hepatitis. It is hoped that this research will lead to the 
development of a vaccine for this disease. 

YERKES PRIMATE RESEARCH CENTER 



The mission of this Center is neural and behavioral research and the study 
of neoplastic and degenerative diseases. This Center has the largest colony 
of great apes available anywhere in the world for biomedical research. 

1. Chimpanzee Language Study 



Considerable progress has been made in this project during the past 
year. A young chimpanzee in a computer-controlled language training 
situation has revealed impressive capabilities for the acquisition 
of language skills closely related to those employed by men in their 
languages. The chimpanzee, after only one year of training has learned 
to a) read and finish sentences validly started, b) that objects have 
names and c) to give the name of familiar objects with great facility. 
This animal has demonstrated the ability to equate projected pictures of 
objects with physical objects. This work serves to reinforce the 
assertion that the chimpanzee in all ways is closely related to man and 
to underscore the possibility that the apes might be used as subjects in 
radical experiments designed to explore the conditions germane to the 
acquisition of language by the human child. 

2. Experimental Chimpanzee Breeding on Ossabaw Island 



A group of four female chimpanzees, one male and one juvenile, 
have been established on Bear Island, one of the Ossabaw group situated 
20 miles south of Savannah, Georgia. The object of this experiment is to 
determine if they would survive year round in the open and whether they 
would breed under these circumstances. The study has already shown 



i 



w 



that the animals can survive the winter, and the recent birth of a 
young chimpanzee suggests that they will be able to breed successfully 
on this island. This study is of special importance due to the 
growing shortage of chimpanzees for biomedical research and the danger 
that in the near future it may be impossible to obtain these animals 
from their native countries. 

WASHINGTON PRIMATE RESEARCH CENTER 

This Center continues to pursue its original missions, namely neurophysiology 
relating to cardiovascular function and the development of an extensive 
collaborative research program involving a large number of scientists in 
many biomedical research disciplines. The following are examples of research 
being conducted at this Center. 

1. Arterial Smooth Muscle Cell in Atherosclerosis 

A new hypothesis of how atherosclerosis is produced has been formulated 
by using tissue cultures of arterial smooth muscle derived from 
pigtailed monkeys. At an early stage in the development of 
atherosclerosic lesions, smooth muscle cells increase in the intima 
of affected arteries, probably as a result of cell proliferation. 
This increase is accompanied by the foinnation of various extracellular 
connective tissue components. In addition, lipids, particularly 
cholesterol and phopholipid, accumulate within smooth muscle cells 
causing them to develop the appearance of "foam" cells. It is this 
increase in smooth muscle cells, connective tissue, and lipids that 
forms the atherosclerotic "plaque." The series of events that give 
rise to the initial changes in arterial smooth muscle is poorly 
understood. The development of these new techniques using the 
pigtailed monkey will hopefully shed light on the causation of this 
important disease. 

2. Auditory Physiology 

The physiological mechanisms underlying hearing dysfunction have been 
studied in rhesus monkeys using environmental factors such as 
conductive hearing losses induced by middle ear pressure changes , 
receptor dysfunction induced by noise trauma and drugs such as 
aspirin; and hearing changes from central auditory dysfunction 
induced by tiimors. These studies on nonhuman primates have allowed 
the investigators to develop an animal model of human function in 
which biomedical questions regarding hearing loss can be investigated. 
Efforts have been made to compare measures of function under similar 
conditions in man and monkey. These measures now permi':: an 
evaluation of physiological function and to define hearing losses 
induced by experimentally controlled pathologies. 

WISCONSIN PRIMATE RESEARCH CENTER 

Neural and behavioral sciences and reproductive biology are the basic 
missions of this Center. Examples of the research accomplishments are 
as follows: 

10 



m 



1. Effects of Noise on Behavior 

Rhesus monkeys were exposed to recorded sounds such as jack hammers 
and hard rock music at the level of 100 decibels for five-hour periods. 
During exposure, the monkeys' behavioral syndrome was marked by four 
distinct phases. The animals typically displayed hyperactivity with 
the onset of noise stimulation. Following the hyperactive phase, 
the monkey subjects engaged almost exclusively in oral and tactile 
exploration of the test chamber. After one hour of exposure their 
behavioral profile reflected passivity and general inactivity. The 
monkeys maintained a sitting posture with eyes fixed on one object. 
During the last one or two hours of the five-hour treatment they 
assumed a prone position and became behaviorally inactive. These 
animals were exposed to high decibel levels for shorter duration 
than humans often experience. Typists live in an environment of 80 
decibels, and many factory workers are often subjected to continuous 
levels of noise over 100 decibels each day. Humans subjected to long, 
loud noises display some effects similar to those noted in monkeys. 
The long-tem. effects of high noise levels in humans need to be 
explored furt:her. 



f 



2. Effects of PCB's on Monkeys 

Adult monkeys appear to be more susceptible than infants to the 
injurious effects of PCB, a commercial industrial chemical. Adult rhesus 
monkeys fed moderately high levels of PCB for three months lost weight 
and hair, had enlarged livers and drastic changes in the bone marrow. 
Infant animals receiving the same levels showed none of these symptoms. 
PCB's are stored in body fat, and since infants have little fat, there 
are fewer cells to deposit these compounds. In addition, the livers 
of infant monkeys are apparently unable to break down PCB, and, 
therefore, it passes through the body unchanged. Livers of adult 
animals convert PCB to more harmful compounds which causes the 
symptoms noted in this experiment. Research of this nature will 
lead to a better understanding of the effects of environmental chemicals 
on humans. 




NEW ENGLAND PRIMATE RESEARCH CENTER 

The core staff are conducting research in the 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. 



1. Primate Model of Drug-Seeking Behavior 

Collaborative investigators working at the Center with several primate 
species are investigating the acquisition and maintenance of orderly 
sequences of behavior leading to the injection of druj^s. They are 
conducting experiments to analyze the behavioral and pharmacological 
factors that determine whether a drug will maintain, suppress 
or have little effect on behavior that precedes its injection. 
Recent experiments show that long, orderly sequences of key-pressing 

11 



J 



i 



behavior can be maintained in primates when behavior results in a A 
single daily injection of morphine or cocaine. The model of drug- 
seeking behavior in primates is analogous to drug-seeking behavior 
in humans. The successful development of this model makes it 
possible to study the effects other drugs and behavioral procedures 
may have on drug-seeking behavior in humans. 

2. Recent Developments in Herpesvirus Research 

Experiments conducted at this Center have proven for the first time \^ 

that the spider monkey is the reservoir host for several strains 

of Herpesvirus ateles . Some of these strains have onco:renic properties. 

Herpesvirus saimiri has been isolated from natural leukemia in owl 

monkeys, and it has been found that this strain is more oncogenic than 

the prototype strain isolated from squirrel monkeys. These studies 

add to our knowledge of the oncogenic properties of Herpesvirus 

in primates and provide a model for the study .of human Herpesviruses. 

CALIFORNIA PRIMATE RESEARCH CENTER 

The mission of this Center is in the areas of infectious diseases and 
environmental health sciences. 

1. Birth Defects in the Nonhuman Primate 

It has been demonstrated that the nonhuman primate is the animal model i 
of choice for the study of many birth defects in man. This is ^ 

particularly true regarding the effects of certain environmental 
chemicals. It has been shown that triamcinolone is quite teratogenic 
resulting in skeletal changes and cleft palate. Such studies 
not only provide valuable knowledge on the effect of such drugs in 
pregnant women, but also provide a laboratory model for the 
scientific study of the mechanism of drug action. 

2. Model for the Study of Bacterial Pneumonias 

A primate model has been developed recently in which pneumococcal 

pneumonia can be reliably induced. The induced infection produces 

sufficient quantities of intrabronchial secretions to allow 

measurement of antimicrobial concentrations. This Center now has 

a choice of animal model to study the therapeutic efficacy of 

antimicrobial agents commonly used in man such as penicillin, 

ampicillin and several others. (^ 

LABORATORY ANIMAL SCIENCES PROGRAM 

The Laboratory Animal Sciences Program 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 \ 

12 



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 $7,505 million in fiscal year 1974, 
which supported 96 discrete animal research and resources projects, 
6 training programs, 13 fellowship awards, and 5 contracts. 

ANIMAL MODELS AND SPECIAL COLONIES 

The major objectives of this program area are (1) to characterize and 
define biological attributes of selected animals which display potential 
for rather broad biomedical research application; (2) to establish, improve 
and/or expand special colonies of well-defined animals which are of proven 
value for specialized research areas, but which are not generally available 
from other sources; and (3) to preserve unique and valuable animal stocks 
and strains which may otherwise be lost (e.g., because of temporary lack 
of project support). 

Support for projects related to the development of research animal models 
and the establishment of special colonies of valuable research animals 
has remained quite static during the past several years, with 22 projects 
supported during FY 1974 (approximately $1,250 million) as compared to 
20 projects supported during FY 1973 ($1,141 million) and 21 projects 
active during FY 1972 ($1,250 million). 

The vast majority of active projects in this area are related to vertebrate 
species (e.g., rats, mice, guinea pigs, hamsters, degus, rabbits, Arctic 
rodent species, frogs, armadillos, dogs, zoo animals, nonhuman primates, 
etc.). However, increased attention has recently been given to the support 
of model development and/or special resources of appropriate invertebrate 
animals, e.g., Xyleborus (wood-boring beetle) and rare species of 
Drosophila for use in several areas of biomedical research activities. As 
a result of planning during the past year, contract efforts will be initiated 
in June 1974 on the development of laboratory mariculture techniques for 
Aplysia (sea hare) and/or related marine gastropods (i.e., Hermissenda and 
Pleurobranchaea ) . These marine invertebrate organisms are used extensively 
in several biomedical research areas, and their uncertain availability and 
quality from natural marine sources has presented problems of increasing 
severity. 

Projects related to the characterization and development of new animal 
models have been limited to those strains and species for which there is 
evidence of good potential utility for activities in several research 
disciplines or disease categories. Efforts of investigators of several 
disciplines over a rather extensive period are usually required to fully 
exploit the potential of such animals as useful models. 

Examples of animal model development projects which are currently 
supported by the Program include (1) a colony of degus (University of 



13 



Vermont) with iinique biological attributes for studies in the areas of 
immunology and eye cataract development; (2) germfree mice and rats 
(University of Notre Dame) under development as potential model systems for 
studies on cancer therapy, environmental pollutants, and gerontology; (3) an 
inbred colony of cats (Washington State University) which possess a number of 
interesting chromosome anomalies being studied as models for Turner's sjmdrome, 
dwarfism, Kleinfelter's sjmdrome, and demyelinating diseases; (4) a newly 
acquired colony of Syrian hamsters (Massachusetts Institute of Technology) 
which are under development for use in a multitude of biomedical research areas 
including genetics and cancer research; and (5) studies on cats (University of 
Alabama Medical Center) which represent potential new models of neurological 
disease. 

Examples of ongoing projects which provide support for maintenance of 
special colonies and serve ?s institutional and/or national resources 
include (1) an inbred rabbit colony (University of Illinois College of 
Medicine) which supports a large research program for investigators of 
immunotherapy; (2) gemfree dogs (Louisiana State University College of 
Medicine) for studies on human encephalopathy, stress ulcers and other diseases; 
and (3) colonies of several species of amphibians which are being studied at 
the University of Michigan to develop new techniques and knowledge to solve 
problems related to laboratory housing, husbandry, and breeding. During 
FY 1974, 11 of these special colony resources undergirded 55 NIH-funded research 
projects with a total funded value of $3,614,000 and 39 other biomedical 
research projects which received funding from other sources (total 
research funding value of $750,000). 

Five institutional primate resource grants constituted an additional 
group of special animal colonies which were used for support of multi- 
disciplinary biomedical research programs within institutions. Four 
of these grants have reached their natural termination during FY 1974, 
after becoming firmly established resources. The value of these 
resources has been well demonstrated in the past. For example, during 
FY 1973, active primate resources supported by the Laboratory Animal 
Sciences Program (LASP) were utilized in support of 95 NIH research grants 
with a total funded value of $8,559,000. In addition, these resources were 
used to support 27 projects funded by other sources (total funded value of 
$1,396,000). Support of the initial establishment of primate resources 
of this nature will remain as an eligible area in the Program. 



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. '^j 
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 

14 



Analysis Branch has identified 1,122 projects ($64 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 increased emphasis beginning in FY 1972 when Congress appro- 
priated 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 the progression of support: 



tx 1971 



FY 1972 



FY 1973 



FY 1974 



No. of Improvement Projects 14 24 28 46 
Dollars Awarded (in $l,000's) 673 2,169 2,318 3,217 
Percentage of LASP Jiudget 11% 35% 37% 55% 



In addition to those projects which were funded, a large backlog of 
approved, unfunded applications developed. During the current fiscal year 
(FY 1974) there was some reduction in the number of new improvement 
applications which were received and reviewed (19, of which 12 were 
recommended for approval) . Thirty-four (34) new awards totaling nearly 
$3.0 million were made. This included 5 new projects ($583,000) which 
were funded during the year with impounded funds released from the 
FY 1973 budget. Thus, a considerable number of projects approved in 
prior years have been funded. However, there will be 19 approved 
applications (requesting approximately $2 million) which will remain 
unfunded. A number of these date back nearly two years and will be 
administratively withdrawn. This will allow those institutions with a 
continuing need to update and improve their proposals. Continuing inquiries 
from additional institutions indicate that requests for assistance in this 
area can be expected to continue at about the current level for the next 
several years . 



DIAGNOSTIC LABORATORIES 



I 



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. A shortage of appropriately 
trained specialists (veterinary pathologists and microbiologists) has been 
a limiting factor, precluding any rapid establishment of new programs. 
However, three new laboratories were funded during FY 1974. Special 
attention is being given to laboratories which have the potential of 



15 



serving more than one Institution. Several laboratories are now ^ 

providing service to other institutions in the same metropolitan area ^ 

or are serving a regional area. Programs of this type will help con- 
serve resources and justify more sophisticated capabilities. 

By undergirding an institution's animal health program, the laboratories 
make a direct contribution to approximately 1,138 NIH supported research 
projects using animals with total funding of nearly $97 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. One laboratory compared the 
three generally accepted techniques for detection of microfilaria in 
canine blood. An assessment of the reliability, costs and time 
involved for large scale screening programs was obtained and as a 
consequence the effectiveness of the institution's quarantine and 
processing program was considerably improved. These results were 
published and are available for consideration by other institutions 
located in areas with a high incidence of heartworms. Collaborative 
studies at one institution revealed clear metabolic and histopathologic 
evidence of significant exposure to lead in wild rats trapped in a 
major urban area while rural wild rats were apparently not exposed to 
the same extent. This work is continuing with outside grant support 
and will extend existing information about the use of wild rats as 
models of environmental exposure to heavy metals . Initial observations 
of an atypical colonic hyperplasia of mice were followed up by another ^ 

laboratory. They were successful in establishing the disease in % 

susceptible mice (Swiss Webster) by oral inoculation of tissue culture 
fluids. Sufficient data were obtained utilizing the techniques of 
light and electron microscopy and cell kinetics employing autoradio- 
graphy to successfully compete for a grant from the Large Bowel Cancer 
Program of the National Cancer Institute. One laboratory became 
extensively involved in studies of lymphocytic choriomeningitis (LCM) 
in Syrian hamsters and other animal species following an outbreak of LCM 
in hospital personnel. The source of infection was traced to a colony of 
hamsters being covertly maintained in a room outside the central animal 
facility. The room also housed a Xerox machine, and the traffic generated 
by it resulted in exposure and infection of a wide range of individuals 
in addition to those primarily concerned with the animals. Findings 
resulting from the study of this outbreak led to improved control of 
animal movement, additional isolation procedures, screening of animal 
tumors for zoonotic pathogens (imported transplantable tumors were 

implicated as the most likely source of the LCM virus) , and the 4 

establishment of an Animal Research Safety Committee. 

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: 

i 
16 



Research Related to Animal Resources 



FY 71 



FY 72 



FY 73 



FY 74 



4 


6 


8 


10 


403 


449 


593 


591 


9% 


7% 


10% 


10% 



Ntimber of Projects 
Awarded (in thousands) 
Percentage of Total $ 

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, diagnosis and control of mammalian encephalito- 
zoonosis, definition of environmental conditions for laboratory 
animals, and development of nonhuman primate embryo transfer. The 
latter project has made progress to date in developing the necessary 
techniques to recover embryos from mated females. The next step will 
involve embryo transfer to the uterus or oviduct of other females. 
If completed pregnancies can be obtained by these procedures, then an 
important tool for the production of selected animal research models 
as well as for the study of genetic diseases and teratology will have 
been developed. 

REFERENCE CENTERS AND INFORMATION PROJECTS 

The Program has continued to support several reference center 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, 

40 laboratories submitted over 3,000 sera from various nonhuman 
primates for B virus antibody testing. The Laboratory also 
provided considerable backup support to the Charles River 
contract (described under Research Contracts Section) by 
testing almost 1,000 sera against multiple antigens. 

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 



D 1 

R 

S 



17 



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. The initial fascicle 
contained descriptions of 16 models and a second fascicle 
completed during the past year included 14 additional models. 
A three-day course in Comparative Pathology will be offered for 
the first time at the AFIP 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 programs in laboratory 
animal medicine since 1967. At that time, six programs were trans- 
ferred from the National Institute of General Medical Sciences, which 
initially supported training in this area. Eight programs were 
supported during the current fiscal year. This number will be reduced 
to seven beginning July 1, 1974. 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 mechanisms, . the Branch has supported training through 
the award of individual postdoctoral and special fellowships . In 
some cases these individuals have enrolled in the 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 98 trainees and fe^.lows 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 34 by other academic, research or 
governmental organizations. The majority (55) are functioning as 
directors or staff members of a vivarium; 38 are engaged in research 
or are obtaining additional training; and 5 are engaged in public health 
and other activities. Retention in the field of laboratory animal 

18 



medicine has been excellent for these programs, emphasizing the career 
orientation provided by the training and the continuing need and 
opportunities available for such individuals. 

A decision to phase out research training supported by the National 
Institutes of Health was reflected in the 1973 budget. This decision 
involved impoundment of a portion of the funds appropriated by Congress 
for training activities. Under the phase-out plan, no new trainees or 
fellows could receive appointments . A lawsuit initiated by the AAMC 
challenged this action and early in 1974 their litigation resulted in 
the release of funds impounded during FY 1973. For ARE this resulted 
in the release of $141,000, which was awarded as a supplement to the 
ongoing programs in February. Accompanying this action was the notifi- 
cation that the prohibition on new trainee appointments was rescinded. 
Funds were provided In the 1974 Appropriation Act to support training at 
the restored level for the period July 1, 1974 — June 30, 1975. However, 
it will take a considerable period of time to recruit new trainees and 
regain the former level of activity. The uncertainties regarding the 
future in terms of long-term continuation of federal support, stipend 
levels, etc., hav!5 made it very difficult for training program directors 
to operate effectively. 



In the fall of 1973 a "new" Manpower Development Program was announced. 
ARB received approval to make awards under this program in the field of 
laboratory animal medicine and science, and $140,000 was allocated for 
this purpose. The program is similar to the old postdoctoral fellowship 
program, but does provide for higher stipend levels. The deadline for 
receipt of application was February 1, 1974. Thirteen (13) applications 
are currently under review, and approximately 10 new awards can be made 
under this program beginning June 1, 1974. It is anticipated that the 
"old" fellowship program will be terminated as soon as the six active 
fellows complete their programs. 



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 1974 were about $500,000, including $300,000 
transferred from NINDS for support of the Caribbean Primate Center. Five 
projects were supported. In addition one project funded in F\ 1973 was 
completed in FY 1974, and one was transferred to the Food and Drug 
Administration. 

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 



19 




from NIH. These activities are a valuable adjunct to the Animal Resources 
Branch program. The ILAR meets ARE 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 animal models and 
genetic stocks and a field survey on the abundance and distribution of 
primates of biomedical interest in selected areas in South America. 
Another special activity funded late in FY 1973 and active this year 
has been a survey and analysis of use of primates for research and a 
review of field study data on primate populations. The purpose of this 
study is to provide information for planning numbers and species of 
primates which should be bred in this country. 

DOMESTIC, COMMERCIAL PRIMATE PRODUCTION 

ARB has renewed for a third year a contract with Charles River Breeding 
Laboratories to provide partial support for determining the feasibility of 
domestic production of free ranging rhesus monkeys on an island in the 
Florida Keys . Although the need for this type of program has long been 
accepted, the low cost of imported wild-trapped monkeys, and long-term 
investment in a breeding program has discouraged commercial firms from 
developing this concept. NIH support has stimulated interest in this 
area and has helped assure a quality program. A change in the contract 
last year will give NIH first priority to obtain primates produced on the 
island, and this may be extremely beneficial to NIH because of reductions 
in the export quota of rhesus monkeys from India. About 350 primates 
have been placed on the island as of April 1, 1974, and it is expected 
that 200 more will go onto the island before July 1. About 20 infants 
were born this past year from the first group of 90 animals placed on 
the island in May of 1973. 

AMERICAN ASSOCIATION FOR ACCREDITATION OF LABORATORY ANIMAL CARE 

The Animal Resources Branch is providing through a small contract partial 
support for site visits at a number of institutions that were accredited 
by AAALAC 3 to 5 years ago. 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 

Late in the fiscal year the Animal Resources Branch awarded a contract 
for laboratory breeding and rearing of Aplysia and/or related species. 
This marine mollusk is used in a variety of biomedical studies and is 
becoming increasingly difficult to obtain from nature (the principal 
supplier now "rations" the animals to researchers) . It is felt that 
with two to three years' effort it is feasible to establish laboratory 
culture of this species, thereby assuring a supply of high quality 
animals. 



20 



n 



CARIBBEAN PRIMATE CENTER 

This primate resource is being supported by funds transferred from the 
National Institute of Neurologic Diseases and Stroke, 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 was in part realized in 
FY 1974 as the Bureau of Biologies, FDA, awarded a contract which 
supports production of 500 rhesus monkeys per year. 

DEVELOPMENT OF A TRAINING PROGRAM FOR ENTRY LEVEL ANIMAL CARE TECHNICIANS 

This project with the University of California San Francisco Medical 
Center came to successful completion in FY 1974. Its purpose was to 
develop training materials to instruct entry level animal care 
technicians. A series of 30 audiovisual lessons, with accompanying 
students and instructors manuals, was developed. Field tests indicate 
the program will be highly successful. The materials are now being 
readied for distribution by the American Association for Laboratory 
Animal Science. 

HOLLOMAN PRIMATE FACILITY 

In previous years the Animal Resources Branch had a contract to provide 
basic support for a large chimpanzee colony and other primates formerly 
supported by the Air Force at Holloman Air Force Base, New Mexico. 
Responsibility for this contract has now been transferred to the Bureau 
of Biologies, FDA, because it is closely related to another contract 
from that agency for chimp.anzee breeding and hepatitis research. 

ADMINISTRATION 

A major administrative activity in fiscal year 1974 has been the development 
of a National Plan for Rhesus Monkey Supply. Rhesus monkeys are the pre- 
dominant species of nonhuman primate used in biomedical activities. Early 
in the fiscal year we were informed that the government of India was 
considering a 40% reduction in the number of rhesus monkeys it would 
allow to be exported (reduction from 50,000 to 30,000). This was later 
confirmed and we were asked by the Director of NIH to develop a plan 
for rhesus monkey supply. The plan we developed features both con- 
servation of use and domestic production of primates. We have held 
meetings with the Federal Interagency Committee on Animal Resources 
and a group representing the Health agencies of DHEW to discuss the 
primate supply situation and means of conserving their use. We have also 
notified all recipients of rhesus monkey certificates of the problem and 
asked that they reduce their use of rhesus monkeys. Overall, the bio- 
medical community is well aware of the problem and is concerned about it. 
We have scheduled a meeting with representatives of the pharmaceutical 
industry in June to discuss the problem with them and to enlist their 



21 



ttf forts la conservation of animals and domestic breeding. We have also 
dffivelopsd a plan for donestic breeding to oeet part of the NIH extramural 
retquireasttts . Funds have been reprogranned to the Division of Research 
Resources to initiate this program through a primate breeding contract 
awarded late in FY 1974. 

A second major administrative effort in fiscal year 1974 was to complete 
work on a "Cost Analysis sad Rate Setting Manual for Animal Resource 
Facilities." In previous fiscal years we became aware that animal 
resources in many institutions were in financial difficulty. As a result 
we initiated a joint effort with the Business Officers Group of the 
Association of American Medical Colleges to develop a manual on cost 
analysis and rate setting for animal resource facilities. The manual 
was field tested in the summer of 1973 and subsequently revised and 
published. The manual will facilitate cost analysis in animal resource 
facilities, and this wLll lead to better cost control, management, and 
establishment of rates that will provide sufficient income for animal 
resource facilities. Much interest was expressed in the manual even 
prior to its publication. It is our Intention that the manual be the 
basis for informing and educating Investigators and sponsors of research 
that the full animal care costs should be supported by funding agencies 
through fees charged to users. 

Another administrative activity this year has been a program evaluation 
of diagnostic laboratories. This activity is being carried out by a 
contract with the University of Missouri. The contract was awarded late 
in FY 1973 and calls for the development of a methodology to measure costs 
and benefits of the various diagnostic laboratory activities. When we 
started this project, we recognized we were dealing with an area that is 
hard to measure objectively; but as a result of recent meetings with (and 
reports from) the contractor, we are encouraged that a meaningful and 
workable system will be developed. 



22 



TABLE I - Primate Research Centers 


Program Applications, 


FY 1974 




Type 


Number 
Receiveci 


Amount 
Requested* 


Number 
Approved 


Aaoant 
Approved* 


Number 
Funded 


Amount 
Funded** 


New 

Renewal 
Supplemental 
Continuation 
Totals 


1 
1 
2 
6 
10 


335,864 
1,606,242 

134,894 
12,109,893 
14,186,893 


1 
2 
6 
9 


1,484,092 

115,418 

10,721,537 

12,321,047 


1 1 
3 

6 9 
10 11 


,492,367 
302,7091/ 
,696,924 
,492,000^/ 



*Direct Costs Only 

**Includes Indirect Costs 

1' Includes 2 prior approvals funded at $260,000 from FY 1973 Impounded Funds. 

TABLE II - Laboratoi y Animal Sciences Program Applications , FY 1974 





Number 


Amount 


Number 


Amount 


Number 


Amount 


Type 


Recei/ed 


Requested 


Approved 


Approved* 


Funded 


Funded** 


New 


36 


2,960,327 


19 


1,070,911 


42 


3,384,955^/ 


Renewal 


15 


1,421,146 


8 


431,134 


8 


662,230l/ 


Supplemental 


2 


52,532 


1 


1,244 


5 


120, 049^/ 


Continuation 


43 
96 


2,625,853 
7,059,858 


43 
71 


2,040,362 
3,543,651 


42 


2,203,766 


Totals 


97 


6,371,000 



*Direct Costs Only 

**Includes Indirect Costs 

^/includes: 19 Prior Approvals funded at $1,679,150 

5 Prior Approvals funded at $583,000 from FY 1973 Impounded Funds 
18 FY 1974 Approvals funded at $1,122,805 



3/ 

— ' Includes : 



—'Includes: 



2 Prior Approvals funded at $159,301 
6 FY 1974 Approvals funded at $502,929 

1 FY 1974 Approval funded at $1,493 
4 Staff Supplements funded at $118,556 



TABLE III - Training Grant Applications in Laboratory Animal Medicine , FY 1974 



Number 



Amount 



Number 



Amount 



Number Amount 



TZE£ 



Received Requested Approved Approved* Funded Funded* * 



New 

Renewal 
Supplemental 
Continuation 
Totals 



49,749 
449,880 
499,629 



49,749 
387,979 
437,728 



15 



194,713^/ 

242,287 

437,000 



*Direct Costs Only 
**Includes Indirect Costs 

1/ Includes: 7 Staff Supplements at $141,000 funded from FY 1973 Impounded Funds 
2 FY 1974 Approvals funded at $53,713 

23 



TABLE IV - Fellowship Applications in Laboratory Animal Science , FY 1974 S 

Number Number Number Amount 
Type Received Approved Funded Funded 

New 10 6 - 145,300 

Renewal - - ~ ~ 

Supplemental - - - - 

Continuation 6 6 6 51,700 ^ 

Totals 16 12 6 197,000 | 

TABLE V - Laboratory Animal Sciences Program Resource and Research Grants , 
Project Distribution FY 1973 and FY 1974 

Project Type No. Projects Amt. in $1, OOP's No. Projects Amt. in $1, OOP's 

Basic Improvement 28 2,313 46 3,229- 

Special Colonies 20 1,141 22 1,250 

& Models 

Primate Resources 5 342 1 25 

Resource Research 8 593 IP 591 

Diagnostic Laboratories 16 1,P26 13 940 

Reference & Information 4 285 4 336 



Totals 81 5,700 96 6,371 

TABLE VI - Laboratory Animal Sciences Program , Research Utilization of 
Selected Animal Resource Colonies , FY 1974 

Dollar Amt. Dollar Amt. Of 

No. NIH of NIH Grants No. Other Other Projects 
Colonies Grants in $l,000's Projects in $l,000's 

Primate Resources 5 95 8,559 27 1,3961/ 
Other Special Colonies 11 55 3,614 39 750 

Totals 16 150 12,173 66 2,146 

—'Includes 5 projects ($583,000) awarded from FY 1973 impounded funds 

2/ 

— Four of five projects completed support in FY 1974. 



n 



24 



Fiscal Year 1974 Annual Report 
Biotechnology Resources Branch 
Division of Research Resources 



MOST BIOMEDICAL RESEARCH INSTITUTIONS ARE "HAVE-NOTS" IN MOST AREAS OF 
BIOTECHNOLOGY! 



True? Yes , if one believes that every scientist who merits NIH 

support also deserves to have state-of-the-art research 
tools reasonably available. 

Critical? Absolutely, if one acknowledges that the vigor and success 

of modern biomedical science would be short-lived without 
its supporting tools and methodologies. 

Inevitable? Probably, at least insofar as biomedical research insti- 
tutions choose or are forced to be exclusively inner- 
directed in attempting to fill their biotechnology needs. 

Immutable? No, not if NIH and the biomedical research community can 

effect successfully the sharing of highly specialized bio- 
technology resources across institutional lines. 

The foregoing questions are the principal issues facing the Biotechnology 
Resources Branch (BRB) . The answers reflect the present views of BRB staff 
and advisors. The following paragraphs review briefly some activities in 
FY 1974 — and some prospects for FY 1975 and beyond — which bear on these 
issues and answers. 



BACKGROUND 

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 
expertise 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 oppor- 
tunities 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 



25 



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 biotechnology capabilities but strong biomedical research 
programs and compelling biotechnology 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 55 grants and five contracts active during FY 1974. 

23 computer resource grants 

2 resource-related projects in computer science 
16 biomolecular characterization resource grants 

6 biomedical image and image processing resource grants 
1 resource-related project in biomedical image and 

image processing 

7 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 
$11 million. A listing of the BRB sponsored activities active during FY 1974 
is given in Table I. A brief description of each Resource's capabilities, 
highlighted with an example of its application, is included in Table II. 
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 category. 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 1974. Whereas in 1967 the average annual award for a computer 
resource was about $174,000, it was approximately $418,000 in 1974. 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. 



26 



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•3:^ 


•H 


Cfl 


>. 


3 


CU c 


C 


CU 


CO 


o 


X cfl 


& o 


D 


cn 


m 


« 


H CO 


« 


. 








„ 


>. 


M 








M 


M 


CU 








CU 


W 


X 




m. 




c 




a. 




c 




o 


^ 


o 




o 




M 


3 


4-1 




CO 




o 


S5 


CO 




Cu 







33 



TABLE II 

JIESOURCE CHARACTERIZATIONS 
Computers 



Grant No . Capability 

RR-03-13 Batch processing, timeshare, 

and graphics 



RR-07-11 Image processing and 

analysj ? 



RR-11-11 Remote job entry to 

cent:ral computer 

RR-15-12 Time sharing and batch 

processing 

RR-16-10S1 Remote job entry to 
institution computer 

RR-145-10 Experiments hardwired to 

mini-computer which is hard- 
wired to resource computer 

RR-241-07S1 Patient monitoring 



ER-249-09 Stand-alone minicomputers 



RR-259-07 Batch processing and tele- 
processing 

RR-267-09 Batch processing and time- 

sharing 

RR-276-09 Dedicated systems and time- 

sharing 

RR-291-09 Batch processing or ded- 
icated digital analog 
system 

RR-311-06S1 Hardwired analog terminals 

and remote access timesharing 



Illustrative Applications 

Biostatistical research; 
modelling ceJl cycle 
dynamics . 

Non-invasive monitoring of 
cardiac fvinction via 
roentgen video densitometry. 

Biostatistical research; 
genetic modelling. 

Biochemical kinetics 
modelling. 

Biostatistical research. 



On-line real-time data 
acquisition in cardiology 
and neurophysiology. 

Clinical research in cardio- 
pulmonary pathophysiology. 

On-line real-time control 
of neurophysiology 
experiments. 

Patient record 
management . 

EKG analysis. 



Computer assisted pulmonary 
function testing. 

Biomathematlcal modelling. 



Acquisition and analysis of 
spectrometry data. 



34 



Computers Ccontinued] 



Grant No. Capability 

RIl-326-08 On-line interactive 

laboratory computing 

RR-353-06 Data communication, batch 
processing 

RR-370-04S2 Computer-based facilities 
for biomedical research 



Illustrative Applications 

Acquisition and processing 
of neurophysiology data. 

Hospital record management. 



Real-time analysis of 
-expired gas. 



RR-374-07 

RR-396-07 
RR-576-03 

KR-578-04S1 
I 

RR-643-03 
RR-667-02 
RR-757-02 



Experiments hardwired to On-line control and analysis 
resource computers plus time- of physiology experiments, 
sharing . 

Dedicated computers and macro- Cardiac rhythm monitoring; 
module systems biomolecular modelling. 



Remote job entry to insti- 
tution's computers; stand- 
alone minicomputer. 

Stand alone medium computer 
with graphics 



On-line real-time control 
of biomolecular character- 
ization devices. 

Biomolecular modelling and 
computer-assisted design 
of organic synthesis. 



Access to timesharing systems Application of artifical 

intelligence to clinical 
decision making. 



Terminal system design and 
fabrication 



Computer-based automated 
laboratory systems 



VHF short-range interactive 
digital computer communica- 
tion. 

Image processing, on-line 
acquisition and processing 
of X-ray crystallography 
data. 



D 

R {' 
S 



^RR-785-OlAlSl 



Remote access through 
computer networks 



Applications of artificial 
intelligence in biology and 
medicine. 



35 



TABLE II 
RESOURCE CHARACTERIZATIONS 
Biomolecular Characterization 



Grant No. Capability 

RR-273-09 Gas chromatography/low 

resolution, mass spectrom- 
etry/gas flow proportional 
counter 

RR-292-09 High-frequency NMR, Multi- 
nuclear capability 



Illustrative Applications 
Metabolic profiles. 



Structure and function of 
hemoglobins and other mole- 
cules. 



RR-317-07 



Mass spectrometry-High reso- 
lution, gas chromatography/ 
mass spectrometry, chemical 
ionization 



Drug identification. Struc- 
ture determination of un- 
known biomaterials. 



RR-330-07 



RR-355-08 



RR-356-08 



RR-480-06 



Mass spectrometry-High reso- 
lution, gas chromatography/ 
mass spectrometry 

Mass Spectrometry-High reso- 
lution, gas chromatography/ 
low resolution 

Mass spectrometry-High reso- 
lution, low resoltuion, NMR- 
Carbon-13, Proton, High 
performance chromatography 

Mass spectrometry-High reso- 
lution, gas chromatography/ 
mass spectrometry, field 
desorption mass spectrometry 



RR-542-04 


High-frequency NMR 


RR-574-03 


NMR-multinuclear capability 


RR-612-04- 


Resource related research 


05 


Mass Spectrometry 


RR-636-02 


NMR-multinuclear capability 




36 



Structure determination of 
potential anti-tumor drugs. 



Structure determination of 
antibiotics. 



Separation and detection of 
nucleosides. 



Structure determination. 
Lipids of biomedical 
importance. 



Enzyme/substrate interaction 
mechanisms . 

Carbon-13 labeled 
macromolecules . 

Application of artificial 
intelligence to mass 
spectrometry. 

Structure and function of 
peptide hormones 



Blomolecular Characterization (continued) 



Grant No. 



RR-639-01A2 



RR-665-01 



Capability 
NMR-Proton, Carbon-13 



Mass spectrometry-High reso- 
lution, gas chromatography/ 
low resolution, chemical 
ionization 



Illustrative Applications 

Carbon-13 studies of 
nucleoside bases. 

Structure identification 
of natural products. 



RR-708-01 Mass spectrometry, gas 

chromatography/low resolu- 
tion, NMR-220MH 



Metabolic studies. Structure 
and function of biomolecules 
using stable isotopes. 



RR-711-02 



NMR - 360MH 



Structure and function of 
macroraolecules . 



RR-719-01A1S1 



RR-862 



Mass spectrometry-High 
resolution, gas chromatog- 
raphy /high resolution, low 
resolution 

Mass spectrometry-chemical 
ionization 



Application of mass 
spectrometric techniques to 
clinical problems. 



Application of mass 
spectrometry to medical 
problems . 



37 



TABLE II 
RESOURCE CHARACTERIZATIONS 
Biomedical Image and Image Processing 



Grant No. Capability 

RR-442-05 Image processing and 
displays 

RR-443-06 Image processing 



RR-570-03S1- One-million volt electron 
04 microscope 

RR-592-04 One-irillion volt electron 
microscope 

RR-679-G2 Electron microprobe 



RR-715-02 Scanning electron micro- 
scope 



Illustrative Applications 
Neuroanatomical modelling. 



Electronmicrographs and 
medical images. 

Structure and function of 
chromosomes. 

Structure and function of 
the nucleolus. 

Histochemistry - quantita."* 
tive analysis of renal cell 
composition. 



Under development , 



38 



i 



TABLE II 
RESOURCE CHARACTERIZATIONS 
Biomedical Engineering and Others 



Grant No. Capability 

RR-12-12 Activities hardwired to 

resource computer 

RR-117-11 Methods of characterization 

preservation and distribution 



RR-346-05 Protein isolation 



RR-716-07 On-line real-time integra- 
tion methods; on-line real- 
time display 



RR-759-01 Serology, toxicology, 
histology 

RR-857-01A1 Microelectronics fabrication, 
packagittg, and evaluation 
capabilities 



Illustrative Applications 

Patient monitoring; medical 
record management . 

Systematic collections of 
microorganisms, viruses, 
cell lines, and other perti- 
nent organisms . 

Large scale preparation of 
enzymes and microbial cells. 

Interfacing of laboratory 
instruments to computers; 
acquisition of electrophysio- 
logical and other biological 
data under computer control. 

Forensic pathology. 



Microelectronics devices for 
biological and clinical 
research. 



39 



TABLE III 

NUMBER & DOLLAR AMOUNT, BY NTH INSTITUTE, OF PROJECTS 

RECEIVING TECHNOLOGICAL SUPPORT FROM A SAMPLE OF 23 OF THE 51 

BIOTECHNOLOGY RESOURCES 

ACTIVE DURING FY 1973 



Institute 



Allergy and Infectious 
Diseases 

Arthritis, Metabolism and 
Digestive Diseases 



Number of Projects 



12 



Stroke 

National Library of Medicine 

Health Services and Mental 
Health Administration 

Contracts 



36 



Cancer 


34 


Child Health and Human 


31 


Development 




Dental Research 


4 


Environmental Health Sciences 


4 


Eye 


8 


General Medical Sciences 


68 


Heart and Lung 


55 


neurological Diseases and 


43 



54 
25 



377 



Dollar Value of Project 
(in millions) 



2.7 

3.5 
2.8 

1.4 
.2 
.3 
8.1 
4.9 
3.5 

.2 

6.8 

7.4 

$ ■42T8 



Projected Totals for all 51 Active Grants 
Number =836 
Value = $ 95 million 



40 



Rapid and far-reaching change is not limited to the computer resource category. 
For example, as the requisite talent becomes available to manage mass spec- 
trometers 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 
metabolic 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. 

The eight new awards made by the Biotechnology Resources Program during Fiscal 
Year 1974 demonstrate the continuing diversification and specialization of 
supported activities. These new resources include a computer resource, four 
biomolecular characterization resources, two biomedical engineering resources, 
and a resource-related research project in high voltage electron microscopy. 

BIOTECHNOLOGY RESOURCE SHARING 

The succeeding sections will describe representative biotechnology resource D 

activities in several areas. It is obvious that these biomedical research 

activities are of great value to their respective research communities. It r 

is also apparent that these research communities are especially fortunate 

in having these excellent opportunities immediately available. g 

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. 

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 
supplementat ion . 

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. 

I 

Because of the varied natures of sharable resources, specific appropriate ^^ 

administrative arrangements are needed. Some biotechnology resources, such ,il' 

as computers 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, partic- 
ipation of qualified researchers, needed training, and ongoing evaluation 
of effectiveness as a shared resource. 



41 



Assembly of related but dissimilar biotechnology resources into shared networks ^ 
offers the advantage of pooling diverse talants and instrument capabilities W 
to produce levels of capability superior to those of any component. 

This pooling effect has special benefits for those investigators and insti- 
tutions 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 Ai 

problems of program management to assure equitable involvement of the "have" 
and "have not" components 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. 



42 



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 pathophysio- 
logical 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, S^tanford 
University Medical Experimental facility. This resource is the first and only 
such installation expressly devoted to research on Artificial Intelligence in 
Medicine (AIM) . The STJIIEX 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 includes 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 will be conducted early in Ff 1975. 



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 signif- 
icant 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 
workshop activities. 






I 



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 specialized computer centers have, interestingly enough, shown 



II 



43 



^ 



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., utilization 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 in the beginning for 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 technology. 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 contribute 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 moderately successful operations is observed. Should this observation 
prove to be consistent in time, it can become a valuable management tool for 
this Program. 



44 



OBSERVATION ON RESOURCE 
EFFECTIVENESS FROM FY' 73-74 DATA 



7000 









o Active resource v/lth future 
funding commitment. 




o 




6000 


- 




• Active resource undergoing 
phase out following Council 
disapproval of renewal request. 








5000 


- 













4000 


• 













3000 














2000 


- 












1000 


o 


o 


o 

^o O 

o 

G 

• 











_•_ 




o o 

1 1 1 1 


1 




-i 



1 



0.02 



0.04 



0.06 



0.08 



0.10 



0.12 



COST EFFECTIVENESS >TETRIC- 
TOTAL COMPUTER PRODUCTION HOURS /ATOUAL AVERAGE BRB FUNDS 



FIGURE I 
45 



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 1968-1973. 

BRB Dollars Per 1968 1969 1970 1971 1972 1973 

Computer Pro- 

duction Hour $91/hr. $70/hr. $72/hr. $52/hr. $32/hr. $27/hr. 



i 



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 
investigation 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 
contractors 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 con- 
tributing experience in computer technology and knowledge of information 
science, and DRR staff members have been providing overall direction. 

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 
research by developing an economical, readily accessible, widely usable 
computer system that, together with specially trained personnel, will help 
clinical investigators to collect, organize, store, retrieve, and analyze 
their research data. Past attempts to develop useful computer systems have 
often failed because development 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 situ- 
ations. Plans for the next phase include a well staffed, well tested, 
evolutionary approach which will 

• implement an initial prototype system; 

46 



i 



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 of the system at and providing 

personnel to an additional clinical research 

center where chere is no CLINFO contractor and 

by (passively) observing its use there. 



Thus in the next thiee years the project is to develop a prototype clinical 
research 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 

• a tested, practical system which can continue to 
operate at the four sites and which can be dupli- 
cated 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. 



>■ 



5 



BIOMOLECULAR CHARACTERIZATION RESOURCES 

During FY 1974 the scope of the Biomolecular Characterization Resources Program 
was expanded to encompass a broader range of capabilities within the areas of 
mass spectrometry and nuclear magnetic resonance spectroscopy. As illustrated 
in Table II, 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. 
Although the technology has not reached the status of a routinely useable tool 
for the clinical chemistry laboratory, sufficient experience was gained during 
FY 1974 to encourage continued emphasis in this area. 



47 



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. 

An important addition to the clinical mass spectrometry program resulted with 
funding of the Biomedical Clinical Mass Spectrometry Resource at the Space 
Sciences Laboratory, University of California, Berkeley. This Laboratory, 
originally financed through NASA, is making available to the clinical community 
extensive facilities and expertise assembled under the national space program. 
Of particular interest is the development of a combined gas chromatography/high 
resolution mass spectrometry system that should have numerous applications in 
the analysis of biological fluids containing minute quantities of unknown 
substances. 

In the area of nuclear magnetic resonance spectroscopy, a 360 MH 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. 

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 
specialized 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 

48 



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 20 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. The Colorado and Wisconsin 
Resources are prepared to allocate up to 50 per cent of the operating time and 
associated technical assistance to outside users, as the demand from this group 
increases sufficiently to require this amount of time. If more microscope time 
is needed for local or outside users, these facilities can operate additional 
shifts. 



During the past year 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 struc- 
tures 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. 

There is a need for better photographic emulsions for the HVEM. Emulsions 
presently available were developed for the lower voltage microscopes and are 
not as sensitive at one million volts. To meet this need BRB awarded the 
Roswell Park Memorial Institute a resource-related research project grant 
designed to develop more sensitive emulsions for the HVEM. The three BRB HVEM 
Resources will cooperate in testing and evaluating the emulsions developed by 
this grantee. 



'•I 



a 



BIOMEDICAL ENGINEERING RESOURCES 

A biotechnology resource specializing in microelectronics for health research 
was funded during this year. This resource is based upon an established program 
at Case Western Reserve University focused on strengthening biomedical engi- 
neering 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 anri patient care. The role of the biomedical 



49 



^> 



engineer in this setting is to reduce the research overhead of medical scien- 
tists by providing ways to gain information jhich is attainable only with micro- 
electronics techniques. 

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 p02 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 

• 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 processe s 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. 



RESOURCE SHARING - SUMMARY 

The following tables display and summarize 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. Table V suggests 
other DRR and NIH programs that might benefit from shared arrangements. 

50 






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 modelin;^ 

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 



TABLE V 
OTHER POTENTIALLY SHAREABLE RESOURCES 
Primate Centers 

Animal Research Resource Development Centers 
Clinical Research Centers 
Pharmacology-Toxicology Centers 
■ Dental Research Institutes 
Environmental Health Centers 
Sickle Cell Centers 



51 



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 sep- 
aration, 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. 

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 (broker function) . 

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. 



52 



Fiscal Year 1974 Annual Report 

Chemical /Biological In format ion- Hand ling Program 

Division of Research Resources 



Fiscal Year 1974 marked the continued maturation of the Chemical/Biological 
In format ion- Hand ling (CBIH) Program and its specialized computer resource 
called the PROPHET System. There was steady growth in all relevant para- 
meters of PROPHET usage (i.e., number of users, diversity of applications, 
intensity of user/ System interaction, and sophistication of user efforts). 
There also was steady elaboration of System capabilities by developers and 
users alike. This simultaneous evolution of both tool and usage produced 
operational problems to be solved, technological challenges to be met, and 
scientific opportunities to be seized. The following paragraphs summarize 
the events and issues which highlight the past year and promise further 
progress in the next. 



BACKGROUND 



THE CBIH PROGRAM 



The CBIH Program, in keeping with the mission of the Division of Research 
Resources, NIH, is concerned with providing biomedical scientists with the 
research support capabilities they most need to pursue their investigations 
effectively. The focus specifically is on (a) designing and developing 
computer-based in format ion- hand ling tools important to studies of chemical/ 
biological interactions (a line of inquiry relevant to almost every major 
medical area); (b) making these tools available to the national scientific 
community in an easy-to-use and highly reliable form; and (c) collaborating 
with the users of these tools in order not only to refine and extend them 
but also to develop deeper insights into the investigative process itself. 
Particular emphasis is placed on questions of where and how computer tech- 
nology and information science can catalyze the emergence of predictive 
capabilities regarding the interactions of chemical substances and living 
systems. 



THE PROPHET SYSTEM 



•V 



The heart of the CBIH Program is the PROPHET System, a computer resource 
specialized to meet the information-handling needs of individual laboratory 
and clinical investigators in the pharmacology/toxicology area. This 
resource is operated in such a way that its unique capabilities are available 
to qualified scientists on a national basis, irrespective of geographical 
location or institutional affiliation. A brief description of this research 
tool is included as an Appendix to this report. 



53 



SCIENTIFIC APPLICATIONS 

As of this writing, the services of the PROPHET System are available prin- 
cipally to scientists at the five sites indicated in Figure 1. At each of 
these sites there is located an identical configuration of equipment- -namely, 
graphic display device, hard copy unit, graphic input tablet, and telephone 
modem. In addition, scientists at two other institutions (Beth Israel 
Hospital in Boston, Mass., and Harbor View Hospital in Seattle, Wash.) make 
use of the System via more limited teletype- like terminals. 

The scientific problems being investigated with the aid of PROPHET span the 
spectrum from quantum pharmacology to human clinical investigation and map 
onto interest areas of most major NIH components. Figure 2 is a listing of 
those user projects funded by NIH/NIMH. This listing shows that the PROPHET 
System is employed within the "im'nstream of research on chemical/biological 
interrelationships. 

A particularly gratifying event in FY 1974 was the invitation to the CBIH 
Program to organize a two-hour session on the PROPHET project for the National 
Computer Conference (NCC). This meeting was an excellent opportunity to 
document in considerable detail in a widely read publication (the NCC Proceed- 
ings) both a characterization of the System and selected examples of the uses 
to which it is put. A description of the NCC Session on PROPHET is included 
as Figure 3. Reprints of the papers indicated are available on request. 

Looking to the future, there is good reason to believe that PROPHET'S positive 
impact on pharmacological science will continue. In addition to the present 
user groups, there are several other cadres of scientists whose proposed 
PROPHET uses already have been adjudged highly meritorious in national compe- 
tition before peer review panels and who await a terminal and accoutrements. 
Within the constraints imposed by the System capacity and the number of 
contractor personnel engaged, the CBIH Program places its highest priority 
on accommodating as many of these prospective users as is consistent with the 
continuing provision of reliable research services and the orderly development 
of prophet's capabilities. 

NEW CAPABILITIES AND FEATURES 

The PROPHET users provide the refining fire for the evolving array of 
information- handling tools offered by the CBIH Program's major contractors 
(Bolt Beranek and Newman Inc. and First Data Corporation). The users also 
are the single most valuable source of critique and guidance, as to which 
candidate new features merit development and in what form. Much effort has 
been and will continue to be expended toward making the PROPHET System user- 
driven. 

The principal results of this user-driven design/development process in 
FY 1974 are summarized in Figure 4. The new data type SAMPLE and its asso- 
ciated procedures represent a quantum jump in terms of easy-to-use data 
analysis tools and furnish a standard interface to guide the continuing 



54 



I 



PROPHET USERS AS OF JUNE 1974 



Department of Pharmacology 
School of Medicine 
University of Pittsburgh 
Pittsburgh, Pennsylvania 



2. Harvard Medical Unit 
Thorndike Memorial Laboratory 
Boston City Hospital 
Boston, Massachusetts 

3. Department of Pharmacology 
Mount Sinai School of Medicine 
City University of New York 
New York, N. Y. 

4. Molecular Biophysics Department 
Medical Foundation of Buffalo 
Buffalo, New York 

5. Research Institute on Alcoholism 
New York State Department of 
Mental Hygiene and 

State University of New York at Buffalo 
Buffalo, New York 



V 



2 



Figure 1. 



55 



USER PROJECTS FUNDED BY NIH/NIMH 

University of Pittsburgh: 

MH- 11682- 07 Hallucinogenic drug action on somatosensory 
systems (primates) 

AI-08192-06 A phenotypic resistance to tetracycline 
(bacteria) 

NS- 07923- 06 Nervous control of urinary bladder and 
large bowel (cats) 

Boston City Hospital (Harvard Medical Unit): 

RR- 00076- 12 General clinical research center . 

GM- 19954- 02 Factors inducing the abnormal metabolism 
of trauma 

GM- 20630- 01 New concepts in parenteral protein sparing 
therapy 

ES-33332 Epidemiologic studies and chronic respira- 
tory diseases 

AI- 04716 Eosinophil functions 

HL-5988-01 Clinical epidemiology of heart and lung 
disease 

HL- 10539- 08 Pathophysiology of the circulation 

HL-15571-02 Water and electrolytes in health and 
disease 

HL- 16237- 01 Computer feedback study of cardiac muscle 
mechanics 

AM- 05060 Metabolism training program 

AM- 05413 Nutrition training program 

AM-08681 Diseases of the liver and portal 
circulation 



G. 


Werner 


R. 


H. 


Connamacher 


W. 


C, 


DeGroat 


F. 


H. 


Epstein 


G. 


H. 


Clowes 


G. 


L. 


Blackburn 


F. 


E. 


Speizer 


M. 


Li 


tt 


F. 


E. 


Speizer 


W. 


H. 


Abelmann 


F. 


H. 


Epstein 


0. 


H. 


Bing 


D. 


A. 


Arky 


C. 


S. 


Davidson 



W.V.McDermott,Jr. 



(continued) 



Figure 2, 



56 



1 



Mount Sinai School of Medicine: 

MH-17489-03 Psychopharmacologic activity -- quantum 
chemical study (rats) 



MH- 25644 



Psychopharmacological changes following 
brain damage 



Medical Foundation of Buffalo: 

AM-05619-05 Training Program in Endocrinology 

AM- 15051- 03 Molecular structures of thyroactive 
compounds 

CA-10906-07 Molecular structures of steroids 

CA- 13540- 02 Cancer of the thyroid and its hormonal 
identity 



GM- 19684- 02 



lonophores, transport and membrane 
structure 



HD-94945-04 Human development and estrogen bio- 
synthesis 

HL- 15378-02 Ultrastructure of antihypertensive 
prostaglandins 

Research Institute on Alcoholism; 

Still in only its first year of operation, this Institute 
now receives the bulk of its research support from New York 
State. Several grant applications now are under review, 
however, by the NIH and other components of the DHEW. 



J. P. Green 
S. Click 

H. Hauptman 

H, Hauptman 
W. L. Duax 

E. M. Volpert 

W. L. Duax 

Y. Osawa 

J. Edmonds 



S 



Figure 2. (cont'd) 



57 



1974 NATIONAL COMPUTER CONFERENCE AND EXPOSITION 

May 6-10, 1974 

McCormack Place, Chicago 

Session Description 
Title: The PROPHET System: Computing in Pharmacology 



Introduction 



The Implementation of the PROPHET System 



Applications of the PROPHET System in 
Correlating Crystallographic Structural 
Data with Biological Information 



William F. Raub, Ph.D. 
National Institutes of Health 

Paul A. Castleman 

Bolt Beranek and Newman Inc. 

Charles M. Weeks, Ph.D. 
Medical Foundation of Buffalo 



Carl L. Johnson, Ph.D. 



Applications of the PROPHET System in 

Molecular Pharmacology: Structure Activity Mount Sinai School of Medicine 

Relationships in Monamine Oxidase Inhibitors 



Applications of the PROPHET System in 
Human Clinical Investigation 

Measurement and Enhancement of PROPHET 
System Performance 



Bernard J. Ransil, M.D., Ph.D. 
Boston City Hospital 

David D. Friesen 
First Data Corporation 



Figure 3. 



58 



MAJOR NEW FEATURES IMPLEMENTED IN FY 1974 

1. The data type SAMPLE 

2. The data type MULTIMOLECULE 

3. Molecular substructure search 

4. Bulk da La entry 

5. TABLE/TEXT scanning 

6. TABLE output on teletype/line printer 

7. TABLE archiving 

8. Terminal linking 



Figure 4. 



2 

m 

I 



59 



accretion of statistical procedures. The MULTIMOLECULE feature allows the 
visualization and manipulation of two or more molecular models in the same 
three-dimensional coordinate space, a capability of obvious utility for the 
study of molecule/molecule interactions. The substructure search option 
makes possible the selective retrieval from a file of molecular structure 
descriptions of only those molecules containing a specified subgraph. The 
remaining items contribute in their several ways to making the System more 
flexible and more convenient to use. Copies of the PROPHET System User's 
Manual are available on request to those readers interested in a more detailed 
description of these and other capabilities. 

The PROPHET users also are developers of new System features via their own 
programming and their collaboration with the PROPHET contractors. Examples 
are (1) the contributions of scientists at Boston City Hospital to the design 
and refinement of the data analysis tools built into PROPHET, (2) the addition 
by scientists at Mount Sinai School of Medicine of multi-exponential fitting 
routines and tabulations of molecular parameter values having general interest 
to quantum pharmacologists, and (3) the addition by scientists at the Medical 
Foundation of Buffalo of new molecule-handling procedures (including the 
classic ORTEP molecular model diagrams) and a unique collection of three- 
dimensional structural descriptions of over 200 steroids. These and other 
user contributions are or will be highlighted in the PROPHET System Public 
Procedures Manual. 

Still other new features come from outside the PROPHET community, for an 
important attribute of PROPHET is its ability to accept relatively gracefully 
large programs developed in other languages and on other computing facilities. 
This attribute was demonstrated in FY 1974 when the staff of Bolt Beranek and 
Newman Inc. arranged for Dr. W. T. Wipke of Princeton University to attach 
his molecular model builder to PROPHET. Dr. Wipke 's work Is generally 
acknowledged as the most nearly comprehensive algorithm for the generation 
of chemically plausible three-dimensional molecular models from only simple 
connectivity descriptions of substances, including those with arbitrarily 
complex ring systems. The capabilities of this program are scheduled to be 
offered to the PROPHET users via the COMPUTE MODEL command early in FY 1975. 

An analogous major accretion in capability, this time In the area of mathe- 
matical tools for PROPHET users, is planned for FY 1975. CBIH Program con- 
tractors are designing and implementing a communication Interface between 
PROPHET and MLAB, a powerful software system developed by Knott and Reece of 
NIH's Division of Computer Research and Technology for fitting various 
functional forms to experimental data. The immediate objective of the work 
on a PROPHET/MLAB interface will be to allow MLAB to operate on data contained 
in PROPHET TABLES. MLAB's capabilities should prove Invaluable to PROPHET 
users for data summarization and should represent a significant step toward 
offering easy-to-use tools for modelling and simulating the behavior of 
pharmacological systems. 



60 



SYSTEM PERFORMANCE 

No matter how diverse and sophisticated their information-handling capabili- 
ties, computer systems must also offer good service if they are to be welcomed 
into the milieu of computer- naive biomedical scientists. And good service 
means many things: (1) hardware and telecommunications lines which function 
reliably all day long and every day of the week; (2) commands and other System 
features which perform "as advertised" in the various manuals; (3) assured 
integrity and privacy of users' files; (4) rapid System response, at least to 
simple requests; (5) low variance in command completion times within and 
between usage sessions; and (6) continuing introduction of System improvements 
with minimal impact on the appearance and availability of tried and true fea- 
tures. Making PROPHET "friendly"--and keeping it so--are high priority items 
for the CBIH Program. 



The quest for friendliness exacts high costs in human, machine, and fiscal 
resources. Extracting reliable performance from graphic display terminals and 
telecommunications services is a never ending battle. Maintaining adequate 
System response times (while simultaneously making functions as easy to use 
as possible and conducting a vigorous development effort in parallel with 
the service effort) is proving to be a severe test of technological and 
managerial skills. Clearly, as the numbers of terminal sites and users con- 
tinue to grow, the PROPHET contractors and staff not only must be careful to 
keep their demands on computer and telecommunications technology well within 
the state-of-the-art but also must be prepared to break new ground in the 
largely unexplored area of managing nationally shared computer resources for 
biomedical research, 

A wide array of efforts focused on performance improvement is ongoing within 
the PROPHET project and still others are planned. In the area of enhancing 
efficiency, for example, the, principal effort is continuous measurement and 
analysis of selected System utilization parameters under various conditions 
of user load. These studies help pinpoint where there are inefficiencies 
and processing bottlenecks and give rise to specific tasks designed to 
eliminate--or at least reduce the severity of--the key problems identified. 
Among these tasks in FY 1974 were (1) the addition of a special command for 
fast response, bulk data entry to TABLES, (2) receding the substructure search 
routine to reduce its running time, and (3) initial development of a second 
pass compiler which performs efficiency optimization on programs written in 
the PROPHET base language (i.e., most of the System). Also, CBIH Program 
contractors and staff developed an overall strategy for upgrading and/or 
reconfiguring both central facility hardware and remote terminal hardware 
over the years immediately ahead. If fiscal constraints permit this strategy 
to be followed, the new hardware will do much to insure high quality service 
and will accommodate more users while decreasing operating costs. 



61 



SELF CRITIQUE 

Evaluation of Federal programs is difficult at best and impossible at worst; 
and the obligation to do so seems most frequently honored in the breach. 
Those removed from day-to-day operations generally cannot wrap the correct 
context around their observations and impressions. Those "in the trenches" 
often find that adrenaline and introspection don't mix. Nevertheless, the 
question "Is this trip really necessary?" is as relevant to the PROPHET pro- 
ject as to other claimants on the public purse and deserves an answer. The 
reader of the following paragraphs hopefully will appreciate the gesture, 
indulge the euphemisms, and forgive the bias. 

First, the good news! The PROPHET System has been in service for over two 
years and is working well. Pharmacologists who once were either intimidated 
or repelled by computer technology now find PROPHET an inextricable part of 
their research life. Pharmacologists who once made only low-level, arms- 
length use of computers via packaged statistical programs now practice a 
style of graphically oriented, interactive data analysis that is at times 
awe-inspiring. Phaimacologists who once limited their investigative horizons 
to data gathering and simple hypothesis testing now find they can formulate 
at least simple mathematical models and use them to organize their knowledge 
and guide their future experimental work. And finally, to include some 
management parameters, the PROPHET project after six years total effort is 
on course, on schedule, and within budget. 

Now the litany of frustration and disappointment! 

1. The PROPHET System is expensive. Making a comprehensive set of 

in format ion- hand ling functions easy to use means very big computer 
programs and a very big machine on which to run them. The successes 
to date notwithstanding, PROPHET has a long way to go to be self- 
sustaining via user fees and/or readily replicable. 

2. PROPHET service is often sluggish. The need to do development and 
service on the same equipment produces inevitable conflicts for machine 
resources. The conflicts usually manifest themselves as slow response, 
and users' productivity and satisfaction diminish accordingly. 

3. The technology leaves a lot to be desired. Neither graphic display 
terminals nor digital telecommunication services seem able to with- 
stand the challenge of PROPHET' s demands without the near constant 
ministrations of well trained and high priced people. 

4. PROPHET project management needs strengthening. The continuing 
operation and development of PROPHET involves an interdependent set 
of contracts whose constituent task orders must mesh cleanly for 
everything to function smoothly. After two years of service operation, 
there remain some areas where the corporate performance of contractors 
and NIH staff in responding to user problems and requests could be 
improved. Also, more attention to assuring the quality of the mathe- 
matical software is indicated. 



62 



The PROPHET System generally needs a protagonist before it penetrates 
a new research environment. The most successful terminal installations 
feature on-site at least one highly motivated user who feels personally 
responsible for helping System personnel to overcome problems and 
colleagues toappreciate PROPHET features that aren't intuitively obvious 
to the uninitiated. The only installation which failed during PROPHET'S 
first two years of service might not have if the CBIH Program manager 
had paid more attention to cultivating such an advocate before a remote 
facility was established; for what should have been short-lived problems 
became chronic, what should have been minor hurdles became major obstacles, 
and the result was unsatisfactory to all concerned. The scientists at 
!u^%!t,? ''^'■^ justified in not adopting the System. The mistake was 
the CBIH Program manager expecting PROPHET to sell itself. 

PROPHET protagonists are hard to find. While PROPHET clearly has 
succeeded in attracting to it many well trained scientists doing high 
quality work in the mainstream of pharmacology research, many others 
remain unaffected by knowledge of the System's existence or skeptical 
as to Its value, By and large, the burden of proof still rests with 
those who advocate the technology and the expanded opportunities that 
powerful tools can offer a prepared mind. 



OUTLOOK 

Weighing both the promises and the problems in the balance, the outlook for 
the PROPHET System is encouraging. The stage is set for steady maturation 
as a nationally shared computer resource. There are no problems that 
shouldn't give way to good taste, good management, and enlightened tenacity. 
There are more high quality, enthusiastic applicants than capacity to accom- 
modate them. The basic PROPHET tools have stabilized to a considerable 
degree. The capability for graceful accretion of important information- 
handling functions developed outside the PROPHET project has been demonstrated. 
The PROPHET users are finding more and more areas where the System enhances 
their research productivity. And PROPHET- media ted sharing of programs and 
data bases among geographically separate groups is beginning to be practiced. 



The fruits of more than a half-decade of work are emerging, 
has begun. 



The harvest 



2 

I 

r 



63 



APPENDIX 
Description of the PROPHET System 

The PROPHET System is a unique, large-scale computer resource designed and 
developed exclusively for the study of chemical/biological interrelationships. 
Its long-range goal is to accelerate the growth of a predictive science in 
this area. Its immediate objective is to facilitate a broad spectrum of 
laboratory and clinical investigations concerned with how chemical substances 
influence- -and are influenced by-- life processes. PROPHET seeks to fulfill 
both of these purposes by making powerful computer-based information-handling 
methods available to individual scientists in a convenient and easy-to-use 
form and by encouraging computer-mediated sharing of data, programs, and the 
like among PROPHET users. 

The PROPHET System hardware/software complex is the result of over five years 
of effort by contractors, advisors, and staff of the Chemical/Biological 
In format ion- Hand ling (CBIH) Program. The software is an extensive array of 
highly integrated special-purpose programs designed and developed by Bolt 
Beranek and Newman Inc. (BBN) of Cambridge, Mass. The hardware is a time- 
shared, digital computer (a Digital Equipment Corporation PDP-10) acquired 
by the NIH specifically for the PROPHET project and housed and operated by 
First Data Corporation (FDC) of Waltham, Mass. A PROPHET user accesses the 
System remotely via a graphic display terminal (the Computek 400) communicating 
over telephone lines. 

The PROPHET System has five features that jointly set it apart from other 
research computer systems: 

1. It is established as a national resource especially for the 
community of scientists concerned with chemical/biological 
interrelationships. 

2. It can be mastered readily by scientists who have little or no 
prior computer experience. 

3. It can be applied effectively to a wide range of complex information- 
handling tasks relevant to chemical/biological interrelationships 
without the user having to write any computer programs. 

4. It can accommodate very sophisticated users /programmers, integrating 
user-prepared procedures automatically into the basic System. 

5. Through the medium of a set of standard logical frameworks (called 
data types) for organizing experimental data, molecular structure 
descriptions, and the like, it seeks to promote the sharing of 
information among users. 

In short, PROPHET is neither a general-purpose facility nor an information 
service in the traditional sense. Rather, it is a computer resource whose 
information-handling power is deliberately concentrated in a few specific 
areas and whose capabilities can grow In a highly orderly way in response to 
users' requirements. 



64 



^l^^ T d^ta and molecular structure descriptions. Conversing with 
matter of r "' ' ^igh level command language (which can be mastered in a 
redefine at will'the'^'' ^^^"^^f ^ -"' ^^"""^ °*^^^^ ^^-S=' ^^) ^efine-and 
their pe.sonIii;;earchdat../ 'f "' "''^'" '^^ ""P"^^^ *^° accommodate 
ture (t) .^^\n nll^. It "^""^ ^^^^ ^^^'^h '^h^y extract from the litera- 
ture (b) add to or alter the content of existing tables and produce displays 
of all or any parts of tables in either tabular or araohical fnm,- r.^ l 

operations on the content of these tables; and (d) share selected tables 
and/or programs with collaborators who reside at geograp hically d istant 
locations. Moreover, for the specific case of mofecular structure descrlo 
dia'r^msT" Tu ^^^^^^^^^ ^° ^--ve input of two-dimensional st^ctirll 
diagrams drawn with a computer- control led stvlus and ^ah1o^ =>„^ I "cruccurai 
and manipulate displays o? three-dimensicnarmo ec^ ar m d 1 Ind'a'lfthe 
be el.'n' ?.''^ ''" '^ ^""°^^' ^^^°"S^ ^^^ high level command language can 

i:n;ui;^^cSrPKSH^x)!^^^ °™ ^^°^^^"^^^ ^'^^"^^ '--^-^^^ ^^o.i:z.r 

o;;iT"\^^'"' ''^^^ ^" ^"*^"" versions of the PROPHET System to offer not 
only extensions to and refinements of the present capabilities for hLdl.^c 

;ro^:eTSs"Lr^"n:tru:ti^^"^^^ "^^^"^^ '^^^^^^^^°'^ 

cesses ^n^^?^ ^""^ exercising models which simulate life pro- 
cesses Prototype implementation of these modelling tools alreadv is unL. 

each indlv?H, .1 °^ ^"^^^^'^'^^1 "^^^s- While there is no desire to abrogate 
each individual user's right to maintain his or her personal files ir,l%,^t 

witr:th:rf "h' "r".^^^ '^^^^ ^^^^^^^^^^^ ^° ^^-^ the r::iits :f tL r^oi^ 
with others who also have access to PROPHET. "-"^ir worK 



65 



I 



* 



Fiscal Year 1974 
Annual Report 
General Clinical Research Centers (GCRC) Branch 
Division of Research Resources CDRR) 

I. Introduction and Goals of the Progra m 

The primary goal of the GCRC Program is the establishment of a resource for 
the clinical investigation of humans in order to increase the total body of 
knowledge of the etiology, progression, prevention, control and cure of 
human disease. To meet this goal certain objectives have been established, 
i.e. the establishment of a resource to: 

a. Increase the knowledge of human physiology and 
pathophysiology by the investigation of the 
epidemiology, etiology, and progression of 
human disease by direct studies in man; 

b. Provide an optimal setting for the performance 
of controlled studies by clinical investigators 
supported tnrough NIH and other research support 
programs; 

c. Encourage and foster disciplinary interaction; 

d. Contribute to the maintenance of a national core 
of qualified clinical investigators; and 

I 

e. Develop technological and therapeutic advances 
to ensure the expeditious translation of 
fundamental biological knowledge into effective 
patient care. 

The GCRC Program evolved in response to the need for specialized facilities 
and trained personnel to meet the demands required by high quality clinical 
research. The study of human physiology and disease with its broad implica- 
tions for the maintenance and restoration of health requires an optimal 
■environment. Furthermore, a single specialized research unit effectively 
meets the needs of investigators studying a variety of categorical disease 
problems in the most effective and economic fashion. 

In 1959, Congress expressed the view that the Nation deserved and should re- 
ceive the benefits of basic research as rapidly as these became available. 
Passage of P. L. 86-798 established the legislative basis for the program, 
and in 1960 Congress appropriated $3 million for the establishment of the 
GCRC's. These units were designed as a locus for clinical investigation; 
they were created to supplement rather than supplant the ongoing medical 
research in universities and hospitals. 



r! 



The NIH defined a clinical research center as "a distinct organizational and 
physical entity providing a continuing framework for a clinical research 
effort, including the necessary laboratory, clinical, and supporting services." 



67 



A center would provide the skilled personnel and an optimal and secure environ- 
ment for human research. 

Specifically, a GCRC was to be a resource to a medical institution permitting 
enhancement of the quality of clinical investigation. This was accomplished 
by establishment of a discrete physical unit or research ward, apart from the 
general care wards, with the well trained staff needed for precise control and 
observation. The research conducted in the center derives its support from the 
various institutes of the NIH as well as from numerous foundations and philan- ^. 
thropic organizations. Funds from the GCRC Program were intended primarily for ^] 
the establishment and maintenance of the separate discrete unit in which clinical 
research was done. 

A center consists of four to 30 beds, the average number being eleven. A typical 
center contains bedrooms, treatment rooms, a core laboratory, diet kitchen, 
patient's lounge, nurses' station, and conference room. Centers can usually acom- 
modate both adults and children but about one-fifth. of the centers are entirely 
pediatric. Several centers specialize in areas involving premature infants, 
maternal-child, or acute surgical problems. 



Over 13,000 individuals are involved with the centers. Center grants provide 
salary support for staff numbering approximately 1,800. Currently, the program 
consists of 83 centers supported throu^the Division of Research Resources, pay- 
ing 83 percent of the extramural research patient care costs funded by NIH. 
Within the centers, senior scientists, research fellows, and house staff are 
exposed to increasingly sophisticated methods and concepts of clinical research. - 
Such training is essential for the continued development of competent investiga- * 
tors and improved medical care in the Nation. An additional benefit of these 
centers is that future medical practitioners develop knowledge that facilitates 
critical evaluation of new medical discoveries with which they will be confronted 
in the course of their careers. In addition, the centers assist in the training 
of large numbers of paramedical personnel. They are usually the primary hospital 
facility in which nurses, dietitians, and laboratory technicians gain practical 
experience in newly developed patient care techniques. 

The GCRC Program grew at an almost constant rate between 1960 and 1967. In the 
past few years, rising costs and fiscal restraints have prevented expansion and 
have forced support for fewer centers and a decreasing number of beds. During 
1974, the GCRC Program supported 83 discrete inpatient centers plus two outpatient 
centers and one surgical scatter-bed center. The inpatient GCRC is a discrete 
center, is a geographical unit with a complement of research beds, a cadre 
of highly skilled research personnel, laboratory facilities, metabolic kitchen, 
and whatever supporting facilities are required to provide the rigid control 
and precise environment needed for clinical research . Scatter-beds are regular 
hospital beds normally used for patient care which may be utilized in certain 
situations for research purposes when they provide unique investigative opportu- 
nities. 

Although centers exist in about two-thirds of the teaching medical institutions, 
a number of such institutions with great potential do not have centers. Table I 
depicts the program history since 1967. The Program has operated reasonably 
effectively m the face of sharp inflationary rises and modest budget increases 
through a number of adjustments, such as termination of support to a number of 

68 



centers, reducing the number of beds supported, savings realized through new 
) discrete costing procedures, service patient policy, and some research carried 
out on an outpatient basis rather than an in-patient basis. Table II provides 
the results of a recent survey on the overall (professional, nursing, dietary, 
etc.) personnel cost increases per position since FY 1969. 



Table I GCRC Program, FY 1967 - 1975 













Full -Time 
















Equivalent 






Fiscal 


Medical 


Number 


Funded Patient 


Positions 




Apportionment 


Year 


Schools 


f Cent 


ers 


Beds Days Funded 


Funded 




I 


in mousands) 


1967 


62 


91 




1131 260,176 








$ 28,463 


1968 


62 


91 




1051 277,663 








30,443 


1969 


64 


91 




1023 284,064 


2,297 






35,004 


1970 


64 


93 




940 252,094 


1,920 






35,004 


1971 


56 


82 




881 238,227 


1,885 






38,004 


1972 


58 


84 




907 246,638 


1,867 






42,181 


1973 


59 


83 




903 239,167 


1,790 






41,300 


1974 


63 


83 




890 228,417 


1,767 






42,405 


1975 


63 est. 


83 


est. 


840 est. 200,000 est. 1,700 


est. 


42,485 est. 










Table II 














% Increase In Personnel Costs. 














FY 


1969 


-1974 (in thousands) 












Fiscal Year 






Ave. Cost/Postion 


%_ 


of 


Increase 




1969 






8,335 












1970 






9,244 




10 


9 






1971 






10,228 




10 


7 






1972 






10,985 




7 


4 






1973 






11,746 




6 


9 






1974 






12,785 




8 


8 





Despite budgetary constraints in recent years, the program continues to support 
the best available resources for clinical research. Roughly two-thirds of all 
hospital beds in the Nation specialized for research on humans are supported 
by this program. 



I 



During 1967-74, a dynamic exchange of beds and centers has occurred within the 
program. In 1967, 1,131 beds were approved in 91 centers. In subsequent 
Scientific reviews, 23 centers with 192 beds were disapproved and NIH support 
terminated. An additional 251 beds on the basis of limited scientific pro- 
ductivity in 46 centers were eliminated with corresponding staff reductions. 
During this same period, 12 new Centers and six reapproved centers (with revised 
applications of higher scientific merit) for a total of 161 beds were funded. 
In addition six of the centers given two year renewals have worked closely with 
staff in revising their programs to compete successfully with programs of higher 
scientific merit. The net result has been a substantial improvement in the 
I overall scientific quality of the program and the funded beds now correspond 



69 



closely with the bed needs of investigators holding NIH-sponsored grants and 
contracts. Despite these reductions and modert increases in appropriated and ^1) 
apportioned funds, rising costs have outstripped available funds. This dif- 
ferential has been met in part through appropriate collections from third 
party carriers initiated in 1970 and in part by encouraging investigators to 
carry out some of their activities through less expensive outpatient protocols, 
whenever feasible. 

II. Modifications and Innovations 

i 

Through the years, the GCRC Program has been responsive to the changing needs ^ 
of the GCRCs by modification of program components. The Branch has also been 
active in anticipating the .needs of the centers and in generating and develop- 
ing resources which facilitate clinical investigation. The following is a 
list of some of the program modifications and innovations of the past seven 
years : 

Outpatient Program 

With program funds beco'ning progressively exiguous and with escalating hospital- 
ization and personnel costs diminishing the value of available funds, an optional 
outpatient program was initiated in 1970. A capability in ambulatory patient 
research enables more latitude in clinical research protocols and promotes max- 
imum efficiency of research dollars. To date, 50 centers have exercised this 
option and two centers have applied for and received support for separate out- 
patient facilities. It is estimated that approximately 40,000 outpatient visits 
will be conducted at the centers in FY 1974. 

Service Patient Policy 

In 1969, program policy was modified from supporting solely inpatient research 
to allowing grantees the option of admitting category B, "service patients" to 
the center. A category B service patient is "a patient admitted to a GCRC 
primarily for care, but who is also participating in a research protocol". 

Service patients are fiscally responsible for their care in the GCRC, as they 
would be if admitted to a regular hospital bed for treatment or diagnosis. 
However, when patients participate in a research protocol the center is 
charged for that portion of their hospitalizaion. 

Clinical Research in Surgery 

Because GCRCs are not designed to provide surgical services, research in 
surgical procedures is somewhat limited. An experimental award v/as made to 
provide an institution with surgical resources for clinical research. The 
GCRC Branch anticipates that an evaluation of the research productivity will 
be made in the near future. 

CLINFO 

CLINFO is a scientific inquiry sponsored jointly by the Biotechnology Resources 
and the GCRC Branches of DRR. It is aimed at identifying and characterizing the 
intellectual tasks and information flows in clinical investigation and at 

70 



i 



developing methods for facilitating these tasks and flows, possibly with the 
. aid of computers. It was initiated in 1972 subsequent to recognition by DRR 
r that a need for a better information system existed in the clinical investigatory 

process. Currently, a consortium of clinical investigators and a computer 

contractor is studying the problem. 

Discrete Unit Costing 

In 1970, the GCRC Branch developed a new accounting method for discrete bed 
centers in hospitals whereby "space charges" are negotiated and paid on an 
i annual basis, while ancillary services (x-ray, laboratory, etc.) are charged 
on an item-by-item basis. This has resulted in substantial savings in many 
centers and in better management of center dollar resources. Negotiation of 
these current rates has lagged due to regionalization of the Office of Grants 
Administration Policy, DHEW. Additional staff is needed in the GCRC Branch to 
expedite these negotiations to realize the full potential savings possible. 

Contribution Papers 

To demonstrate some significant GCRC resources contributions towards the accum- 
ulation of new medical knowledge, a series of contribution papers were written 
by center investigators and by GCRC Branch staff. The contribution papers which 
are available from the Branch are: 

a. Atherosclerosis Contribution Paper; The Roll of Clinical Research 
in the Development of Knowledge in this Medical Area. 



i 



!i 



b. Growth and Development: Research into the Early Years of Life 

c. Drug Abuse 

d. Studies on Narcotic Addiction 

e. Diabetes 

f. Sickle Cell Anemia 

g. Cancer 

h. Transplantation 

Annual Ranking of Centers 

Anticipating continuing inflation and relatively fixed budgets, the GCRC Branch 
staff, also in 1970, devised a mechanism by which centers of lower scientific 
merit may be identified and withdrawn from program support equitably and with 
minimal disruption to the program as a whole. Under this new mechanism each 
new or renewal application is reviewed in its preterminal year and is ranked 
along with all other new and renewal applicants reviewed within that fiscal year. 
Among other advantages, centers face uncertainty as to their continuation in 
only the preterminal year of each project period. Once support is committed, 
a center can, within reasonable limits, be assured of continued support until 
its next competitive review. 






71 



Resource-Related Research Grants 

The Resource-Related Research Project Grant was established in 1973 to improve 
the research capabilities of the GCRCs through application of existing scientific 
technologies to clinical research or through development of new, or modification 
of existing, technologies and their application to clinical research. 

Clinical Associate Program 

Meritorious investigation necessitates the maintenance of a highly qualified 
core of clinical investigators. Until recently, training of these investigators 
was supported by various training programs. In fiscal year 1971, a total of 
$206,979 in fellowship support, $3,205,048 in research development awards, and 
$17,386,305 in training grants were identified as support for projects using the 
GCRCs. Because the status of this support is uncertain, it may become increas- 
ingly difficult to meet the objectives of the GCRC Program. 

To compensate for this projected loss of scientific manpower, the GCRC Program 
instituted the Clinical Associate Physicians Program in October 1973. This 
program is work-oriented to accomplish the following research goals: 

1. Provide competent senior clinical investigators 
undertaking studies on GCRCs with an important 
component of the research team to satisfactorily 
accomplish their research goals. 

2. Provide an opportunity for promising young 
medical scientists with demonstrated aptitude 

in research to develop into independent clinical 
investigators . 

3. Supplement professional patient care for patients 
on the center. 

4. Provide core laboratory direction and assistance 
by clinical associates. 

To date, nine centers have approved clinical research associate positions. 
Mixed Centers 

A few centers have been tried where a limited number of Category C service 
patients (not on a research protocol) are mixed with research patients. This 
has proven a satisfactory method of center operations in select centers pro- 
vided proper administrative controls are exercised. 

NIH Clinical Research Coordinating Group 

In FY 1973, the General Clinical Research Centers Program provided 83% of the 
NIH-awarded research patient care cost and the categorical Institutes provided 
$108 million to investigators using the General Clinical Research Centers. A 
coordinating group, established in 1974, will facilitate the effective inter- 
action of NIH extramural clinical research, ensuring that the maximum potential 

72 



of clinical research resources be realized. With increasing contract agree- 
ments being established, a Coordinating Group will recommend uniform policies 
for using contract funds to offset "ancillary" studies on patients hospitali- 
zation on the Centers. 

Third Party Payments 

In 1970, the Program initiated a policy of charging third parties for patients 
on the research centers for time which they would normally have been admitted 
for therapy. Table 111 presents the dollars that have been credited to the 
General Clinical Research Centers Program in 1972 and 1973. 



TABLE 


III 


Service 


Patient 


Credits 


to the 


GCRC Program 



FY Credits 



1972 $2,935,282 

1973 $5,354,985 

This practice is now yielding nearly a ten percent saving of funds. 



\t 



The evaluation began in December, 1971. A General Clinical Research Centers 
subcommittee was established to advise and assist staff. A staff committee 
comprised of the General Clinical Research Centers Branch scientific and grants 
management staff, Program Analysis Branch staff, and the Special Assistant for 
Program Evaluation, DRR together with the subcommittee, devised an evaluation 
format consisting of three phases in which objectives were defined, program 
components were evaluated, and recommendations were formulated. This formal 
lln-depth review ended in February, 1974. The evaluation data was assembled and 

73 



D 



Program Evaluation t, f 

The General Clinical Research Centers Branch undertook a program-wide review 
in response to a DHEW evaluation policy stated by the Secretary in an October 
1, 1969, memorandum which states in part: 



2: 



We are faced with stringent budgets in the years 

ahead. This challenges all of us to insure that 

the programs this Department administers are having 

maximum impact. I have told the President and the Jf 

Congress who are also very much concerned about the J 

effectiveness of our programs that we will meet this 

challenge by making a comprehensive effort to improve r™ 

their managment and determine how successful our i •«» 

programs are in reaching their objectives. This r 

requires a substantial increase in the evaluation « 

efforts of the operating agencies and the Office of f 

the Secretary, all of whom have an important role to ,„ 

play. 






critically reviewed by the General Clinical Research Centers Branch, the Office 

of the Director, DRR, the General Clinical Research Centers Committee, and the { 

National Advisory Research Resources Council, with respect to the achievement 

of each specified objective. 

The following summarizes the evaluation evidence that the program achieved its 
stated goals: 

Goal #1. For the clinical investigation of humans in order to 

increase the total body of knowledge of the etiology, progression, | 

prevention, control, and cure of human disease. 

In FY 1974, there are 83 General Clinical Research Centers 
utilizing approximately 890 research beds in 76 institutions, 
including 63 medical schools. More than 83% of NIH support 
of research patient care cosL in 1972 and 1973 was provided 
by the General Clinical Research Centers Program. 

Goal #2. To increase the knowledge of human physiology and pathophysiology 
by the investigation of the epidemiology, etiology, and progression of 
human diseases by direct study in man; and with this knowledge develop 
technological and therapeutic advances to ensure its expeditious translation 
into effective patient care. 

The Contribution Papers (see page 71 ) highlight selected areas of 

the investigations undertaken on the centers and illustrate the vital 

role the centers had in elucidating disease processes and developing M 

effective preventive and therapeutic measures. ' 

Publications and presentations were tabulated for FY 1971 to 
demonstrate the scope of research and quantitate investigative 
productivity. A total of 3,911 publications appeared in 481 
books and journals and were presented at 522 scientific meetings, 
and were attributed to research performed on the centers. 

Goal #3. To provide an optimal setting for the performance of 
controlled studies by clinical investigators supported through 
NIH and other research support programs. 

General Clinical Research Center investigators reported DHEW 
support of their research, other than General Research Support 
and General Clinical Research Centers Branch support, for the 
years FY 1970, FY 1971, and FY 1972, was $91,178,222, $94,126,380, 
and $108,574,618, respectively. More than 95% of this federal 
support came from NIH. By FY 1972, General Clinical Research 
Centers investigators reported nonfederal support from 305 grants 
from 173 foundations and private sources to support 628 protocols. 
Program Directors and their assistants competed successfully for 
$9,094,995 of non-GCRC support from 125 NIH grants and contracts 
in FY 1971. 



74 



Goal #4. To encourage and foster disciplinary interaction. 

Anatomical and pathophysiological codes of the types of research 
performed on the GCRCs was developed by the Program Analysis 
Branch to indicate the magnitude of studies in various bodily 
systems. These data were compiled for FY 1970, 1971, and 1972 
and indicate the broad range of research being conducted at the 
GCRCs. A listing of the numbers and titles of research protocols, 
patient discharges, patient days, and approximate GCRC dollar support 
for the various anatomic and pathophysiologic codes is available 
from the GCRC Branch. 

Goal #5. To contribute to the maintenance of a national core of qualified 
clinical investigators. 



In order to determine tne commitment to medical research training 
on the GCRCs, the number of medical students, interns, residents, 
fellows, dietary interns, and nurses trained on these centers in 
FY 1970 and FY 1971 as part of their educational experience in 
research wa; tabulated. About 3,000 students trained on the centers 
in FY 1970 and FY 1971. In addition, approximately 4,000 house staff 
and fellows trained on the centers in FY 1970 and FY 1971. Approximately 
1,000 nurses and dietary interns received training during FY 1971 and it 
is believed that the educational experiences in research will influence 
their careers in clinical investigation. An additional means of 
contributing to the maintenance of a national core of full-time personnel 
dedicated to clinical investigation is through the direct support of 
professionals. In FY 1971, Program Directors and their assistants 
received direct salary support for 124.4 full-time equivalent positions. 

As a result of the evaluation study, a number of recommendations have 
been formulated and are in various stages of implementation. These 
recommendations are briefly discussed below. 

1. Annual Ranking of Centers (see page 71) 

Since 1970, a ranking system based on peer review by the best available 
scientific talent has been developed and refined with the GCRC Committee 
and National Advisory Research Resources Council. The system allows 
competition between new centers of excellence and existing centers and 
permits continued upgrading of the quality of the program. This system 
should be continued. 



r 



2. Outpatient Research (see page 70) 

It is recommended that this program be expanded where possible; it 
appears to be an effective means of increasing clinical research 
opportunities in selected areas at moderate cost. 



ii. 



75 



3. Third Party Payments (see page 73 ) 

It is recommended that this policy be continued and refined to maximize 
research dollar efficacy. 

4. Clinical Associate Program 

It is recommended that this Program be continued. 

5. Mixed Centers (see page 72 ) 

This method of operation deserves further evaluation because it allows 
flexibility in matching center bed size to scientific need and productivity. 

6. Discrete Unit Costing (see page 71) 

Additional staff is needed in the GCRC Branch to expedite negotiations 
to realize the full savings potential. 

7. CLINFO (see page 70) 

Implementation of a data collection and analysis system (CLINFO) may 
facilitate investigations in the GCRCs . Further investigation is being 
done to determine the feasibility and applicability of this project. 

8. Contribution Papers (see page 71) 

These papers seem to be effective in illustrating program accomplishments. 
They illustrate the vital role the centers had in elucidating disease 
processes and developing effective preventive and therapeutic measures. 

9. Resource-Related Research Grants (see page 72) 

It is recommended that this type of research grant be further evaluated 
as an instrument to stimulate the development of techniques derived 
from mathematical, engineering, and biological sciences for use in the 
GCRCs . 

In summary, the evaluation has provided an opportunity for in depth study of 
the program by Branch and Division staff and its extramural advisors. Several 
areas for further study have been identified and are in various stages of 
exploration, including new methods of center operations. 

Data from the evaluation study have been presented to extramural advisory groups, 
and to the NIH Executive Committee on Extramural Affairs and will be used in 
program review activities during the coming year. A major difficulty has been 
the lack of staff resources to adequately execute a number of identified 
potentially fruitful activities. 



76 



The following documents are available as the full evaluation report: 



Volume I 



Volume 2 



1. History of the General Clinical 
Research Centers Program 

2. Program Data Paper 

3. Contribution Papers 

4. Program Modifications and Innovations Document 



III. Training 

A paramount problem today in the area of clinical research is the dwindling 
number of talented senior investigators with the growing demands on their 
research time because of increased teaching, service, and administrative 
responsibilities. The program serves an important function by providing 
institutions with an essential resource where young physicians participate in 
the work of experienced clinical research teams and assist busy senior invest- 
igators . 

Within the centers, senior scientists, research fellows, and house staff are 
exposed to increasingly sophisticated methods and concepts of clinical research. 
Such training is essential for continued development of competent investigators 
and for improved medical care of the Nation. In these centers, future medical 
practitioners develop foundations of knowledge that facilitate critical evalua- 
tion of new medical discoveries with which they will be confronted in the course 
of their careers. In addition, the centers assist in the training of large 
numbers of paramedical personnel. They are the primary hospital facility in 
which nurses, dietitians, and laboratory technicians gain practical experience 
in newly developed patient care techniques, generally resulting in better 
quality of hospital care. Table III shows the numbers of individuals receiving 
training in the GCRC during the past five years. 

Table III. Training in GCRCs, 1968-1972 





1968 


1969 


1970 


1971 


1972 


Medical Students 


2538 


2939 


3065 


2872 


3152 


Interns 


863 


1019 


911 


921 


873 


Residents 


1576 


1870 


1751 


1646 


1745 


Fellows 


1227 


1340 


1321 


1169 


1281 


Dietary Interns 


404 


422 


487 


578 


460 


Student Nurses 


697 


1066 


1089 


914 


944 


IV. Fis.cal Summary 













f 



Figure I gives program appropriations ceilings since 1966. Appropriations have 
not been adequate to meet recommended expenditures. It can be seen from Figure II 
that personnel and hospitalization costs have been the key factors in the rising 
costs of the program. Despite the decline in beds, hospitalization and personnel 
costs have continued to increase. 



77 



y. Program HighlJRhts 

As will be seen, investigators have used centers for the study of virtually 
all aspects of human disease. The scope and vigor of the supported clinical 
research is demonstrated below by presenting scientific highlights, the 
summaries of which were submitted by individual centers as exairples of pro- 
mising work in progress. The following highlights a few of the major areas 
of interest and accomplishments among the centers. 

Respiratory Distress Syndrome (RDS) 

Over the past decade, the rate of survival of infants with Respiratory 
Distress Syndrome (RDS) who require mechanical ventilation has not increased 
rapidly. Recently, a modification to a Bennett PR-2 Ventilator was 
accomplished so that a positive ^nd-expiratory pressure could be provided as 
well as continuous flow. Now in use for one year, these modifications have ■ 
been responsible for an increase in the overall survival rate of infants 
with RDS to 797o fror.i previous rates of 607, in the years 1969-1972. The in- 
cidence of bronchopulmonary dysplasia and "respirator lung disease" during 
the past year has also been reduced considerably. Thus, the simple 
modifications of equipment have reduced both morbidity and mortality in pre- 
mature infants with severe RDS requiring mechanical ventilation. 

Infectious Disease 

Adenovirus infections are one of the most common infections in infancy and 
childhood. Illnesses are usually mild but, on occasion, severe illness 
including pneumonia and death may result. At one center, investigators 
developed a vaccine which has afforded significant protection to those 
patients vaccinated. This offers a new approach for the prevention of adeno- 
viral illnesses in infants and children. 

Sickle Cell Disease 

At one university, the Departments of ^Uman Genetics and Internal Medicine, 
in collaboration with the Department of Internal Medicine, Divisions of 
Hematology and Nutrition, have explored the treatment of sickle cell disease 
with zinc. The investigators have shown that samples of red blood cells, 
hair and nails show evidence of zinc deficiency in about 207, of patients with 
sickle cell disease. Urine collections show that there is an increase of 
urinary loss of zinc in this disease and it is postulated that when red 
blood cells hemolyze within the blood stream, zinc is released and then ex- 
creted in the urine. The delayed puberty, decreased growth and poor wound 
healing, particularly of chronic leg ulcers commonly seen in this disease, 
are similar to the findings in zinc deficiency in patients in the Middle 
East and in experimental animals. Preliminary studies seem to show that 
when zinc is given intravenously it is removed from the blood and taken up 
by the tissues more rapidly in zinc deficient sickle cell patients than in 
normals. When zinc was given as therapy for patients with sickle cell 
disease, leg ulcers did seem to improve, growth occurred in a boy with 
retarded growth, and pubic hair appeared in a boy with late puberty. 



78 



Hematologic improvement occurred in one patient but was not obvious in five 
other patients. Thus, a new treatment has become available which, if pre- 
liminary observations are confirmed, could lead to a distinct improvement in 
the management of some patients with sickle cell disease. 

Blood Lipid Abnormalities in Children and Adults 

Atherosclerotic cardiovascular disease is the major cause of death and dis- 
ability in the United States and several other industrialized nations. The 
causes of atherosclerosis are complex but probably the most important single 
factor is the relationship between elevations in the concentrations of 
cholesterol in blood and the rate of development of atherosclerosis. One of 
the major ongoing research projects in one pediatric center has been the 
development of normal values of the various blood lipid fractions (choles- 
terol, cholesterol est-ers, low density lipoprotein cholesterol, triglyceride, 
phospholipid, and free fatty acids) at various ages, and the study of those 
factors which may result in arnormal concentrations of the blood lipids. In 
addition, work has been directed toward the detection of children at risk 
for the development of atherosclerosis. Studies are currently in progress 
involving various modes of intervention, including dietary change and drug 
therapy. These studies have indicated that approximately 1 to 2% of appar- 
ently healthy adolescent school children have abnormal elevations in cho- 
lesterol concentration and approximately twice that number have triglyceride 
values that exceed the accepted normal distribution. In family studies 
carried out on such children we find that something less than half of the D 

detected abnormalities are explained on the basis of familial or genetic 
abnormalities of cholesterol or triglyceride handling. It is in this group R 

of children that the probability of early development of heart disease is 
high. In preliminary dietary intervention studies, approximately half of S 

the abnormal patients have been normalized by dietary change. Drug therapy 
has been applied to a much smaller group of patients. Results from these 
observations are still pending. Of special interest is the finding noted 
for the first time that the very high lipid levels routinely seen in children 
with severe liver disease can be normalized by the administration of the 
drug phenobarbital. The mechanism by which phenobarbital results in lowering Jj! 
of blood lipid levels is under further study. Furthermore, phenobarbital is 
now being used in a group of children and young adults with inherited high 
cholesterol but without evidence of liver disease. 



■■+ 



3! 



Of additional special interest is the recent observation regarding the '"] 

blood lipid concentrations in families (parents and siblings) of children l^ 

with diabetes mellitus treated in the clinic. Patients with diabetes _ " 

mellitus were placed on a diet quite similar to the so-called "prudent diet" i] 
presently recommended by the American Heart Association and other groups as f 

the type of diet which should be utilized for most Americans, and the entire j, 
family utilized the same diet as the diabetic child. Detailed lipid analysis ^-^ 
in over 50 families in which the child has had longstanding diabetes mellitus 
revealed that the mean cholesterol and triglyceride levels in the fathers, 
mothers, and normal brothers and sisters of these children are well below 
the mean concentrations of cholesterol and triglyceride obtained in age and 
sex matched controls in the general population eating a normal American diet. 
A preliminary conclusion from this study is that the "prudent diet" is 

79 



acceptable to most families and is effective at lowering lipid levels. 
Whether this will have a longterm beneficial effect in lowering the incidence 
of cardiovascular disease in these individuals remains to be seen. 

Cardiovascular Disease 

Studies conducted at several centers involve the effect of direct revascular- 
ization surgery as therapy for coronary artery disease. Patients have been 
studied after direct revascularization and the state of their myocardium 
compared before and after surgery. From these studies, it appears that these 
procedures produce significant benefit in some patients. 

Hypertension 
Preliminary studies in a group of hypertensive patients suggest that patients 
with normal renin hypertension can be divided into two groups on the basis of 
renin-aldosterone responses to acute volume depletion. This has profound 
therapeutic implications in that, on the basis of this screening test, the 
physician would be able to determine which of his hypertensive patients will 
have a therapeutic response to diuretic therapy. Further work is under way 
to clarify these findings. 

Alcoholism 

Of this country's ten million alcoholics, many will die prematurely from 
disease secondary to alcohol consumption. Investigators at one center dis- 
covered that the administration of moderate amounts of alcohol to normal 
subjects does not influence plasma triglyceride levels, but alcohol admini- 
stration to subjects with a preexisting elevation in plasma triglycerides 
causes a further elevation. Therefore, since elevated triglyceride levels 
predispose to myocardial infarction, alcohol may well be more deleterious to 
that segment of the population with preexisting hypertriglyceridemia. 

Liver Disease 

Hepatic cirrhosis is the fourth leading cause of death in American males aged 
45 to 54 years, is increasing in incidence, and is particularly prevalent in 
large American cities. Blockage of the blood flow through the cirrhotic 
liver results in increased venous pressure and sometimes sudden severe gastro- 
intestinal bleeding. Determination of blood flow patterns in cirrhotic and 
bleeding patients is important in deciding which operation may best serve a 
patient. Study of such blood flow patterns in cirrhotics is now possible 
using a technique which provides access to the portal venous system and direct 
portal blood flow determination. Sudden deprivation of blood flow to the 
liver may be avoided by proper selection of operation in a particular patient. 
If perfusion of the liver can be maintained postoperatively, liver failure 
(the most common cause of death in cirrhotics following such necessary 
operations) could be avoided in a number of patients suffering from this 
common disorder. The availability of a new shunting procedure (Warren 
Shunt) developed in a GCRC now allows preservation of most of the blood flow 
to the liver in those patients in whom a high liver blood flow is found pre- 
operatively by this technique. 



80 



i 



Amino Acid and Protein Requirements of Man 

Investigators at one GCRC have used new techniques to explore protein meta- 
bolism in humans and to define the metabolic response to alterations in the 
level of protein intake. A potential practical outcome is the development 
of sensitive diagnostic tools for evaluating protein nutritional adequacy. 
It will also lead to an understanding of the changes which occur in disease 
states and lead the way to a definition of the appropriate nutritional 
therapy. Another portion of this program has been concerned with the develop- 
ment of new techniques for assessing the needs for amino acids which cannot 
be made by the body and must be diet supplied. These are called the essential 
amino acids and their concentration in various protein sources determines 
how well the food source meets the hvrnian requirements. They developed a new 
approach for estimating the physiological needs for these amino acids, and 
studies conducted in people of 70 years or older indicate that the essential 
amino acid requirement does not increase with aging. Appropriate dietary 
programs provide an essential component of comprehensive medical care. 
These studies are providing an orderly accumulation of nutrition knowledge 
and offer a basis for the design and implementation of dietary regimes which 
should best meet the needs of people for achieving a maximum, resistance to 
disease. 

Cancer 



^ 



Treatment of malignant disease by altering the patient's immune response re- 
presents one of the most exciting and innovative approaches to cancer therapy 
of the past decade. A recently employed tool for altering cellular immunity 
is transfer factor, a small molecular weight substance obtained from white S 

blood cells. Preliminary trials of transfer factor therapy in acute 
leukemia, solid tumors, and fungal infections have resulted in a better 
understanding of which diseases and which stages of a disease are most likely 

to respond to this type of therapy. 

If 

Surgical Research , 

In an ongoing project, the blood flow capability of femorotibial bypasses for * 
salvage of severely ischemic lower extremities is being studied. Recently, 

it has been shown that the limb salvage in patients with arterial blockage i 

can be achieved by bypassing to the very small vessels of the distal lower |, 

extremity (as low as the ankle or below) . This surgical technique has i 

enabled limb salvage in 51 of 79 patients recently operated on in whom , 

primary amputation above or below the knee would have been necessitated if '■ 

standard operative techniques were employed. Evaluation of the long-term J 

effectiveness of this new procedure and the blood flow capabilities of such f 

distal bypasses continues. Additionally, newer techniques for producing * 
improved grafts capable of function when used for distal bypass is being 
evaluated in an effort to salvage, from amputation, severely ischemic lower 
extremities in patients suffering from arterial disease. 



81 



Nutritional Management of Outpatients with Chronic Renal Failure 

In studies published this year, it was shown that nutritional therapy can 
substitute for dialysis in selected patients with chronic renal failure. By 
supplying building blocks of proteins, together with a low protein diet, 
accumulation of waste products which require excretion is diminished. In 
patients with at least 27o of kidney function remaining, it has been shown 
that dialysis can usually be avoided altogether; in subjects with less renal 
function (or absent function) , the interval between successive hemodialyses 
can be substantially prolonged. 

The impact of such management upon the health care problem of chronic kidney 
disease could be expected to 'be highly significant in view of the massive 
expenditures now required for chronic hemodialysis in a substantial fraction 
of the population. To evaluate the full expectations and limits of such a 
program requires that large numbers of outpatients be evaluated with careful 
observation of patient progress and well-being. Such studies are now ongoing 
in an outpatient GCRC setting with the expectation that (a) the interval 
between dialyses can oe extended in patients with kidney failure who require 
artificial kidney maintenance; (b) the need for hemodialysis can be tempo- 
rarily eliminated in many subjects who have insufficient kidney function; and 
(c) the beginning of dialysis treatment can be forestalled in subjects with 
impending kidney failure and perhaps progression of the underlying disease 
can even be delayed. 

Clinical Evaluation of Home Peritoneal Dialysis Equipment 

In the past five years, a radically new concept for peritoneal dialysis has 
been developed which consists of permanent implantation of silastic peri- 
toneal catheters into patients requiring dialysis for irreversible kidney 
failure. One such implanted in 1967 is still functional resulting in a home 
peritoneal program and rehabilitation of the patient. This method expanded 
to the treatment of many patients and has found wide acceptance in the United 
States. 

During the past year, a number of automated peritoneal dialysis machines were 
developed and tested on patients on a GCRCo The machine permits the prepara- 
tion of sterile, pyrogen- free dialysis solution from tap water and a sterile 
sugar-electrolyte concentrate at the bedside. The new system is simpler and 
safer to operate than conventional machines, thus permitting home dialysis for 
patients who cannot master the more complex hemodialysis machines. Parti- 
cularly it has been helpful in facilitating home dialysis in small children. 
In addition, the new system costs less to manufacture and, in comparison with 
conventional dialysis machines, the cost of maintenance has been reduced by 
757o. Five prototypes of this new system were tested in the past year with 
simultaneous home training for the patients or their parents. The evaluations 
included bacteriological studies, electrical-mechanical reliability, safety 
functions, machine-patient interaction, and ease of handling in a clinical or 
home setting. 



82 



Based on experience with this new system evaluated on a GCRC, it is believed 
that peritoneal dialysis will become a widely used, major treatment modality 
for chronic renal failure, supplementing chronic hemodialysis and renal 
transplantation. Small children and older patients, notably those with 
cardiovascular disease, will benefit most from these developments. 

POST-TRANSPLANT HYPERTENS ION 



Renal homotransplantation in man is associated with a post-transplantation 
hypertensive incidence of about 20 percent. The cause of this hypertension 
was unknown, but attributed to corticosteroid therapy. Using the facilities 
of a GCRC, thirteen hypertensive post- transplant patients and six normotensive 
post- transplant patients underwent angiography, transplant vein catheteriza- 
tion, and Xenon '--^ blood flow studies six to 38 months following renal 
homotransplantation. All patients had comparable steroid dosage. Transplant 
vein renin activity was five times higher in the hypertensive patients. 
Angiography showed abnormalities of cortical vessels in eight hypertensive 
patients correlating with biopsy findings of chronic rejection. Hyper- 
tensive patients could not be distinguished from normotensives by pre- 
transplant blood pressure, type of donor, presence of old kidneys, original 
disease or glomerular filtration rate. 

The tentative conclusions of the study were: (1) hypertensive patients, 
following renal homotransplantation, are characterized by low cortical 
blood flow and high renin activity resulting from transplant artery stenosis 
and/or chronic rejection, and (2) knowledge of sodium balance is necessary 
to interpret renin activity in post- transplant patients. The results 
completely refute the widely held belief that post-transplant hypertension 
is the result of corticosteroid therapy. 



D 
R 



Epilepsy 

Epilepsy is a major public health problem in this country, affecting between 
two and four million persons. Despite many drugs, a large number of patients 
remain insufficiently controlled to be able to lead normal lives. At one 
GCRC, a large clinical effort in the alleviation of epilepsy has taken place. 
Better methods for classification, seizure identification, and treatment 
have been developed on the basis of advances in technology, including the 
use of videotaped seizures with simultaneous electroencephalography and the 
development of telemetering capability. 

Withdrawal From Opiate Dependence 

Results from a study at a GCRC indicate that one can entirely withdraw 
narcotics addicts on known doses of methadone in less than 24 hours using 
gradually increasing dosages (administered intravenously) of the narcotic 
antagonist naloxone. The withdrawn patients were nonresponsive to addi- 
tional doses of the antagonist within 24 hours and thereafter had mild 
abstinence signs which generally could be treated using tranquilizers on an 
outpatient basis. Twenty-seven addicts were so studied. The same program 
works equally well with patients addicted to heroin, Diluadid, oxymorphone, 
and methadone. The program has been so well tolerated that several patients 



I 

r, 



It 1 1 



83 



were treated as outpatients and allowed to give themselves injections of 
naloxone. In the longterm followup of patients so treated more than half 
of the patients have not relapsed to the use of narcotics. 

The fact that addicts will volunteer for treatment in which they give 
themselves medication bringing on moderately unpleasant abstinence signs 
indicates the necessity for a radical revision in the psychological con- 
ception of the narcotic addict. 

Schizophrenia 

Schizophrenia is a psychiatric disease chronically disabling thousands of 
Americans and partially disabling thousands more. Psychiatric research 
has indicated an inherited predisposition and suggested that the basis of 
schizophrenia may not be strictly emotional or environmental, but that 
there may be a biochemical defect susceptible to therapy. While drugs 
introduced in the last few years have dramatically helped many schizo- 
phrenics and enabled them to leave institutions, the cause of schizophrenia 
has remained elusive and specific therapy is not available. 

Studies performed on a GCRC have established a new postulate for a bio- 
chemical cause of schizophrenis in some patients or patients predisposed to 
schizophrenia. It is a theory which is susceptible to study and which has 
excited researchers in the psychiatric field. 

Studies have suggested a mechanism by which a deficiency of folic acid could 
interfere with normal brain chemistry and suggest that this deficiency, or 
other defects in the same chemical pathway, could be of importance as a 
predisposing factor in a number of patients with schizophrenia. Further 
studies are in progress to establish the role of this, or similar defects, 
and of folic acid in general as- a cause of schizophrenia. 

Psychosomatic Illness 

In dealing with diabetic children manifesting emotional arousal by going 
into diabetic ketoacidosis (i.e., diabetic ketoacidosis for these children 
represented a true psychosomatic illness) , a conceptual model was formulated 
at one GCRC for spychosomatic illness in children. This model outlines the 
interactional characteristics of the "psychosomatogenic" family and the role 
of the child in family conflicts. In order to test this model in a pro- 
spective and scientific manner, a family task was devised in order to 
evaluate the interactional characteristics, and a family diagnostic study - 
was devised in order to test the role of the child in family conflict. Free 1 
fatty acids were used as a marker of emotional arousal during the diagnostic 
interview since they also played a key role in the metabolic process leading 
to the psychosomatic sjnnptom in these children, that is, diabetic keto- 
acidosis. The results in these diabetic children were highly encouraging, 
both from the point of view of validating the conceptual model for psycho- 
somatic illness and also in terms of deciding upon appropriate therapeutic 
intervention. 



84 



With this model, investigators focused their attention on illnesses tradi- 
tionally viewed as major psychosomatic problems, such as anorexia nervosa, 
a clinical sjmdrome characterized by voluntary refusal to eat and associated 
with a loss of greater than 207= of body weight. This disease has been 
associated with prolonged hospitalizations, and frequent relapses have 
characterized the clinical course. Deaths have occurred in some 10 to 157o 
of the patients and longterm followup studies indicate a success rate of 
less than 507o. 

The research aspects of this study are now being analyzed. Videotapes of 
the family task and the family diagnostic sessions will be rated in order to 
test the hypotheses outlined previously. Preliminary results are highly 
encouraging and indicate that free fatty acids, which had been used as a 
marker of emotional arousal during the family diagnostic interview, do not 
correlate with the psychological ratings. On the other hand, the success 
rate of this program has been extraordinary: in contrast to the previous 
reports in the literature the current success rate . is 907o. Indeed, the only 
failures of the program have been those in which the family was withdrawn 
from therapy. Success is defined as a child for whom eating is no longer a 
problem, who has appropriate peer relationships, and where no new sjmiptom 
has appeared either in that child or other members of the family. 



VI. Future Objectives and Trends 

A. Resource-Related Project Grants . 

This program serves as an administrative locus for projects which aim to up- 
grade clinical research capabilities through development or adaptation of 
technical or conceptual tools for use in GCRCs. The Branch had not im- 
plemented this project because of fiscal constraints in the entire program. 
However, with the recent release of impounded funds, the Branch initiated 
the program and is currently reviewing 5 proposals. 

B. Clinical Research Center Associates Program 

To ensure that the greatest potential for clinical investigation can be 
appropriately achieved, applications for GCRC Associates will continue to be 
reviewed. It is expected, however, that the number of center associates 
will be limited inasmuch as high quality research is one of the prerequisites, 






C. General 



The proposed budget for FY 1975 shows a modest increase over the levels 
previously available and would require further program retrenchment 
commensurate with the diminished purchasing power of the dollar. During the 
past three years, the program has been maintained at a relatively stable 
level through savings achieved by trimming less essential positions, reducing 
the number of beds, savings from the service patient policy now amounting to 
almost ten percent of the budget, and shifting appropriate research protocols 
to an outpatient basis. Our current assessment of center activities leads us 
to believe that further significant savings through these technics are 



unlikely without eroding the research productivity within the program. I 
is possible that some additional sailings may be achieved with the operatic? 
of a few mixed units in limited numbers. 

During the past several years, the program has attempted to maintain optimal 
clinical research productivity through an annual ranking of centers and 
projects competing for available funds. We plan to continue this process. 
Last year those centers in their preterminal year which were near the fund- 
ing cutoff line were held over for an additional year to compete with 
applications in their preterminal year this year. Thus, in addition to tbM 
17 competing grants and four new applications which will be evaluated by 
the Committee and Council in May and June, there are four or five hold over 
grants from last year which will be included in this year's annual ranking. 
The centers of greatest scientific productivity will be assured funding with 
less meritorious centers being held over to compete with centers competing 
in their pretei.-minal year next year. Additional program activities, such 
as the CLINFO project, will be funded in accordance with the results of the 
upcoming review this spring. 

It is expected that approximately the same number of centers will be 
maintained although occupancy, beds and personnel will be reduced depending 
upon final budget figures and the rate of cost increases. 



i 



86 



FIGURE I 



GENERAL CLINICAL RESEARCH CENTERS 

HISTORY OF APPROPRIATIONS AND CEILINGS RECOMMENDED 
BY THE NATIONAL ADVISORY RESEARCH RESOURCES COUNCIL 

FISCAL YEARS 1966 - 1974 

O COUNCIL RECOMMENDED CEILING 
EZl flPPROffiiflTiON 



50 -■ 



40 ■- 



30 -- 



20 -- 



10 -■ 



-L 




1966 1967 1968 1969 1970 1971 1972 1973 1974 

FISCAL YEARS 



i i 



87 



HiaiONS 
OF OOOflRS 

50 T 



O 



GENERAL CLINICAL RESEARCH CENTERS 

HISTORY OF EXPENDITURES 
BY SELECTED BUDGET CATEGORIES 

FISCAL YEARS 1965 - 1973 



TOTAL EXPENQCO 
A PERSONNEL 
+ HOSPITflLIZflTION 
X RENOV 4 EQUIPMENT 
ALL OTHER 



110 .. 



30 •• 



20 ■• 



10 





1965 



1966 



1967 



1968 1969 

FISCflL YEflR 



1970 



1971 



1972 



•BiINCLUOES flHRROEO ORTfl FOR 32 ROE'S NOT YET RECEIVED 



Fiscal Year 1974 
Annual Report 
General Research Support Branch 
Division of Research Resources 



The General Research Support Branch in FY 1974 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 



The General Research Support Grant (GRSG) program was initiated in 1962 
after the passage of Public Law 86-798. GRSG funds are awarded for the 
general support of health-related research activities to medical and other 
health professional 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 pro- 
fessional schools. 

The GRSG/BSSG programs complement the NIH and NIMH categorical program grants 
by providing self-determined flexible short-term support for purposes such as 
pilot projects, central and shared equipment and facilities, new investigators, 
unexpected and emergency needs of projects supported by categorical programs, 
maintenance and enhancement of investigators' biomedical research skills, new 
and more effective patterns of use of facilities and equipment, preliminary 
investigations in new fields and fields new to an investigator, development of 
departmental and interdepartmental programs responsive to new biomedical 
science needs, support of affirmative action plans to involve minority persons 
in biomedical research, and support of compliance with animal welfare require- 
ments. Some of these needs frequently require relatively small amounts of 
funds that do not justify incurring the overhead costs of central NIH review, 
some are multicategorical and therefore unsuitable for categorical support, 
some require quick response if the opportunity is to be grasped or costly 
delays to be avoided , and all represent important contribution to the goals 
of optimal effectiveness and efficiency of the national biomedical research 
effort. 



iz 



Table I shows how GRSG funds were used in FY 1972, 



89 



TABLE I 
FY 1972 Expenditure of General Research Support Grant Funds by Activity 



f 



RESEARCH PROJECTS 



Number 



7.778 



Dollars (in thousands) % of Total Dollars 



New Pilot Proj. 1,604 

Cont. Pilot Proj. 1,276 

New Reg. Res. Proj. 1,513 

Cont. Reg. Res. Proj. 3,385 



$ 4,398 


9.9 


3,914 


8.8 


6,087 


13.7 


15,617 


35.3 



CENTRAL RESOURCES 

Animal Facilities 
Computer Facility 
General Use Equip. 
Instrument Shop 
Central Lab. Facility 
Photog. and Med. Arts 
Other 



2,282 
1,646 
1,585 

542 
1,932 

335 
2,290 



5.2 
3.7 
3.6 
1.2 
4.4 
0.8 
5.2 



RESEARCH TRAINING 



2,342 



5.3 



OTHER ACTIVITIES 
Total 



1.313 

$44,283 



2.9 



100.0 



Fiscal and Administrative Considerations 

During FY 1974, FY 1973 impounded funds were released; $29,043,000 for the 
GRSG program and $4,533,000 for the BSSG program. Supplemental FY 1973 
awards were made to 327 GRSG and 117 BSSG institutions. In addition, 
$38,225,000 was awarded to GRSG institutions and $6,007,000 to BSSG institu- 
tions from FY 1974 funds. Tables II and III show for the GRSG and BSSG 
programs respectively, (1) the trend in allowable research grants awarded 
by NIH and NIMH to eligible GRSG or BSSG institutions (entitlement) since 
the initiation of the programs, (2) the trend in award funds, c.nd (3) the 
relation between entitlement and awards. 



90 



TABLE II 

GENERAL RESEARCH SUPPORT GRANT PROGRAM 

Trends in NIH/NIMH Research Grant Awards 

(Entitlements) ll and in General Research Support Grant Funds, FY 1962-1974 



Fiscal Year 

1962 
1963 
1964 
1965 
1966 
1967 
1968 
1969 
1970 
1971 
1972 
1973 
1974 



NIH/NIMH Awards 


GRSG Funds 


Ratio (%) 


(Entitlement) 


Awarded 


GRSG/Entitlement 


$108,234,000 


$20,000,000 


18.48% 


192,408,000 


30,000,000 


15.59 


241,426,000 


35,000,000 


14.50 


286,832,935 


43,985,365 


15.33 


320,415,167 


39,200,000 


12.23 


354,893,188 


41,700,000 


11.75 


393,366,592 


48,174,445 


12.25 


441,064,040 


48,200,000 


10.93 


448,080,707 


45,802,000 


10.22 


430,721,426 


43,423,000 


10.08 


495,806,184 


44,298,000 


8.93 


577,966,843 


46,277,000 2/ 


8.00 


667,273,190 


38,225,000 


5.73 



1^/ Previous Fiscal Year Awards Received From the NIH Institutes and NIMH by 
GRSG Awardees. 
\ 21 Includes $29,043,000 released impounded funds awarded as 1973 supplements. 



TABLE III 



BIOMEDICAL SCIENCES SUPPORT GRANT PROGRAM 

Trends in NIH/NIMH Research Grant Awards 

(Entitlements) and in BSSG Funds, FY 1966-1974 U 





NIH/NIMH Awards 


Fiscal Year 


(Entitlement) 


1966 


$ 80,233,656 


1967 


87,564,767 


1968 


108,925,527 


1969 


119,007,903 


1970 


123,150,660 


1971 


122,385,049 


1972 


138,129,124 


1973 


160,949,957 


1974 


174,303,033 



BSSG Funds 


Ratio (%) 


Awarded 


BSSG/Entitlement 


5,000,000 


6.23% 


6,000,000 


6.85 


7,500,000 


6.89 


7,500,000 


6.30 


7,125,000 


5.79 


6,777,000 


5.54 


6,914,000 


5.01 


7,223,000 y 


4.48 


6,007,000 


3.45 



I) 



V Previous Fiscal Year Awards Received From the NIH Institutes and NIMH by 

BSSG Awardees. 
y Incluaes $4,533,000 released impounded funds awarded as 1973 supplements. 

91 



It was planned to merge the GRSG/BSSG programs into one program in FY 1974, 
but due to the uncertainty of the future status of funding, the GRSG/BSSG 
programs were not merged and were administered in accordance with the policies 
which governed FY 1973 awards, including eligibility requirements. Approxi- 
mately the same number of institutions received GRSG/BSSG awards as in FY 1973 
but at a greatly reduced funding level, as shown in Tables IV, V and VI below. 



TABLE IV 

GENERAL RESEARCH SUPPORT GRANT PROGRAM 

Number of Grantees by Type for the General Research 
Support Grant Program FY 1967 - 1974 



Type of 
Grantee 
Inst. 



FY 
1967 



FY 
1968 



FY 
1969 



FY 
1970 



FY 
1971 



FY 
1972 



TOTAL 



294 



311 



330 



344 



326 



339 



FY 
1973 



327 



FY 

1974 y 



Medicine 


90 


95 


99 


100 


100 


101 


104 


104 


Dentistry 


49 


49 


49 


49 


33 


34 


34 


30 


Osteopathy 


5 


5 


5 


5 














Pub. Health 


12 


12 


12 


12 


12 


12 


12 


12 


Pharmacy 


9 


10 


12 


15 


15 


16 


14 


12 


Vet. Med. 


13 


15 


17 


17 


17 


16 


15 


14 


Nursing 














2 


4 


3 


3 


Allied Health 





. 














1 


1 


Hospitals 


64 


71 


75 


79 


76 


79 


71 


66 


Health Dept. 


3 


3 


3 


3 


2 


2 


2 


2 


Res. Inst. 


49 


51 


58 


64 


69 


75 


71 


70 



314 



1/ Estimated. Final awards have not been made, 



92 



TABLE V 

GENERAL RESEARCH SUPPORT GRANT PROGRAM 
Distribution of General Research Support Grants by Size of Awards 
and Funds Awarded for Fiscal Years 1967 Through 1974 

Number of Institutions 



Size 


of 


Grant 


FY 


FY 


FY 


FY 


FY 


FY 


FY 


FY 1/ 


(in thousands) 


1967 


1968 


1969 


1970 


1971 


1972 


1973 


1974 


Under 


_ 


$ 30.0 


22 


27 


30 


49 


34 


46 


17 


42 


$ 30 


- 


49.9 


58 


54 


46 


47 


51 


54 


67 


64 


50 


- 


99.9 


60 


74 


80 


85 


77 


78 


69 


68 


100 


- 


149.9 


36 


41 


49 


41 


50 


36 


41 


48 


150 


- 


199.9 


40 


40 


36 


34 


36 


45 


41 


45 


200 


- 


249.9 


26 


21 


21 


26 


25 


26 


36 


15 


250 


- 


299.9 


17 


19 


29 


31 


25 


21 


19 


32 


300 


- 


349.9 


14 


13 


12 


8 


8 


10 


12 





350 


- 


399.9 


9 


13 


9 


23 


20 


23 


25 





400 


- 


449.9 


12 


9 


18 


— 


— 


— 


— 





450 


- 


499.9 


— 


— 


— 


— 


— 


— 


— 





500 


- 


599.9 


— 


— 


— 


— 


— 


— 


— 







TOTAL 


294 


311 


330 


344 


326 


339 


327 


314 




Range 






Amounts 


(In Thousands) 






Grant 


FY 


FY 


FY 


FY 


FY 


FY 


FY 


FY -•-/ 


(All 


Inst.) 


1967 


1968 


1969 


1970 


1971 


1972 


1973 


1974 


Low 




$ 14 


13 


12 


5 


11 


12 


11 


14 


High 




441 


424 


429 


396 


383 


367 


359 


252 


Average 


142 


155 


146 


133 


133 


130 


141 


106 



2- 



Total General Research Support Grant Funds Awarded (In Millions) 



FY 
1967 



YY 
1968 



FY 
1969 



FY 
1970 



FY 
1971 



FY 
1972 



FY 
1973 



FY 
1974 



Total Funds 

Awarded $41.7 $48.2 $48.2 $45.8 $43.4 $44.3 $46.2 i/$38.2 



jL/ Estimated. Final awards have not been made. 

2/ Includes $29.0 (millions) released impounded funds, 



93 



TABLE VI 



BIOMEDICAL SCIENCES SUPPORT GRANT PROGRAM 
Distribution of Biomedical Sciences Support Grants by Size of Awards 
and Funds Awarded for Fiscal Years 1967 Through 1974 



Number of Institutions 



Size of Grants 


FY 


. FY 


FY 


FY 


FY 


FY 


FY 


FY 


(In thousands) 


1967 


1968 


1969 


1970 


1971 


1972 


1973 


1974 


Under - $ 30.0 


_ 


.. 


1 


8 


8 


14 


7 


16 


$ 30 - 49.9 


32 


27 


36 


35 


36 


36 


38 


42 


50 - 99.9 


54 


60 


59 


59 


57 


59 


53 


45 


100 - 149.9 


6 


11 


11 


9 


9 


5 


11 


1 


150 - 199.9 


] 


3 


2 


2 


1 


2 


2 


4 


200 - 249.9 


- 


1 


1 


- 


1 


1 


2 


— 


Total No. of 


















Grants 


93 


102 


110 


113 


112 


117 


113 


108 



Amounts (in thousands) 



Grant Range 


FY 


FY 


FY 


FY 


FY 


FY 


FY 


FY 


(All Inst.) 


1967 


1968 


1969 


1970 


1971 


1972 


1973 


1974 


Low 


$ 33 


$ 36 


$ 29 


$ 15 


$ 12 


$ 15 


$ 27 


$ 23 


High 


179 


219 


220 


199 


210 


212 


221 


187 


Average 


65 


74 


68 


63 


61 


59 


63 


56 



< 



Total Biomedical Sciences Support Grant Funds Awarded (In Millions) 



Total Funds 
Awarded 



FY 
1967 



$6.0 



FY 
1968 



$7.5 



FY 
1969 



FY 
1970 



$7.5 $7.1 



FY 
1971 



$6.7 



FY 
1972 



$6.9 



FY 
1973 



FY 
1974 



$7.2 -i/ $6.0 



^ 



_1/ Includes $4.5 (millions) released impounded funds, 



94 



Numerous Congressional and grantee institution letters were received 
concerning the problems that the uncertain GRSG/BSSG budget for FY 1973 1974 
and 1975 is having on institution planning. The original FY 1973 GRSG/BSSG 
allocation was $19,924,000. Released impounded funds added $33,576 000 The 

war fz 2 oSo'^Th^^"^ "^V ^^'i^' '°^ $9,500,000, but thf f inal'aZcatJL 
thP At, lie P^^-^dent's budget for FY 1975 requested no funds for 

witb^P program. It has been very difficult for an inscitution to plan 
with the uncertainties of the GRSG/BSSG budgets. 

GRSG/BSSG Program Plans 1975 

The General Research Support Program Advisory Committee and Staff of the 
Division of Research Resources will continue efforts underway in FY 1974 to 
determine steps that should be taken to keep the GRSG/BSSG programs responsive 
oMlctTeloTmV''^ opportunities, including the newly adopted contemporary 

Although the Administration's fiscal year 1975 budget requests no appropria- 
tion for GRSG/BSSG because other biomedical research programs were Judged ?o 
have a higher priority and choices were made in seeking to achieve expenditure 
ritr,uolr I ' ^"^ t^ Prudent to continue work on the issues that confront 
GRSG/BSSG because the details of the 1975 appropriation that ultimately will 
be enacted cannot be foreseen, and because budgetary constraints may be eased 
so that support for these valuable programs can be resumed without prolonged 
delay. Issues being addressed include usage of funds, eligibility criteria 
determination of award amounts, merger of GRSG and BSSG programs, and reporting 
and accountability by grantees. 



R 

HEALTH SCIENCES ADVANCEMENT AW^RD PROGRAM S 



The moratorium on new applications for Health Sciences Advancement Awards 
resulted in complete phase out of the program in FY 1974. During FY 1974 the 
final two non-competing continuation awards were made to the following: 

University of Kansas 1^^ 

Duke University 2 

During FY 1975 it is planned to have an evaluation made of the Health Sciences 
Advancement Award program. P 

MINORITY BIOMEDICAL SUPPORT PROGRAM [" \ \ 

The Minority Biomedical Support (MBS) program started in FY 1972 by the ' ( 

\ Division of Research Resources was designed to strengthen the institutional 
^ health-related research capabilities of four-year colleges, universities and "" 

health professional schools in which student enrollments are drawn mainly from ' '■ 
ethnic minority groups. It constitutes the major focus and concentrated effort *'' 
of the NIH to involve minority institution scientists in biomedical research j 

and to expose minority students to the challenges and opportunities in bio- i 

medicine. 

This program was initiated, at the encouragement of the Senate Appropriations ! 

J Committee, in order that minority groups may have equality of opportunity to 
J become investigators in biomedical research. 

95 ' 



since the MBS program was modeled after no other program within NIH, it is 
unique and therefore has been experimental and changing in nature. Conse- 
quently, the program has been improved as need for modification has been 
gained through experience. 

The goal of the MBS program is to increase the number of ethnic minority 
individuals in the biomedical sciences by developing and improving opportuni- 
ties for biomedical research and research participation of ethnic minority 
faculty, students and other investigators, and by assisting in the provision 
of appropriate settings conducive to these opportunities. 

During FY 1974 the program was gradually modified to include four -year 
colleges where there are large numbers of minority (i.e.. Black, Spanish- 
speaking, American Indian, or Oriental) students, but not necessarily a 
majority (as required under the original MBS program guidelines.) There are 
also a few junior colleges and community colleges where there are large 
numbers of minority students enrolled. By including these institutions and 
others such as the American Indian Tribal Councils, the program could reach 
a considerable number of minorities, including Spanish-speaking people and 
American Indians , as well as many Blacks , who were originally excluded from 
the program. The desirability and feasibility of such changes in institu- 
tional eligibility is being closely followed. 

Program Data and Fiscal Considerations 

Table VII below shows the number of awards and amount funded since the MBS 
program was initiated in FY 1972. The President's budget requests $7,270,000 
in FY 1975; a decrease of $730,000 from that awarded in FY 1973. Currently 
66 MBS grants are supporting 72 institutions. 

TABLE VII 
MINORITY BIOMEDICAL SUPPORT AWARDS 



FY 1972 



I2£± 
New 

T22e 

New 

Renewal 

Continuation 



I2£± 

New 

Competing Supplements 

Continuation 



Number Awarded 


38 


FY 1973 


Number Awarded 


14 


1 


36 


51 


FY 1974 


Number Awarded 



15 
13 
51 

79 



Amount Funded 
$ 2,000,000 



Amount Funded 

$ 968,551 

54,947 

3,976,502 

$ 5,000,000 



Amount Funded 

$ 1,806,128 y 
774,325 
5,419,547 

$ 8,000,000 



1/ Includes 8 eighteen-month awards made from $1,000,000 
FY 1973 released impounded funds. 



96 



Table VIII below shows the predominant minorities being supported at the 
72 institutions receiving MBS support. 

TABLE VIII 
Minority Biomedical Support Program 



Predominant Minorities at 72 Institutions 
Being Supported by MBS Awards 



Institutions 

54 
13 

2 

3 



Black 

Spanish-speaking 
Hawaiian 
American Indian 



72 



Table IX below shows the faculty and student support since the MBS program 
was initiated in FY 1972. There has been an increase of 150 percent in 
faculty support, 215 percent in undergraduate student support, 225 percent 
in graduate student" support, and 100 percent in postdoctoral support between 
FY 1972 and FY 1974. 



TABLE IX 



1972 



Faculty and Student Support 

from 

Minority Biomedical Support Awards 

Undergraduate Graduate Postdoctoral 
Faculty Participation Participation Participation Total 



199 



288 



44 



532 



1973 



1974 



358 



499 



h43 



906 



94 



143 



1,095 
1,550 



Several MBS grantees have strongly requested that indirect cost payments be 
allowed. Indirect cost payments are not paid because the annual appropriation 

act states that " none of these funds shall be used to pay recipients of 

the general research support grant programs any amount for indirect expenses 
in connection with such grants." The MBS program is under the authorizing 
legislation for general research support (Section 301 [d] , Public Health 
Service Act, Amended). It is estimated that an additional 30 percent in 
funding would be required in FY 1975 if indirect costs were authorized. 
Because of commitments this increase could not be absorbed. 



97 



Projects being supported by the MBS Program include such diverse 

areas as the following: ^ 

"chromosome Specificity of Incorporated Exogenous DNA." 
(Tuskegee Institute) 

"Sequencing of Peptides Using Negative Ion Mass Spectrometry." 
(California State University, Los Angeles) 

"A Clinical Study of Acute Mycardial Infarction in Black Americans." 
(Howard University) 

"The Effect of Prostaglandins on Ploidy Distribution in Rat Liver." 
(Albany State College, Albany, Ga.) 

"Eukaryotic Transcription by RI\A Pol3rmerase. " 
(Atlanta Univeisity) 

"Morphine Addiction: Instrumental Behavior and the Hypothalamus." 
(Jackson Stats College) 

In April 1974, students and faculty presented 73 papers in biological 

sciences, 24 in biochemistry, 36 in chemistry, and 12 in pharmacology 

at the Annual Xavier University MBS Symposium in New Orleans. Additionally, 

students and faculty have presented papers at regional AAAS , ACS, Society 

of Microbiologists, and other meetings in the past year. At least two of the 

student papers presented in meetings of Beta Kappa Chi have received cash jjj 

awards for the best paper presented at the meeting. ^ 

Investigators have already submitted papers for publication in scientific 
journals; some have already submitted grant applications to NIH and other 
research granting agencies and have received funding. 



98 



Fiscal Year 1974 Annual Report 

Program Analysis Branch 
Division of Research Resources 



The Program Analysis Branch is responsible for continually assessing the 
Division's data requirements and structuring an appropriate Division-wide 
data base. This includes aspects of system analysis and design attendant 
to establishing a system, maintenance of data in the systems and use of 
the systems to produce the required output, including the project planning 
and programming functions. Some of the Program Analysis Branch efforts 
initiated during the past year to meet the Division's requirements for data 
reporting and program evaluation have been: 

1. A program was written and catalogued to edit the GRSG and BSSG 
expenditures and annual progress report data. Before automation, this 
function was done manually by the General Research Support Branch staff. 

2. A system for the collection of data on the Minority Biomedical 
Support Program is being developed. The first phase -- awards and 
expenditures data -- has been implemented. Further discussions are 
planned regarding the scientific research project, trainee and 
personnel supported data before a procedure is established. This 
will be accomplished within the next few months. 

3. The Biotechnology Resources data system was expanded to include the 
budget operating levels of the grantees, as well as the expenditure 
data reported in the Progress Report. A masterfile of the research 
projects was designed and implemented on a test basis. 

4. The scientific data for fiscal year 1971 GRS and BSS grants were 
collected. Because of the uncertainity of these two programs and the 
large volume of work, this project has been temporarily discontinued. 

5. The General Clinical Research Centers data items on the master 
file were redesigned to include NARRC budget and personnel recommen- 
dations. Programs have been written to produce several reports 
previously prepared by hand. 

PAB provides computation services for the GRS and BSS grant awards by 
performing the tasks associated with the calculation and award of these 
grants. PAB has developed and is responsible for an intricate series of 
computer programs and subroutines which apply a multiple set of conditions 
to an institution's entitlement, calculate the amount of the award, punch 
the cards used to prepare the award statement by computer and produce 
listings and tables of the relevant data. When the need arises, PAB adapts 
these 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. In the 
past year, the Branch calculated a vast array of experimental awards to 



99 



assist the GRS staff in redesigning the GRS and BSS awards program in this 
regard. 

PAB is still developing a "Division of Research Resources Basic Data Book" 
which will be a collection of highlighted DRR data and related facts in 
a pocket-size booklet. Considerable historical tabular data has been 
compacted into various creative displays to experiment with and select 
those which will be mos.t communicative and useful to the Division. 

The PAB continues to assist the General Clinical Research Centers Branch in 
establishing criteria and processing appropriate data to be used in 
evaluating characteristics and effectiveness of the center's program, even 
though the formal evaluation study has concluded. 

The Branch has supported the program planning activities of NIH by assisting 
in the development of an evaluative study for the Institutional Profile 
Subcommittee of the Center Grants Task Force. Data was queried from DRG 
and many lists produced for review. Many different samples were prepared. 
Considerable time and energy has been spent in developing the methodology 
to obtain the necessary data and designing strategies and techniques for 
surveying grantee institutions. 

The data system established by PAB for the Division contains approximately 
309 data items which are defined and described in the PAB Handbook of 
Definitions and Specifications for the three distinct master files 
maintained, as well as in the documentation for the Publication Retrieval 
System master files. A completely computerized system has been established 
and, depending on the nature of the task, access to the data is accomplished 
through th£ 360/20 remote or the IBM 2741 Communication Terminal. Various 
methods are used such as computer programs, the Inquiry and Reporting 
System (IRS), and the Publications Retrieval System (PRS). 

The source documents for these data are grant applications, award statements, 
expenditures reports and annual reports submitted by grantees. From this 
data bank, PAB produces annual and periodic publications such as: 

1. The "Research Resource Grants" booklet which contains highlights, 
graphs, highlight tables, summary tables and listings that pertain 

to the DRR grants and that reflect the magnitude, scientific and 
technical diversity, geographical coverage, and general vitality of 
these programs of support for resources, 

2. A publication for the National Advisory Research Resources 
Council, "Division of Research Resources Handbook," which is a 
compendium of current and historical data on the appropriations and 
awards of the Division and its four programs, and which presents a 
brief description of the goals, objectives and general activities of 
the Division's programs. 

3. The General Research Support Program Awards History Booklet which 
lists the name, location, type of institution, grant number and amount 
of award for each recipient of general research support since the 

100 



inception of the program in 1962, and includes summary tables by type 
of institution within fiscal year and by geographic division within 
fiscal year. 

4. A Biomedical Sciences Support Program Awards History Booklet which 
contains the same type of information for this program as described 
under (3) for the GRS program. 

5. The General Research Support Expenditures Booklet which shows the 
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. 

6. A Biomedical Sciences Support Program Expenditures Booklet similarly 
constructed as that described in (5) above. 

In addition, the Branch has responded to inquiries for data maintained by 
DRG. PAB has written queries to obtain on a regular basis such information 
as active NIH research grant support at selected institutions, grants 
with $10,000 or more awarded for Hospitalization, and NIH grant support 
using vertebrate animals. The CRISP files were accessed to obtain infor- 
mation on grants using marine invertebrates and those doing research on 
sleep disorders. ^^ 

The above exemplify some of the Program Analysis Branch's efforts to meet R 

the Division's requirements for data reporting and program evaluation 

as they fit into the decision making process. During the coming year PAB S 

will continue to study the Branches ' data needs in order to expand its 

data base for analysis. Future plans include 



1. - expanding the MBS data base to collect the scientific and trainee 
data; 

2. - establishing a procedure to analyze and link DRR resource user's 
to other components of NIH. 



a: 



101 



il 



« 



Office of Science and Health Reports 

'"How Children Grow,' published by the National Institutes of 
Health, explains what research scientists have been learning 
about growth and development of children. Included is a 
chapter on adolescent obesity. Single copies are free 
from. . ." 

National Observer article 

by Daniel Henninger 

"From my review of the publication, it was apparent that it 
follows closely the course outline and content of the 'Human 
Behavior and the Social Environment Course' and would be a 
vital and useful tool to students in the class," 

letter from Daniel R. Rubens tein, Ph.D. 

Chairperson, Dept. of Social Work 

West Virginia College of Graduate Studies 

"I have reviewed it, and feel it would be most suitable for 
our course on growth and development." 

letter from Theresa A. Hudak, R.N. 

New Ulm School of Practical Nursing, Minn. 

"I have found the booklet an excellent source for the teaching 
of students and an excellent reference for future careers; 
consequently, I wonder if it would be possible to obtain 200 
copies which I can distribute to the students in my class. . ." 

letter from Norman Kretchner, M.D., Ph.D. 

Faber Professor of Pediatrics 

Director, Section of Developmental Medicine 

Stanford University Medical Center 

new Director of NICHD 

From all across America, professionals and plain citizens alike wrote to 
request copies of DRR publications. In calendar year 1973, the Office of 
Science and Health Reports received almost 59,000 individual requests for 
material. The majority of this varied audience requested "How Children Grow," 
confirming the strong effect of continued communications activities by the 
Office involving the booklet. 

During the fiscal year, "The Family Economist," published by the Insurance 
Institute of America carried a major feature article on "How Children Grow," 
which they mailed to over 1,400 editors throughout the United States. "Child 
Development Abstracts and Bibliography" of the Society for Research in Child 
Development published an abstract complimentary of the publication. The 
National Observer recommended it to its readers, and House and Garden carried 
the message to its 1 million readers. Women's Circle magazine and FREE AND 
INEXPENSIVE LEARNING MATERIALS published by George Peabody College of Teachers 
both featured it. The publication was reviewed and recommended by the Journal 



103 



of Nutrition Education , which called it an "excellent reference for nutrition^,! 
educators, parents, teachers, and many others concerned about children's 
welfare." The Day Care and Child Development Council of America reprinted 
the publication in its entirety. This organization noted that "How Children 
Grow" contained "excellent information which can be of great use for those 
who are training staff to work with young children." Individual citizens 
wrote letters of praise. A mother in Plaster City, California, told the 
Office: "'How Children Grow' has answered many questions that had been 
troubling me, and it now has a permanent place on my book shelf." A lecturer^ 
in the Growth Sciences Division, College for Human Development, Syracuse ™ 
University, wrote: "I intend to emphasize the book as a resource for students 
in working with children and their parents in nursery and elementary schools," 
The Coordinator of Parents Classes at Washington's Columbia Hospital for 
Women complimented the Division on the excellence of its publication. Through- 
out the year, parents, directors of day care facilities, dietitians, nutrition- 
ists, pediatric nurses, medical students, public health nurses, pediatricians, 
child psychology students, and educators praised the booklet and requested it 
for their use. 

During the year, the Office developed, wrote, and published a new folder 
titled "Do We Care About Research Animals?," which quickly became popular. 
The National Society for Medical Research featured it in their newsletter and 
requested 3,000 copies for distribution to interested persons. The Assistant 
Director of Scientific Activities of the American Veterinary Medical Association 
called it an "excellent new folder." A teacher at State University of New 
York wrote: "As an instructor of veterinary science one of the biggest Ay* 
problems I have is that of 'emotional-reactive' students toward the use of ' 
laboratory animals, whether it be for vivisection, injection instruction, 
intraorbital bleeding, and on, and on. Would it be possible for you to send 
me an additional 150 copies of the above publication. I believe it would 
greatly benefit in explaining what we are doing." 

The Director of Public Relations at Duke University Medical Center requested 
copies to counter public criticism that resulted from a newspaper story on 
research animal facilities at Duke. 

The American Association for Laboratory Animal Science featured the folder in 
its bulletin. People across the country began writing AALAS for copies, after 
prints of a one-minute television spot, which the Office of Science and Health 
Reports had helped to develop in conjunction with AALAS, began to appear on 
local television stations. 

The National Society for Medical Research sent the new folder individually to (|| 
all members of Congress. Senators Stafford, Eastland, Taft, Bayh, Abourezk, 
and Beall and Congressmen Patten, Stafford, Young, Mizell, Whitehurst, Davis, 
Casey, and Congresswoman Holtzman wrote NSMR to thank them and to order 
additional copies. 

In an unusual move, The Frederick Post reprinted the entire folder on its 
editorial page under the headline "NIH Cares About Animals." 



104 



In other activities, a television documentary which was an office project had 
a repeat showing over hundreds of TV stations of the ABC network. On August 9, 
"How To Stay Alive" brought dozens of news clips which were directly connected 
with the Office's activities. Publicity appeared in many newspapers, including 
the Richmond Times Dispatch , Buffalo Evening News , Syracuse Herald Journal , 
Cleveland Press, and the Atlanta Journal . 

As part of the show, the Office of Science and Health Reports made arrangements 
for the Chief of the General Clinical Research Centers Branch to appear for a 
second time in a short filmed segment. He appeared in other portions of the 
hour. 



The NIH's clinical research centers received billing next to the main title of 
the special. As participants, each of the Division's grantee program director 
experts and his institution received additional billing. At the end of the 
special, the Division received full credits. 

A major story on ambulatory centers, an offshoot of the General Clinical 
Research Centers Program, appeared in Laboratory Management . The piece was 
written and photographed by the Office, It told the story of the emerging 
outpatient clinical research centers at Vanderbilt University Medical Center 
in Nashville, Tennessee. 

Ron Maselka of the Buffalo Evening News wrote a number of articles about the 
National Institutes of Health. Recently, in an effort to tell more about it- 
self, the NIH reprinted these articles in booklet form. The Office had 
worked very closely with the correspondent on two of the articles featuring 
DRR programs among the 13 that were reprinted. These covered animal resources 
and clinical research centers. In addition, the Office furnished background 
information for a Maselka story during the year on a group of Buffalo medical 
researchers. They were becoming a part of the Division's pharmacology and 
toxicology computerized information system known as PROPHET. This piece used 
extensive quotes by the Chief of the Biotechnology Resources Branch as he 
described the program. 



•^ 



^ 



The PROPHET System was also the subject of articles in Chemical and Engineering 
News and the Federation Proceedings published by the Federation of American 
Societies for Experimental Biology. Both articles emphasized quotes from the 
Branch Chief. They described in detail the inner workings of this innovative 
approach to pharmacology/toxicology research and heralded the use of advanced 
information science tools in biomedical research. 

The Office of Science and Health Reports originated and placed articles and 
pictures on the degu, the rat-like animal with two thymus glands, in Medical 
Tribune , Children Today , Lab Animal , Federation Proceedings , ILAR News (in 
which it was the cover story) , and DVM , the veterinary medicine magazine. 

Operating in close cooperation with Xavier University of New Orleans which 
provided pictures and some background, the Office produced a news story with 
photos on the Second Annual Xavier-Minority Biomedical Support Symposium. 
These went to a representative minority press list throughout the United States, 
Arrangements were made for an article on the MBS Program written by the Office 



105 



to appear in the upcoirdng special September education issue of FASEB's 
Federation Proceedings , together with picturej. 

Earlier in the year, a feature news article on MBS was written and mailed to 
black weekly papers. Among the users were the Iowa Bystander , the Monroe, 
La. , News Leader , and the Twin Cities Courier . 

The Office produced a heavily illustrated booklet on the UCLA Health Sciences 
Computing Facility for the Biotechnology Resources Branch. Working closely 
with the staff at UCLA, the Office covered the activities of the center, 
wrote the narrative for the booklet, developed layout and dummy, and checked 
these with the scientists and administrators involved. A beautiful publi- 
cation on this strongly-suppor'ted biotechnology resource resulted. As the 
fiscal year drew to a close, arrangements had been made to reprint a portion 
of the booklet in the Federgtion Pr oceedings , published by FASEB, and 
negotiations were proceeding on a major piece from the booklet for Government 
Data Systems . In addition. Enterprise Science News was showing interest, and 
news material and the booklet itself had been sent to all data and computer 
publications. 

In the audiovisual area, the Office arranged for and set up the tabletop 
Primate Research Centers exhibit at the 1973 annual American Medical Writers 
Association in Bethesda, Cooperating with the Animal Resources Branch, 
assistance was also provided in running the ARB exhibit at the national 
convention of the American Association for Laboratory Animal Science in Bal 
Harbour. 

During the year, a custom-built display was designed by the Office for use in 
emergency and temporary situations. This unit was used to advantage during 
the National Advisory Research Resources Council and the General Research 
Support Program Advisory Committee meetings in the spring. 

In cooperation with the University of Alabama, the Office wrote a story on a 
Division-supported animal resource featuring cats with a disease similar to 
Tay-Sachs in humans. This story was widely carried in the Jewish press, 
including the Baltimore Jewish Times , the Jersey City Jewish Standard , the 
Buffalo Jewish Review , the Kansas City Jewish Chronicle, the Newark Jewish 
News , and the Philadelphia Jewish Exponent . Other papers ran the story, 
together with the Washington Star-News . 

A news story developed by the Office about a shortage of nonhuman primates in 
biomedical research was run by Science magazine. Featuring extensive quotes 
from the Chief of the Primate Research Centers Section, the news story 
announced the start of a worldwide primate census of biomedically iroportant 
animals. This survey was financed by the Animal Resources Branch end run by 
the Institute of Laboratory Animal Resources. In addition, the story was 
carried by Lab Animal , Drug Research Reports , the AALAS Bulletin , the 
Laboratory Pr ima t e Newsletter , and the Federation Proceedings . The Denver 
Post ran a major article on the problem of declining primate populations, 
which was sparked by the Science story. It gave extensive space to quotes 
from the Chief of the Primate Research Centers Section. 



106 



Two major articles were conceived, written, and illustrated for Lab Animal . 
\ The first piece was called "A New 'Hot' Lab for Primate Pathogens," and 

covered the special isolation facility at the Delta Primate Research Center. 
Though it was not photographed by the Office, photos were provided. The 
second article, "Manpower Development for Laboratory Animal Science" was 
devoted to a long interview with the Chief of the Animal Resources Branch on 
the program's new special training activities. Pictures were shot by the 
Office and provided with the interview to the bimonthly publication. 

The Office also provided Lab Animal with tapes of two major NTH meetings which 
) were co-sponsored by the Animal Resources Branch. Reports appeared in two 
consecutive issues on "Automated Animal Caging Systems" and "Bioprotective 
Caging Systems." 

An in-depth report on marine invertebrates, which resulted from a meeting of 
20 marine experts at NIH brought together by the Animal Resources Branch, 
appeared in the Federation Proceedings of FASEB. The meeting report, written 
by the Office, resulted in dozens of requests for reprints from all over the 
world. 

"This particular species of beetle may become a more versatile insect model 
for the current frontiers in modern biology and biomedicine than Drosophilia 
was for genetics," said Dr. Dale M. Norris in an Office-generated story about 
the wood-boring beetle. During the year, a feature story about this unique 
new animal model was used prominently by Lab Animal, the National Society for 
Medical Research Bulletin , the Federation Proceedings , and "Dateline Science" 
in Scholastic Magazine . 

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 individual 
placements and projects, too numerous to mention, in which the Office was 
involved. 



1 



107 



\ 



HOW TO USE 

THESE SEPARATORS 

Use one page for 
each separation. 

Select appropriate 
tab, add further 
identification If 
desired, and cover 
It with sc crt c h 
tape. 

Cut off and discard 
all tabs except the 
one covered by tape. 




TABBED SEPARATOR SHEET 
Form HEW-69 

(3-56) 






t 



DIVISION OF RESEARCH SERVICES 



Report of Program Activities 
July 1, 1973 through June 30, 197/i 

CONTENTS 

Page 

Division of Research Services . 1 

Biomedical Engineering and Instrumentation Branch 9 

Individual Project Reports 

1. Pharmacokinetics 25 

2. Trace Element Analysis in Biological Materials 29 

3. The Role of Fluid Dynamics and Mass Transfer in 

Development of Atherosclerosis 31 

4-. Implant Device Development 33 

5. Multicomponent Plastics in Biomedical Use . , 35 

6. Nuclear Magnetic Resonance Techniques for Biochemical 
Analysis 37 

7. Television Image Processing Techniques for Biomedical 
Research 39 

8. Diagnostic Ultrasound 4-2 

9. Measurement of Low Level, Rapid Chemical Reaction Rates 
by Laser Jump, Temperature Jump and Stopped Flow 

Techniques 4-4- 

10. Automatic Test Set for Evaluating Electrical Safety of 
Clinical Equipment 4-6 

11. Biomechanlcal Concomitants of Head Injury /Head Injury 

Model Program ' 4-8 

12. Atraumatic Electrical Sensing in Human Brain Cortex ... 50 

13. Pregnant Sheep Hyperthermia: Effect of Elevated Body 
Temperat;ire on Fetal Vitality 52 

Environmental Services Branch 53 

Library Branch 63 

Medical Arts & Photography Branch 71 

Veterinary Resoiirces Branch 77 

Individual Project Reports 

I"! Pathology of Adjunctive Effect of Immunosuppression and 

Thymectomy on Canine Pulmonary Allografts 97 

2. Different Levels of Dietary Protein for Laboratory Rats . 98 

3. Genetic Analysis and Animal Model Development 99 

4. Development of Diets for Laboratory Animals 101 

5. ' Tyzzer's Disease 103 

6. A Comparison of the Effectiveness of Suture Materials on 
Bronchial Stimip Closure Following Pneumonectomy 105 

7. Selection for 6-Week Weight in Inbred and Noninbred 

Strains of Mice 106 



2 



Page 

8. Sodium Cyanate Neurotoxicity in Macaca Nemistrina 

Primates 107 

9. Erythroceljus Patas MoiAey as an Animal Model for 
Cardiovascular Research 108 



NATIONAL INSTITUTES OF HEALTH 

DIVISION OF RESEARCH SERVICES — DR. JOE R. HELD, DIRECTOR 

Report of Program Activities 
July 1, 1973, through June 30, 197-4 

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 
professional and technical personnel organized into five Branches: 
Biomedical Engineering and Instrumentation, Environmental Services, 
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 the i 

following : ' 

1. The application of engineering principles and techniques to the 
solution of biomedical problems. 

2. The design, fabrication, and maintenance of special research 
instruments. 

3. Environmental surveillance to detect and eliminate conditions ' 
adverse to conducting high quality research or hazardous to ; 
patients, employees, or the community. 

4. Library and bibliographic services. 

5. Foreign language translation. 

6. Still photography and motion picture production. H'l' 

7. Graphics arts services and exhibits design. *'' 

8. Medical illustration and model making. 

9. Animal production, procurement, conditioning and holding. 

10. Animal health services. 

11. Experimental surgery and related activities, 

12. The production of tissue cultures, microbiologic medias and animal 
biologies. 

13. Central processing and sterile preparation of laboratory glassware. 

C. Program Progress and Accomplishments 

1. Biomedical Engineering and Instrumentation 

Several major projects initiated and developed in preceding years matured 
and were reduced to practice. Mathmatically derived chemotherapeutic 
protocols were established for managing certain cancer cases. Pharma- 
codynEonic principles were applied and achieved more optimal hemodialysis 
of patients suffering from renal failure. 



I 



Prototype clinical instrumentation systems based on video technology were 
accepted as practical tools for monitoring cardiac performance and the 
condition of aortic ball valve prostheses in vivo ; noninvasive ultrasonic 
imaging for measurement of heart muscle dimensions has becom.e relatively 
routine . 

Previously developed concepts and equipment for investigating concussion 
were regularly used to generate and analyze reproducible data from head 
injury experiments. Formalized inspection and maintenance routines for 
patient care apparatus in the Clinical Center were implemented. The 
Scientific Equipment Rental Program was broadly accepted and used by a 
substantial portion of the NIH community as a reliable, economic resource 
and expanded markedly. 

Investigations with substantial potential for future applications were 
initiated in several important areas, including the identification and 
assessment of trace metallic complexes in cancer therapy and environmental 
contamination, the interaction of implanted polymers with blood and body 
fluids, fluid mechanical influences on atherosclerotic plaque formation, 
ionic concomitants of cortical metabolism, faster and more sensitive 
microcalorimetry, and comprehensive instrumentation for investigating the 
behavioral effects of anti-epileptic drugs. 

Demands for consultation and assistance with collaborative and extramural 
programs exceeded resources available, as did requests from other 
government agencies for fabrication of unique technical systems based upon 
BEIB designs and prototypes. 

2. Environmental Services 

The Environmental Services Branch devoted major program effort to 
assessment of chemical carcinogen hazards; procurement of laminar flow 
biological safety cabinets; and review of laboratory facilities working 
with potentially hazardous Class III, IV and "non-natural" organisms. 
The most notable review of laboratory facilities was in association with 
the NIAID for compliance with the "Memorandum of Understanding and Agreement" 
for the safe handling of Adenovirus Type 2 - SV4-0 Hybrids. 

A survey of chemical carcinogen usage was initiated in response to 
tentative standards under the Occupational Safety and Health Act. Preliminary 
data provided basic information on chemical carcinogen use in research 
environments to the DHEW panel of experts formulated to develop standards. 
At NIH there are approximately 150 users of chemical carcinogens, 63 whom 
reported using one or more of the 14 designated chemical carcinogens of 
interest to the Department of Labor. An NIH program is now being formulated 
to deal with proper carcinogenic chemical identification, risk assessment, 
and control measures to be employed. Employee education will be included 
as a control measure. 

Procurement of laminar flow biological safety cabinets at NIH reached a 
crisis point during the year because of unexpected demand for this safety 



device — not only at NIH where it was developed, but in outside laboratories. 
Seventy-five new LFBSC's were put in use with approximately 100 more on order 
at the end of the fiscal year. The NIH specification for the cabinets was 
modified three times during the year. The Office of Materiel Management was 
informed by GSA late in the year that NIH could proceed with the development 
of a Qualified Products List for this equipment. The first LFBSC's 
constructed to NIH specifications were purchased during the year. 

Pollution of the NIH stream on the Bethesda campus has apparently been brought 
under control, as the major contamination sources have been eliminated. 
Water pollution control activities at the National Institutes of Health 
Animal Center continued. The Sewage Treatment Plant experienced operational 
difficulties, as did the automatic water quality monitors. Noise control 
developed into a time-consuming program because of new Federal regulations. 
The chemical waste disposal program was developed to the point that the NIH 
treatment facility is under contract for renovation. A contract was initiated 
for disposal of chemicals which cannot be handled on NIH premises. The 870 
chemical fume hoods were surveyed under contract to the DOW Chemical Company. 

The contract to construct the Tri-Services Incinerator was cancelled and 
negotiations were begun with Montgomery County, Maryland, for the development i 
of a Medical-Pathological Incinerator by the County to serve NIH and other 
medical research facilities within the County. 

The training effort of the Branch was increased in several areas. A 

literature review entitled "Biological Laboratory Hazards" was developed 

and distributed quarterly to Laboratory and Department Chiefs at NIH. 

Approximately 150 research and technical staff of various institutes ' 

attended seminars on The Theory, Operation and Use of the Laminar Flow ; 

Biological Safety Cabinet. Of particular note was a cooperative effort with 

other NIH safety groups in the development of a series of safety posters 

and accompanying information in the NIH RECORD. An NIH sponsored short 

course on Introduction to Biological Laboratory Techniques was offered to S' 

summer employees. ESB personnel received 1,007 hours of training at ^' 

designated short courses or classroom experience at local community colleges Wd 

and universities. Three COSTEP trainees worked in the Branch. mi<; 

J 
3. Library Services f \ 

■III : 

The suit of V/illiams and Wilkins Company against the Government for alleged [,, 

copyright infringement relating to the photocopy service of the NIH Library " i 

and NLM and the copyright law was decided by the Court of Claims in favor H! \ 

of the Government in a four to three decision. The publishing company is .» 

appealing the Court of Claims decision to the Supreme Court. 'I 

The monthly listing of books, journals, and other literature added to the 
Library's collection is now issued as a memorandum from the Librarian. 
Translated articles are also listed. 



A Scope and Coverage Committee was appointed to draw up a plan of action 
to formulate a Library policy for scope and coverage of literature acquired 
for the Library Collection. The first step, delineation of current B/lAi 
research and administrative needs through analysis of published programs, 
was completed. 

Site surveys of automated circulation procedures in area libraries and 
literature studies were made by Library staff. 

The Library participated in the NIH celebration of Black History and Native 
American Weeks. The Brancy Chief, a member of the NIH Minority Cultural 
Program Committee, served as a session Mistress of Ceremonies during Black 
History Week. Exhibits prepared by Library staff for each program were 
displayed in the outside corridor. High school students participating in 
the programs were given tours of the Library. 

<4. Medical Arts and Photography Services 

Demands for MAPB services remained high. With a completely renovated Photo 
Lab, requests were serviced within five days and the Branch is committed 
to the reduction to seven days for photomicrograph and photomacrograph 
services by the end of FY 1975. The newly named and reorganized Design 
Graphics Section cut production 10 percent in reprint material, however, 
design and delivery of exhibits increased 100 percent. Medical Illustration 
continues a substantial steady output. MAPB increased its use of outside 
contract services by 26 percent. With new equipment and facilities, the 
Branch continued fco improve and broaden its skills to meet increased 
program demands. 

5. Veterinary Resources 

A Catalogue of NIH Rodents was published. Characteristics of more than 100 
strains and stocks of rodents and rabbits maintained in the VRB genetic 
repository are described in loose-leaf notebook form. Approximately 150 
breeding nuclei of VRB strains of mice were provided to the international 
biomedical research community. 

Investigators' requirements for VRB produced rodents and rabbits increased 
and total issues remained at about 500,000 despite a reduction in permanent 
personnel; however, an imbalance of temporary employees was utilized in some 
areas to maintain adequate production levels. Issues of noninbred animals 
from contract sources decreased. 

The importance of maintaining the genetic pool of VRB noninbred stocks was 
demonstrated to be essential for the continuance of effective testing of 
biologicals. VRB colonies of mice now originate from hysterectomy-derived 
barrier-maintained breeding stock. New pathogen-free colonies were 
established this year and the old conventional colonies phased out. 

While rodent, rabbit, and cat production dropped, laboratory reared dogs, 
timed-pregnant nonhuman primates, and ungulate production increased. 
Contracts were used to supplement canine, primate, and ungulate production as 
well as rodent production. 

4 



Cutbacks in rhesus moiikey exports from India in 1974 prompted VRB to initiate 
domestic breeding programs. A new facility at Perrine, Florida, was obtained 
from the Environmental Protection Agency and is being stocked with over 700 
rhesus breeders. Contracts are also being negotiated to initiate other 
domestic breeding colonies to produce 500 or more rhesus monkeys per year for 
use in NIH intramural research. 

Experimental animal holding for dogs, which has long been over capacity, was, 
in part, contracted. With the Phase I renovation of Building 14-D, protected 
facilities are available for holding 1,000 nonh\M[ian primates. Over 1,700 
primates will be held in this building on completion of Phase II and III 
renovations . 

The Animal Disease Investigation Service was reorganized to insure rapid i 

response to requests. The number of calls made to the BID has increased by 
22 percent, from 150 to 183. They involved consultative, diagnostic, and 
therapeutic activities and included rodents, rabbits, primates, carnivores, 
and miscellaneous feral animals. The complexity of the calls also varied and 
involved all Institutes. This service, well received by the BID investigators, 
has gradually increased in scope. It has been mutually beneficial to 
investigators and to the VRB professional staff in providing an overview of 
laboratory animal facilities and practices at NIH. \ 

D. Division Management 

1. Personnel Appointments 

Mrs. Jacqueline Waters, formerly with the Veterans Administration, was > 

appointed Division Training Officer replacing Mr. James Byrne who transferred 
to the Department of Interior. 

Mr. Charles Gensheimer joined the Personnel Management Specialist staff. 

A key position, EEO Technician, was created during the year and Mr. Arthur Parks «li« 
was recruited to broaden and strengthen the Division-wide EEO program. JI; 

Ml 

A reexamination of the management any alysis functions of the OD resulted in 
recruitment of Mr. Newell Quinton for manpower measurement and utilization f" 

studies throughout the organization. •«» 

2. Equal Employment Opportunity /*■ 

til 1 

The Division Human Relations Committee (HRC) continued to play a major role in ,„ 
channeling significant employee concerns to the Director. An EEO Seminar, the '" 
first in two years, was held in May to enhance awareness and understanding of 
aspects of the EEO program which tended to be overshadowed by problems of *'' 

minority groups. The Seminar provided an opportunity to focus attention on | 

attitudes toward reverse discrimination and sex discrimination. The HRC I 

developed a quarterly report which will highlight significant accomplishments ' 
in EEO during the year. This report will be distributed throughout the i 

Division to upgrade employee-management communications. 



1 



The creation of an EEO Technician position provides much needed assistance to 
the Division's EEO Coordinator and establishes a focal point for human relations 
problems at the GS-7 employee level or lower. 

3- Employee Development 

A selected group of approximately 60 key supervisory and administrative 
personnel participated in a two-day experiential laboratory to gain greater 
awareness of how individuals communicate with each other. In a similar 
effort, the Veterinary Resources Branch provided an opportunity for all 
supervisory personnel to attend a thirty-hour Leader Effectiveness course. 
In each instance, a major objective was to improve understanding of the 
importance of listening and its impact on the communications process. 

DRS personnel continued to actively participate in the Adult Education and 
Upward Mobility College programs. It is anticipated that enrollment, 
particularly in the General Education Development program, will increase as 
employees become more involved in establishing career goals. 

4. Training 

A new direction in DRS training places emphasis on providing courses and 
programs to meet not only the functional needs of the Division but also to 
play a role in the long-range career development of the individual. To 
promote efficiency within the Training Office and to provide continued 
guidance for DRS personnel, career development folders are being established. 
When completed, these will present a complete training history for each 
employee . 

Other plans for training include an internal program for on-the-job and 
Division orientation, supervisory training sessions geared to the specific 
needs of the participants, and a formal evaluation system to determine 
quality, feasibility, and effectiveness of training received by DRS 
personnel. 

5. Management Analysis Projects 

Personnel from the Division's Biomedical and Instrumentation Branch and the 
OD Management Analysis staff participated in an ongoing NIH-wide Materiel 
Management System study awarded to Arthur Young & Company. This study would 
coordinate inventory management, materiel flow, and financial accounting in 
all inventory systems with direct impact on the procedures used to collect 
cost and sales data in BEIB. 

The Management Analysis staff initiated an extensive study of the flow of 
management information at all supervisory levels of the Division. The 
Data Reporting System, installed four years ago, is being critically 
reviewed in terms of its responsiveness to management's needs. Recurring ADP 
responsibilities at the OD level are being phased into the NIH support 
activities of the Division of Computer Research and Technology, The 
objective of the latter is to redirect existing systems analysis manpower from 



routine EDP/ADP fimctions to broader work measurement and manpower 
utilization surveys throughout DRS. 

6. Personnel Management 

In cooperation with the Division EEO Coordinator, the Personnel office 
initiated a placement follow-up program for DRS. The personnel generalist 
and EEO Coordinator or technician met with each new Division employee 90 
days after entrance on duty. The objective is to make employee orientation 
more effective and promote better communications on Division and NIH-wide 
matters . 

Personnel and EEO staff met with supervisory personnel at all levels to 
enhance understanding of the annual performance appraisal system. The I 

meaning of specific adjectives used in the rating system were clarified j 

resulting in a more objective approach to employee appraisals. 

The promotion review program, initiated in 1973, was continued and established 

as an annual procedure. Through this mechanism, the potential of every , 

employee is reviewed in terms of his or her career goals as related to 

feasibility of advancement within the organization. j 

The Personnel Management staff participated extensively in the acquisition 
and staffing of a primate breeding facility in Perrine, Florida. Working 
closely with Environmental Protection Agency officials, DRS personnel staff 
was effected a smooth transfer and transition of Perrine employees to the 
NIH. 

1 
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 
design and refurbishing of conference rooms for more effective visual . 

presentation in the Office of the Director, NIH and the Director, National ^ 
Cancer Institute. Consultation was also provided on graphic presentation •*» 
in the conference room of the Director, National Heart and Lung Institute *]'' 

and on briefing materials for presenting research programs in other ". 

Institutes. r* 

Work continued on the NCI series of slide/tape biohazard control and safety 
training packages. Two additional presentations were completed, "Selecting 
a Laminar Flow Biological Safety Cabinet" and "Decontamination of a Laminar 
Flow Biological Safety Cabinet." One additional script on safety in 
handling laboratory animals was edited. These projects were done in 
collaboration with the Office of Biohazard and Environmental Control, NCI, 
and a contractor, Dow Chemical, U.S.A. Negotiations were completed 
for this series of training materials to be reproduced and sold through 
the National Audiovisual Center of the National Archives. The NCI sponsored 
course on "Principles of Biohazard and Injury Control in the Biomedical 
Laboratory" at the University of Minnesota was evaluated for conversion of 
lectures and visual materials to slide/tape presentations. 



Consultation was provided in planning, preparation and production of 
various manuals, guides, catalogs and other publications and on the /I 

planning, organization and delivery of various presentations for briefings, - ^' 
speeches and seminars. 



( 



Consultation began on design and creative direction of a series of TV 
vignettes for training psychiatric nurses in which coordination between the 
Clinical Center nurse training office and a contractor was required. 

Work continued on building a centralized file of original slides. This file 
provided materials to a number of NIH lecturers. A second group of 
historic NIH slides was gathered, identified and prepared for submission to 
the National Library of Medicine's historic collection. 

The Visual Communications Project Officer continued to lecture on effective 
communication techniques to NIH and NIH-related audiences. He also 
continued to coordinate and edit DRS scientific documents, reports and 
visual materials. Liaison was maintained with the NIH/OD, other BIDs on 
reporting and informational matters. 

A slide presentation, "The DRS Story," won an award for writing/editing 
from the Federal Editors Association, 

F, DRS Services Index 

The brochure, "Services and Facilities of the Division of Research 

Services," a catalog for users, was coordinated, written, published and j 

distributed throughout the NIH community. Yearly updating is planned. * 



DIVISION OF RESEARCH SERVICES 
Summary of Branch Activities July 1, 1973, through June 30, 1974 

BTGMEDICM, ENGINEERING AND INSTRUMENTATION BRANCH Dr. Lester Goodman, Chief 

I. SUMMARY 

Fiscal Year 1974 was highlighted by the maturing and reduction to practice 
of several major projects initiated and developed in preceding years. The 
utility and effectiveness of previous analysis and experimentation were 
demonstrated via the establishment of mathematically derived chemotherapeutic 
protocols for managing certain cancer cases, and application of pharmaco- 
dynamic principles to achieve more optimal hemodialysis of patients suffering 
from renal failure. Prototype clinical instrumentation systems based on video 
technology were accepted as practical tools for monitoring cardiac performance 
and the condition of aortic ball valve prostheses in vivo ; non-invasive ultra- 
sonic imaging for measurement of heart muscle dimensions has become relatively 
routine. Previously developed concepts and equipment for investigating 
concussion were regularly used to generate and analyze reproducible data from 
head injury experiments. Formalized inspection and maintenance routines for 
patient care apparatus in the Clinical Center were implemented. The 
Scientific Equipment Rental Program expanded markedly and was broadly accepted 
and used by a substantial portion of the NIH community as a reliable, 
economic resource. 

Investigations with substantial potential for future applications were initi- 
ated in several important areas, including the identification and assessment 
of trace metallic complexes in cancer therapy and environmental contamination, 
the interaction of implanted polymers with blood and body fluids, fluid 
mechanical influences on atherosclerotic plaque formation, ionic concomitants 
of cortical metabolism, faster and more sensitive microcalorimetry, and 
comprehensive instrumentation for investigating the behavioral effects of anti- 
epileptic drugs. New concepts and designs for more reliable and economic 
mechanized apparatus for materials handling and sample processing were 
formulated, especially in the context of clinical chemistry; refined surgical J 
tools for ophthalmology and neurology were brought to the proof of concept , 

stage. 



Ml|:| 

nit' 

2 

r; 



Demands for consultation and assistance with collaborative and extramural 
programs exceeded resources available, as did requests from other government 
agencies for fabrication of unique technical systems based upon BEIB designs 
and prototypes. 



( 



I 



II. BRANCH PROGRAMS 



A. Objectives 



To provide direct and consultative engineering support to clinical and biomed- 
ical research projects, including advice on systems analysis, experimental 
design, and synthesis of technical expedients. 

To design, develop, fabricate, and evaluate special -pur-pose 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 units. 

1. Instrument Fabrication 

Production, modification, and minor design of medical equipment and instru- 
mentation systems requiring special tools and skills in the electronic, 
electrical, glass, mechanical, optical, rubber, plasties, 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. 



I 



11 



c. Commujiication 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 demands of 
local programs and operate as integral parts of the resident team but are 
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 maintain- 
ing the chief benefits of centralized resources. 

C. Program Progress and Accomplishments 

1. Technical Services 

a. Instrument Fabrication Section 



Backlogs increased steadily throughout the year, even though the number of 
requests for service decreased by 18 percent from the previous year. Response 
acceptable to investigators was maintained by substantial use of overtime. 
The section completed approximately 3>V00 projects valued at $750,000 compared 
with 4,500 projects valued at $966,000 in FY 1973. 

b. Systems Maintenance 

CurtaiLnent of preventive maintenance routines, because of reductions in staff, 
restricted services almost completely to meeting emergency requests, reduced 
the number of tasks performed, and increased the average cost per assignment. 
Substantial overtime was necessary to complete approximately 8,200 jobs at a 
cost of $1,200,000 compared with 9,600 and $910,000 respectively in FY 1973. 

The Scientific Equipment Rental Program expanded substantially over the year; 
growth is summarized in the following table: 



Number of pool equipment items 
Prevailing dollar value 
Number of items on rental 
Prevailing utilisation rate 



Gross rental revenue 

New rental equipment investment 







Percent i 


July 1, 1973 


July 1, 1974 


Increase 


330 


430 


30 


$390,000 


$485,000 


24 1 


90 


210 


133 


26^ 


49% 


88 
Percent 


FY 1973 


FY 1974 


Increase 


$ 22,000 


$ 65,000 


195 


4,200 


17,500 


320 



12 



Limitations r,r, space and personr.el have become serious Impedimenta to the 
effective operation of this program that has become 30 popu] ar with mil 
investigators. 

e. Supply Unit 

Reduced levels of activities throughout MIH and r>Mb;itantia] price increases 
resulted in a 5 percent decrease in the number of transactions and a 2.5 per- 
cent rise m value of goods sold in comparison with PT 1973. Transactions' 
dropped from 22,000 in the previous year to 21,000 aiid cost of goods sold 
rose from $415,000 to $426,000. Ji y^Jis soia 

2. Engineering and Applied Sciences 
a. Chemical Engineering 

Considerable progress was made in applying principles of chemical reaction 
?^^TT7 ^^ P^'^bl^"'^^^ drug, metabolite and trace contaminant distribution 
in the body._ Pharmacokinetic modeling has permitted the elucidation of speci-£ 
differences in_both metabolized and nonmetabolized substances. It has also 
enabled operational assessment of the quantitative importance of physioloeic 
processes and biochemical interactions which determine uptake, distribution 
and elimination. _ Of primary concern was the assessment of toxic risk to man 
fn S'l^ envirormiental contaminar.ts on the basis of experiments conducted 
m animals or from simplified in vitro screens. 

The invention of a device for slow controlled release of an anticancer dru2 
provided^for more complete comprehension of the biological response of tumor 
and sensitive normal tissue and suggested methods for improved therapy A 
cooperative clinical protocol has been established in which patients will 
receive drugs at mathematically predicted rates to maintain concentrations 
toiovmto be effective in experimental systems. Pharmacokinetic and pharmaco- 
dynamic principles have been usefully applied to achieve more optimal hemo- 
dialytic therapy of patients with kidney failure 



2 



Growing interest in metallic elements in biological systems led to improved 

methods for assay of platinum in tissues and fl^iids to support pharmacologic 1 

studies and assess risk associated with platinum based catalytic converters "^ 

on automobiles. The role of calcium in right heart failure of rabbits, after r 

recei^/ing the anticancer drug adrlamycln, is being examined. It has been l. 

suggested that appropriate use of gallium might protect patients from excessive f 

ezposiire to radioactive tracers. ^^oo±vk: ^ 

Fundamental thermodynamic and kinetic studies of l:.-r)ortarzt biom8^erial- have '" 
helped clarify the interaction of multicoirroonent polymer systems vkth bio- ' IL 
logical environments. Elution of mobile and potentially toxic materials from 
the polymer and absorption by the polymer of body constituents, such as MrvMs < 
have been studied. A new composite ball heart valve was successfully implanted 
m a calf and subsequent experiments are planned. Segmented polyurethan* , now 
commercially available, has been applied successfully in several new biomedical 
prostheses; high order of biocompatibility and ease of fabrication continue to 
oiler fiirther exciting prospects for blomedicine. 

13 



The roles of fluid mechanics, transport and kinetics are being examined in the 
development and progression of atherosclerosis. An electrochemical technique 
was developed to study shear stress distributions in a model of the canine 
aorta near bifurcations where plaque formation arises. The experimental 
investigation is being supported by hydrodynamic analyses. 

Extensive consultation was provided to a variety of intramural, collaborative, 
and extramural programs. 

b. Electrical and Electronic Engineering 

BEIB completed a substantial number of new designs for electrical and elec- 
tronic apparatus for the NIH research program; projects deserving special 
mention are summarized as follows: 

New developments in clinical instrumentation include a noninvasive televised 
technique for detecting artificial aortic valve ball variance; a dual ion- 
selective microelectrode and associated electronics for measuring K"*" ion con- 
centration in cortex; a low dose level, high resolution dental X-ray system; 
advances in dynamic two-dimensional organ visualization via ultrasonic scan- 
ning; and a special purpose audio stimulator for assessing behavioral side 
effects of anti-epileptic drugs. 

Noteworthy laboratory instriimentation projects produced a rapid biological 
cell freezing system; faster, more accurate measurement and signal processing 
apparatus for microcalorimetry; enhancement of the l^c NMR system performance; 
a nuclear isotope raster scan and mapping process; and a novel frequency 
domain fluorescence decay analyzer. 

The patient electrical safety program featured Inauguration of formalized in- 
spection and maintenance routines for much of the critical patient care 
apparatus in the Clinical Center, utilizing previously developed and new 
automatic test equipment. 

EEES provided substantial support to the NHLI/NASA team, evaluating the effects 
of prolonged weightlessness on Skylab astronauts, and extensive consultation 
to numerous other intramural, collaborative and extramural programs. 

c. Mechanical Engineering 

Continued close collaboration with research and service staff throughout the 
NIH resulted in several substantial developments. Mechanization and automa- 
tion of routine procedures received emphasis. Efficiency and effectiveness of 
biological sample analyses were enhanced via several new automatic materials 
handling devices for aliquots and reagents. Distinct improvements were 
achieved in methods for large-scale processing of laboratory glassware and 
media. These systems continue to reduce the cost and time of routine manual 
tasks and enable reallocation of manpower to more productive and challenging 
assignments . 

Considerable attention was devoted to fundamental and applied research on the 
mechanisms of head injury, processing of electrophoretic preparations, 

1-; 



physiological effects produced by mechanical stress on nerve tissue, mechan- 
isms of eye lubrication, and effects produced on unborn infants by elevated 
temperature in the mother. 

The state of the art in recording electrical signals from the brain, in vivo , 
was advanced with the innovation of devices for precise atraumatic insertion 
of electrodes into cortical regions; and for remote eye siorgery using a chin- 
operated "joy stick" which manipulates all adjustments on a microscope during 
operations, thus freeing the hands of the surgeon for other functions. 

Extensive consultation was provided to intramural, collaborative, and extra- 
mural programs . 

d. Florence Agreement 

Fulfilling the NIH responsibility related to the "Florence Agreement" has been 
delegated to BEIB. 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 the intended 
application, investigation of availability of domestically produced 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. Activities for FY 1974 
are summarized as: 

Number of applications received by NIH 580 

Referred to other agencies. 90 

Processed by NIH 490 

Processed independently by NIH Florence Agreement 

Committee Executive Secretary (BEIB) 420 

Processed with help of other Committee members 70 

PLecommendations for approval 350 

Recommendations for disapproval 10 

Recommendations for resubmission 130 

The Executive Secretary, as a result of the need to be thoroughly knowledgeable 

in modem scientific equipment, has become recognized as a reliable source of *l" 

expert guidance, especially in the areas of transmission and scanning electron •"" 

microscopy. 

3- Technical Advances 

A NOVEL DENTAL DIAGNOSTIC SYSTEM incorporating X ray, electrooptical data 
acquisition, image enhancement, and video processing provides improved 
displays with sharply reduced radiation exposure. 

A PLASTIC PHANTOM HEAD MODEL is useful in assessing the spatial and absorptive 
resolution of transverse axial tomography systems. 

A THIN FILM CAPACITIVE SENSOR in a resonant bridge and lock-in amplifier 
substantially enhances speed and resolution of temperature measurements. 



15 



12 



r 



A NONDESTRUCTIVE BONE STRENGTH TESTER enables examination of periosteum and 
oxygen effects on the healing rate of fractures. 

AN AUDIO STIMULATOR, lightweight and battery powered, features flexibility in 
generating programmed clicks and white noise for right and left ears and 
provides reference signals for computer processing. 

CHOLESTEROL DEPOSITS ON ARTERY WALLS are automatically mapped on excised, 
expanded sections using a digitally driven Geiger tube, in a raster mode, 
to detect radio tracer intensity. 

AN OSCILLATING PRIMATE TURNTABLE, under servo control, enables frequency 
response studies of central vestibular units being stimulated by rotation 
of the semicircular canals. 

AN IMPROVED SYNCHRONOUS GATE used with the superconducting FFT NMR system 
reduces test time by an order of magnitude by enhancing the nuclear Overhauser 
effect without disturbing the 13c fine structure arising from proton couplings. 

PREDETERMINED CORTICAL CONTUSIONS and intracranial pressure transients for 
studying head injury phenomena in primates are generated by a high performance 
servo controlled drive system. 

A HYPOTHERMIA CHAMBER elevates temperature in pregnant sheep to enable 
investigation of the effect of fever on the fetus. 

POTASSIUM ION CONCENTRATION in exposed cat cortex, measured with ion selective 
electrodes, together with ECOG and NADH monitoring helps clarify the relation- 
ship between neural activity and potassium ion transport. 

A FLUORESCENCE DECAY RATE MEASUREMENT SYSTEM for dynamic studies of stimulated 
squid axon, permitting illumination at lO'^ times greater than commercial 
apparatus markedly enhances speed and sensitivity of detection. 

A SWITCHED GAIN ULTRASONIC SCANNER substantially improves the clarity and 
accuracy of cardiac structure images. 

A VITREOUS HUMOR EXCHANGE DEVICE facilitates eye surgery by enabling one- 
handed control of intraocular fluid volume by the surgeon. 

AN INFANT BEHAVIOR MONITOR generates visual and aural stimuli while recording 
movement responses to help elucidate the phenomena of mother-child 
interaction. 

AN ISOLATED ORGAN PERFUSION CHAMBER maintains viability and enables prolonged 
study of excised animal hearts and kidneys for research on transplantation. 

A CLINICAL FLOW MICROCALORIMETER provides for rapid thermochemical analysis 
of patient blood. 

AN IMPROVED PHOTOELECTROSPECTROPHOTOMETER extends ability to analyze molecular 
structures with ultraviolet radiation. 



16 



A LYMPHOCYTE HARVESTER mechanizes the transfer of cell samples from microtiter 
tray wells to filter paper for subsequent processing. 

PORTABLE ANIMAL ISOLATORS incorporating self-contained air handling expedite 
transportation and holding of small animals. 

OPTIMUM COOLING OF BIOLOGICAL MATERIALS through liquid, eutectic, and solid 
phases is enabled by a novel feedback temperature control system. 

4 . Training 

An effective professional and technical training program was essential in 
maintaining high quality support and service to the NIH programs. Forty-five 
employees participated in 67 academic, administrative and technical courses. 
Six (65 man-days) undertook formal university education and training courses. 
Eight ( Jl man-days ) received specialized training on scientific equipment at 
manufacturers' facilities and at the NIH. Thirty-one attended various admin- 
istrative, clerical, technical and scientific courses and training seminars. 
One employee attended Basic Adult Education at NIH sponsored by the Montgomery I 
Coimty School System and five were enrolled in the Upward Mobility College. 

The Glassblower Trainee, hired under the Affirmative Action Program and subse- I 
quently promoted to the WG-8, Intermediate level, was promoted in FY 74- to 
Glassblower, WG-10, after demonstrating proficiency at the higher grade. A 
second Glassblower Trainee was hired, bringing to four the total number of 
employees at various stages of development under this program. All are con- 
tinuing to receive academic instruction at local colleges and technical 

schools, as well as intensive on-the-job training. 

I 
_ J 

D. Program Plans 

Fiscal 1974 was distinguished by the reduction to practice and practical demon- 
stration of several important concepts and designs innovated in preceding iIh 
periods . 4 

1. Considerable attention will be devoted in the coming year to refining, J 

reinforcing, and extending applications in the laboratories and clinics, 

especially in the areas of: f' 

a. Mathematical prediction and implementation of optimized chemotherapy and [ 
dialysis. " 

b. Noninvasive physiological measurements. „ 

c. Rational design of long-term implanted prostheses. 

d. Mechanized and automated materials handling. 

e. Elucidation of electrical, mechanical, and chemical concomitants of 
neural, muscular, and cardiovascular phenomena. 

f. Standardized hospital safety functional and operational criteria. 

17 



2. Allocation of additional space for the Scientific Equipment Rental 
Program is expected to alleviate a serious constraint and enable more effec- 
tive operation and service to the NIH community. 

3. Utilization of available opportunities to supplement BEIB staff and 
indoctrinate career aspirants is contemplated; substantial use of programs 
such as Intergovernmental Personnel Act (IPA), Project Access, Project Stride, 
Excepted "Schedule A" appointments for students and faculty members, Stay-in- 
School, and EEO Affirmative Action Plan Training is anticipated. 

L,. Efforts will be made to increase collaborative intradi vision activities 
to improve the quality and timeliness of DRS support for the entire NIH. 

5. The effectiveness with which BEIB Implements these plans and fulfills its 
mission depends crucially on the availability of adequate staff. Prevailing 
constraints must be relaxed if satisfactory performance is to be provided, 

E. Publications and Patents 



1. Publications 

Bischoff, K.B.: Commentary on pharmacokinetics. In Iberall, A.S. and 
Guyton, A.C. (Eds.): Regulation and Control in Physiological Systems . 
Proceedings of the Conference, August 22-24, 1973, University of Rochester, 
Rochester, N.Y . Pittsburgh, Instrument Society of America, 1973, pp. 54-56. 

, Himmelstein, K.J., Dedrick, R.L., and Zaharko, D.S.: Pharmacokinetics 



and cell population growth models in cancer chemotherapy. In Chemical 
Engineering in Medicine. Advances in Chemistry Series 118 . Washington, D.C. 
American Chemical Society, 1973, pp. 4-7-64. 

Boretos, J.W.: Machining of plastics. In Ray, CD. (Ed.): Medical 
Engineering . Chicago, Year Book Medical Publishers, 1974, pp. 1173-1181. 

Polymer considerations for implant electronics. In Ray, CD. (Ed.): 



Medical Engineering . Chicago, Year Book Medical Publishers, 1974, 
pp. 1120-1123. 

^ and Gabelnick, H.L.: Letters to the Editor. Characterization of 



biomedical polymers. J. Biomed. Mater. Res . 7: 267, 1973. 

Dedrick, R.L.: Animal scale-up. J. Pharmacokinet . Biopharm . 1: 435-461, 
1973. Also in Teorell, T., Dedrick, R.L., and Condliffe, P. (Eds.): 
Pharmacology and Pharmacokinetics . ( In press ) 

Book review: Transport Phenomena and Living Systems: Biomedical 



Applications of Momentum and Mass Transfer, by E.N. Lightfoot. 
Amer. Institute of Chemical Engineers T . (in press) 

Pharmacokinetic and pharmacodynamic considerations for chronic 



hemodialysis. Supplement to Kidney International, (in press! 



18 



: Physiological pharmacokinetics. In Iherall, A.S, and Giiyton, A.C. 

( Eds . ) : Regulation and Control in Physiological Systems . Proceedings of the 
Conference, August 22-24-, 1973, University of Rochester, N.~ Pittsburgh, 
Instrument Society of America, 1973, pp. 65-68. Also in Trans. ASME, J . 
Eynamic Systems, Measurement, Control , 95: Series G, No. 3, 255-258, 1973. 

and Forrester, D.D.: Blood flow limitations in interpreting Mchaelis 

constants for ethanol oxidation in vivo . Biochem. Pharmacol . 22: 1133-114-0, 



Cannon, J.N., El Dareer, S.M. , and Mellett, L.B.: Pharmacoki- 



netics of 1-6-D-Arabinofuranosylcytosine (ARA-C) deamination in several 
species. Biochem. Pharmacol. 22: 2405-2417, 1973. 



, Zaharko, D.S., and Lutz, R.J.: Transport and binding of methotrexate 

in vivo . J. Pharm. Sci . 62: 882-890, 1973. 

- , , , and Drake, J.C: Device for controlled drug release: 

Application to methotrexate infusion in mice. Biochem. Pharmacol , (in press) 

Dehn, W.R. : An all-glass device for fabricating gel electrophoresis slabs. 
In Proceedings, The Eighteenth Symposium on the Art of Glassblowing , Denver, 
Colorado, Jime 12-15, 1973. The Merican Scientific Glassblowers Society, 
Wilmington, Delaware, 1973, pp. 92-96.^ 

Dvorak, J. A., Schuette, W.H., and Whitehouse, W.C.: A simple video method for 
the quantifying of geometric parameters of microscopic objects. J. Microsc . 
( In press ) 

Friauf, W.S.: An aversive stimulator for autistic children. Med. Biol. Eng . 
11: 609-612, 1973. 

: Test equipment for hospital safety programs. In Proceedings of the 

27th Annual Conference on Engineering in Medicine and Biology. ( In press ) 



, Cascio, H.E., and Jones, A.R. : 

biomedical equipment. Med. Electron. 



Automated test set for checking 
Data, 4: 54-60, 1973. 



Gaasterland, D., Kupfer, C, Ross, K., and Gabelnick, H.L. : Studies cf 
aqueous humor dynamics in man. III. Measurements in young normal subjects 
using norepinephrine and isoproterenol. Invest . Ophthalmol . 12: 267-279, 1973. 

Gennarelli, T.A., Ommaya, A.K., and Thibault, L.E.: Comparison of transla- 
tional and rotational head motions in experimental cerebral concussion. In 
Proceedings of Fifteenth Stapp Car Crash Conference, November 17-19, 1971. 
Coronado, California. New York, Society of Automotive Engineers, Inc., 1972, 
pp. 797-803. 

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! ( In press ) 



3 



19 



Goldstein, S.R. : A servo-force balance isometric muscle force transducer. ^ 
J. Appl. Physiol . ( In press ) ^ 

, Friauf, W.S., and Wells, J.B.: A novel instrument for dynamic and 
static measurement of large length changes in muscle. J. Appl. Physiol . 
36: 128-130, 1974. 

and Salcman, M. : Mechanical factors in the design of chronic recording 



intracortical microelectrodes. IEEE Trans. BME . BME-20, 260-269, 1973. 
, 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 Ifedicine and 
Biology . ( In press ) 

and Smith, E.: An electrohydraulic system for ultrasonic echocardi- 



ography on exercising subjects. In Albert, R. , Vogt, W. , and Helbig, W. 
(Eds, ): Digest of the X International Conference on Medical and Biological 
Engineering . Dresden, GDR, August 13-17, 1973. The Conference Committee of 
the X International Conference on Medical and Biological Engineering. 
Vol. II, 1973, p. 135. Also in Proceedings of the 26th Annual Conference on 
Engineering in Medicine and Biology, 1973, Minneapolis, Minnesota . 
Arlington, Va., The Alliance for Engineering in Medicine and Biology, 1973, 
Vol. 15, p. 427. 

Goodman, L. : Book review: Concise Guide to Biomedical Polymers, Their 
Design, Fabrication, and Molding , by J.W. Boretos, J. Assoc. Adv. Med. Instrum . 
7: 165-166, 1973. Also in Med. Biol. Eng . 11: 373, 1973. 

The engineer and advanced medical systems. In Davies, D.F. and 



< 



Tchobanoff, J.B. (Eds.): Health Evaluation. An Entry to the Health Care 
System . New York, Intercontinental Medical Book Corporation, 1973, pp. 1-5, 

Quality in preventive maintenance and equipment control. Clinical 



Engineering Newsletter, AAMI , 9-12, Sept. -Oct., 1973 

Griffith, J.M. and Henry, W.L.: A real time system for two-dimensional echo- 
cardiography. In Proceedings of the 26th Annual Conference on Engineering in 
Medicine and Biology, 1973, Minneapolis, Minnesota . Arlington, Va., The 
Alliance for Engineering in Medicine and Biology, 1973, Vol. 15, p. 422. 

aJid : A sector scanner for real time two-dimensional echocardi- 



ography. Circulation , (in press' 

and : Switched gain: Simplifies ultrasonic measurement of 



cardiac wall thickness. In Proceedings of the 27th Annual Conference on 
Engineering in Medicine and Biology . (In press) 

aj^d : Video scanner-analog computer system for semiautomatic 



analysis of routine echocardiograms. Am. J. Cardio. 32: 961-964, 1973. 



20 



Himmelstein, K.J. and Bischoff, K.B.: Mathematical representations of cancer 
chemotherapy effects. J. Pharmacokinet . Biopharm. 1: 51-68, 1973. 



and 



: Models of ARA-C chemotherapy of L1210 leukemia in mice. 



J. Pharmacokinet. Biopharm . 1: 69-81, 1973. 

Kalmbach, K. and Mardiney, M.R., Jr.: An improved system for controlled rate 
cooling of biological material. Cryobiology, 9: 572-574, 1972. 

Leighton, S.B. and Dow, B.M. : Instrumental Note. Servo-controlled moving 
stimulus generator for single unit studies in vision. Vision Res . , 
13: 1195-1198, 1973. 



J. 



and Kent, K.M. : 

Appl. Physiol. 34: 



Precision gas mixing technique for medical applications, 
502-503, 1973. 



Levitsky, S., Schuette, W.H., Kempner, K.M. , Sloane-, R. , Souther, S.G. , 
Mullin, E.M. , and Morrow, A.G. : Experimental and early clinical evaluation 
of heart tracking ( Radarkymography ) as a noninvasive method for meas;iring 
myocardial contractility. Am. J. Cardiol . 32: 156-161, 1973. 

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 . ( In press ) 

Lewis, D.C., O'Connor, M.L., and Schuette, W.H. : Oxidative metabolism during 
recurrent seizures in the penicillin treated hippocampus. Electroencephalogr . 
and Clin. Neurophysiol . ( In press ) 

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 ! ( In press ) 

Marcus, M.L., Schuette, W.H., Whitehouse, W.C, Bailey, J. J., Douglas, M.A., 
and Glancy, D.L.: Use of a video system in the study of ventricular function 
in man. Am. J. Cardiol . 32: 175-179, 1973. 

Ommaya, A.K., Metz, H., and Post, K.D.: Observations on the mechanics of 
hydrocephalus. In Harbert, J.C. (Ed.): Cisternography and Hydrocephalus — 
A Symposium . Springfield, 111., Charles C Thomas, 1972, pp. 57-74. 

and Thibault, L. : Head and spinal injury tolerance with no direct head 

impact. In Proceedings of the International Conference on the Biokinetics 
of Impacts , Amsterdam, June 26-27, 1973. Lyon, France, Laboratoire des chocs 
de I'ORGANISME NATIONAL DE SECURITE ROUTIERE, May 1973, pp. 311-319. 

Peterson, J.I., Friauf, W.S., and Leighton, S.B,: A high precision fluorom- 
eter for biochemical measurements. Anal. Biochem. 58: 255-271, 1974 



i2 

a; 



21 



Holland, J.W.,, Jr., Dehn, W.R., and Swank, H.D.: Construction of a 



partitioned gel slab electrophoresis cell of fused borosilicate glass, 
Anal. Biochem . 55: 623-625, 1973. 

, Tipton, H.W., and Chrambach, A.: A gel slicer for the transverse 

sectioning of cylindrical polyacrylamide gels. Anal. Biochem . (in press) 

Pierce, W.S., Kazama, S., Metz, H., Prophet, G.A., aiid Waldhausen, J. A.: 
Twenty-four hour left ventricular bypass in the unanesthetized dog: A study 
employing transthoracic canniil-ation and a paracorporeal roller pump. 
Aim. Surg . 179: 39-45, 1974. 

Higgle, G.C., Bagley, D.H., Jr., and Beazley, R.M. : Microthermocouple probe 
for gradient temperature measurements. Cryobiology 10: 345-346, 1973. 

Schuette, W.H.: Video-log: A technique for recording analog signals in the 
television video format. Proceedings of the Eleventh Annual Rocky Mountain 
Bioen^rineerl ng oymposJum and Eleventh International ISA Biomedical Sciences 
InslruinenLaLIoii oynipoaium, IJoAFA . ( In press ) 

, Grauer, L.E., Whitehouse, W.C., Itscoitz, S.B., and Redwood, D.R.: 

Measurement of ventricular ejection fraction in man utilizing roentgen 
videodensitometry. In Proceedings of the 27th Annual Conference on 
Engineering in Medicine and Biology . ( In press ) 

, Wliitehouse, W.C, Lewis, D.V. , O'Connor, M. , and Van Buren, J.M. : 



A television fluorometer for monitoring oxidative metabolism in intact 
tissue. J. Assoc. Adv. of Med. Instrum . (In press) 

Straw, J. A., Hart, M.M. , Klubes, P., Zaharko, D.S., and Dedrick, R.L. : 
Distribution of anticancer agents in spontaneous animal tumors. 1. Regional 
blood flow and methotrexate distribution in canine lymphosarcoma. 
J. Natl. Cancer Inst . ( In press ) 

Teorell, T,, Dedrick, R.L., and Condliffe, P. (Eds.): Pharmacology and 
Pharmacokinetics . ( In press ) 

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 . ( In press ) 

Thompson, E.J., Griffith, J.M., Schoenberg, D.G., and Nirenberg, M.W. : 
An improved method for extracellular recording of action potentials from 
single cultured neuroblastoma cells. Med. Biol. Eng . (in press) 

, Wilson, S.H., Schuette, W.H., Whitehouse, W.C, and Nirenberg, M.W. : 

Measurement of the rate and velocity of movement by single heart cells in 
culture. Am. J. Cardiol. 32: 162-166, 1973. 



22 



Vurek, G.G., Kolobow, T., Pegram, S.E., and Friauf, W,S.: Oxygen saturation 
monitor for extra-corporeal circulation applications. Med. Instru . 
7: 262-267, 1973. 

Zaharko, D.S. and Dedrick, R.L. : Applications of pharmacokinetics to cancer 
chemotherapy. Pharmacology and the Future of Man. Proceedings Fifth 
International Congress on Pharmacology , San Francisco 1972, vol. 3, 
pp. 316-331 (Karger, Basel, 1973) 

, , 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. Ther . ( In press ) 

2. Patents 

No report. 



I 



23 



. 



* 



III. INDIVIDUAL PROJECT REPORTS 

Serial No. DRS-BEIB-1 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Chemical Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973, through June 30, 1974 

Project Title: Pharmacokinetics 

Previous Serial Number : Same. 

Principal Investigators: Robert L. Dedrick, Daniel. S. Zaharko 

Other Investigators: Henry L. Gabelnick, Richard A. Bender, 
Anthony M, Guarino, Robert J. Lutz, 
Kenneth B. Bischoff 

Cooperating Units: LCHPH-NCI, LT-NCI, OD-NIEHS, AK-CU Program NIAMDD 

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 metabolic data to in vivo cases. 

(5) Predict effective dose schedules of anti-cancer drugs in individual 
patients. 

Methods Employed : Mathematical models are developed from physi go chemical, 
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. 

25 



wit' 

I 



Major Findings: 



I 



(1) Pharmacodynamics of methotrexate have been further clarified by extensive 
studies with constant infusion in mice from a new implantable device. 

(2) Methotrexate uptake by canine lymphosarcoma appears to be described by a 
modified form of a model developed for normal rat tissues. 

(3) A pharmacokinetic model, originally developed on the basis of extensive 
studies in mice, is adaptable to predict plasma concentrations in individual 
patients. 

(4) During chronic hemodialysis: 

(a) Significant intercompartment transport resistance may cause chemical 
disequilibrium. 

(b) Patient response may be significantly delayed after a change in treatment. 

( c ) Patient response may be more dependent on dialysis schedule than generally 
realized. 

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 emphasis on pharmacokinetic modeling with particu- 
lar attention to pharmacodynamic and cytokinetic events. Increased emphasis 
on clinical applicability through prediction of most effective individual 
patient dose schedules. 

Honors and Awards : None. 

Publications : 

Bischoff, K.B.: Commentary on pharmacokinetics. In Iberall, A.S. and 
Guyton, A.C. (Eds.): Regulation and Control in Physiological Systems , 
Proceedings of the Conference, August 22-2A, 1973, University of Rochester, 
Rochester, N.Y . Pittsburgh, Instrument Society of America, 1973, pp. 54-56. 

_, Dedrick, R.L., Zaharko, D.S., and Longstreth, J. A.: Methotrexate 



pharmacokinetics. J. Pharm. Sci . 60: 1128-1133, 1971. 

_, Himmelstein, K.J., Dedrick, R.L., and Zaharko, D.S. : Pharmacokinetics 



and cell population growth models in cancer chemotherapy. In Chemical Engi- 
neering in Medicine. Advances in Chemistry Series 118 . Washington, D.C., 
American Chemical Society, 1973, pp. 47-64. 

Dedrick, R.L.: Animal scale-up. J. Pharmacokinet . Biopharm . 1: 435-461, 
1973. Also in Teorell, T., Dedrick, R.L., and Condliffe, P. (Eds.): 
Pharmacology and Pharmacokinetics. ( In press ) 



26 



Dedrick, R.L.: Physiological pharmacokinetics. In Iberall, A.S. and 
Guyton, A.C. (Eds.): Regulation and Control in Physiological Systems . 
Proceedings of the Conference, August 22-24, 1973, University of Rochester , 
N.Y . Pittsburgh, Instrximent Society of America, 1973, pp. 65-68. Also in 
Trans. ASME, J. E^amic Systems, Measurement, Contr ol 95: Series G, No. 3, 
255-258, 1973. — 

and Forrester, D.D. : Blood flow limitations in interpreting Michaelis 



constants for ethanol oxidation in vivo . Biochem. Pharmacol . 22: 1133-1140, 
1973. 

_, Cannon, J.N., El Dareer, S.M. , and Mellett, L.B. 



Pharmacokinetics of 1-3-D-Arabinofuranosylcytosine (ARA-C) deamination in 
several species. Biochem. Pharmacol . 22: 2405-2417, 1973. 

_, and Ho, D.H.W. : In vitro — in vivo correlation of drug metabo- 



lism — Deamination of l-B-D-Arabinof\iranosylcytosine. Biochem. Pharmacol . 
21: 1-16, 1972. 

and Zaharko, D.S.: Letter to the editor — Extrapolation of teratogenic 



effects. Cham. Eng. News 5-6, 1971. 

, , and Lutz, R.J.: Transport and binding of methotrexate in vivo . 

J. Pharm. Sci . 62: 882-890, 1973. 

and Drake, J.C.: Device for controlled drug release: 



Application to methotrexate infusion in mice. Biochem. Pharmacol , (in press ^ 

Himmelstein, K.J. and Bischoff, K.B.: Mathematical representations of cancer 
chemotherapy effects. J. Pharmacokinet . Biopharm . 1: 51-68, 1973. 

and : Models of ARA-C chemotherapy of L1210 leiikemia in mice. 



J. Pharmacokinet. Biopharm. 1: 69-81, 1973. 



fSit' 



Straw, J. A., Hart, M.M. , Klubes, P., Zaharko, D.S., and Dedrick, R.L. : Distri- 
bution of anticancer agents in spontaneous animal tumors. 1. Regional blood JJ 
flow and methotrexate distribution in canine lymphosarcoma. J. Natl. Cancer J 
Inst . ( In press ) 

Teorell, T., Dedrick, R.L., and Condliffe, P. (Eds.): Pharmacology and 

Pharmacokinetics . ( In press ) ' ' 

Zaharko, D.S. and Dedrick, R.L.: Applications of pharmacokinetics to cancer 
chemotherapy. Pharmacology and the Future of Man. Proceedings Fifth Inter- 
national Congress on Pharmacology , San Francisco 1972, vol.3, pp. 316-331 

(Karger, Basel 1973) ,i 

\ 

and : Pharmacokinetic models: Application to antineoplastic 
agents . In Sartorelli, A.C. and Johns, D.G. (Eds.): Handbook of Experimental 
Pharmacology, Antineoplastic and Immunosuppressive Agents f! (In press) 



27 



and Oliverio, V.T.: Prediction of the distribution of metho- 



trexate in the sting rays dasyatidae sabina and sayi by use of a model 
developed in mice. Comp. Biochem. Physiol . 42A: 183-194-, 1972. 

, , 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. Ther. (in press) 






^ 



28 



Serial No. DRS-BEIB-2 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Chemical Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973, through June 30, 1974 

Project Title: Trace Element Analysis in Biological Materials (new title) 

Previous Serial Number: Same. 

Principal Investigators: Andre F, LeRoy, Harry M. Olson, Anthony M, Guarino 

Other Investigators: Robert L. Dedrick, Charles L. Litterest, 
Theodore E. Gram, Rebecca E. Munroe, 
Harry L. Sponseller 

Cooperating Unit: LT-NCI : 

Man Years: ' 

Total: 2.0 
Professional: 1.2 
Other: 0.8 

Project Description: , ' 

Objectives : Improve analysis and identification of metal complexes in 
biological materials. Enhance analytical methods with detection limits in j 
the order of nanograms to picograms in one milligram samples, with emphasis ■ 
on analysis of Pt and Ga compounds used in cancer therapy. Platinum group *5?' 
metals will become environmental trace contaminants if catalytic exhaust J*|| 
systems are used to control emissions. Emphasis also on analysis of Ca and 
Mg in tissue that appear to interact with an antineoplastic drug, Adriamycin, 
with frequent right heart failure of humans and test animals. 

Methods Employed : Flameless atomic absorption spectrophotometry to analyze 
for specific elements. Successful direct analysis of biological tissue by 
this means has been limited; procedures with chemical agents are used to 
promote release of metals from the biological matrix with smoother, more 
complete combustion. Cleaner combustion can be realized in some cases with 
solvent extraction. 

Electrophoresis to separate protein fractions and determine distribution of 
metal species among fractions. Biopsy drills may be used to obtain cardiac 
muscle samples for calcium and magnesium analysis. 



29 



I 



Major Findings : Sensitivity of platinum determination is presently about one 
nanogram. Urine samples from monkeys treated with cis-dichlorodiammlne plat- 
inum were analysed by methods described. Determinations on liquid and pre- 
cipitated solids showed 4-0-100 times more in liquid than, in solids in 64 
samples collected from 10 monkeys. Sensitivities for Ca and Mg are approxi- 
mately 40 and 3 picograms respectively, using the flameless atomic absorption 
spectrophotometer. The best sensitivities are realized with samples 
pretreated by dry or wet ashing. 

Significance : Quantitation and identification of metals at trace levels in 
biological tissue is important for cancer therapy. Characterization of such 
compoimds and assays in tissues and body fluids can help identify drug action 
and suggest other potentially useful compounds. These methods offer an 
alternative to administering radio labelled substances to human subjects. 

Analysis of trace contaminants is necessary in establishing priorities for 
environmental control. 

Proposed Course : Broaden applicability of direct combustion method to more 
tissue types. Modify electronic temperature programmer and use feedback con- 
trol to regulate rate of temperature increase. Determine detailed time 
course of drug concentration in blood and urine samples after single doses 
and correlate with pharmacokinetic models for better understanding of drug 
behavior. Pursue Ca and Mg tissue analysis in more detail; e.g., in cardiac 
mitochondria to better define site of drug-metal interaction. 

Honors and Awards : None . 

Publication : 

LeRoy, A.F. and Morris, J.C.: The kinetics of hydrolysis of rutheniumnitro- 
syltrichloride . J. Inorg. Nucl. Chem. 33: 3437-34-$ 3, 1971. 



I 



i 



30 



Serial No. DRS-BEIB-3 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Chemical Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973, through June 30, 1974 

Project Title: The Role of Fluid Qynamics and Mass Transfer in Development 
of Atherosclerosis 

Previous Serial Number: Same. 

Principal Investigators: Robert J. Lutz, Joseph N. Cannon 

Other Investigators: Donald L, Fry, Robert L. Dedrick, Kenneth B. Bischoff, 
Robert K. Stiles 

Cooperating Units: OD-IR-NHLI, Howard University 

Man Years: 



Total: 


1.0 


Professional: 


1.0 


Other: 


.0 



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. 

Methods Employed : An electrochemical technique is used, based on an 
oxidation-reduction reaction at electrodes implanted at a fluid-solid inter- 
face, which determines mass transfer rates of redox ions. Velocity gradients 
at the wall ( shear rate ) are calculated from mass transfer rates with suit- 
able boundary layer equations. 

Major Findings : Shear stress experiments in rigid casts of the canine 
arterial tree indicate peaks in shear stress near bifurcation points and 
branches, which are also regions of high plaque involvement in experimental 
animals. Pulsatile flow generated disturbances between branches and produced 
mean shear stresses higher than steady shear stresses at the same average 
flow rate. A pseudo-steady state approximation to the mass transfer boundary 
layer equations is adequate for calculating time varying shear stresses 
during low frequency sinusoidal flow. 

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. 



2 



31 



Proposed Course : Extend experimental studies to steady and pulsatile flow in 
distensible arterial models. Investigate the role of other (salient) trans- 
port properties of the arterial wall in models of arteries; e.g., ultra- 
filtration of large molecular weight lipoproteins, and diffusion through 
medial sections of arterial wall. 

Honors and Awards : None . 

Publications: None. 






32 



Serial No. DRS-BEIB-^ 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Chemical Engineering Section 

3. Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1973, through June 30, 1974 

Project Title: Implant Device Development 

Previous Serial Numher: None. 

Principal Investigator: John W. Boretos 

Other Investigators: John W. Brown, William S. Piej-ce, Robert E. Baier, 

Robert D. Stiehler, Andre F. LeRoy, Robert L. Dedrick 

Cooperating Units: SB-NHLI, National Bureau of Standards, 

Pennsylvania State University, Calspan Corporation 



Years: 




Total: 


1.5 


Professional: 


1.2 


Other: 


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. 

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 adsorption spectroscopy. 

Major Findings ; Ten heart assist devices with segmented polyurethane blood 
contact surfaces were implanted in calves for up to 35 weeks. No lipid 
absorption was observed; physical strength remained stable; surfaces 
developed a biocompatible protein layer. 

A series of ventricular-aortic bypass devices functioned satisfactorily for 
periods up to 17 weeks in dogs with minimal blood damage. This procedure may 
be s\iltable for future clinical use. 

Cure schedules for silicone rubber appear to affect failure of heart valve 
poppets . 

33 



IMHt 

1 



Significance : Phyaiologically compatible polymers with enduring strength 
are needed for such applications as heart valves, heart assist devices and 
vascular implants. Characterization of blood-material interaction is 
essential to successful performance and must be established before clinical 
use can be justfied. 

Proposed Course : 

(1) Extend experimental studies to further characterize the sijrfaces and 
bulk properties of segmented polyurethane to determine more specific informa- 
tion on its blood interaction, 

(2) Study the cure systems of silicone rubber to reduce inherent stresses 
and inadequately combined chemical portions. 

Honors and Awards : None . 

Publications: None. 



i 



34 



Serial No. DRS-BEIB-5 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Chemical Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973, through June 30, 1974 

Project Title: Multicomponent Plastics in Biomedical Use 

Previous Serial Number: Same. 

Principal Investigator: Henry L. Gabelnick 

Other Investigator: Margaret L. Wehling 

Cooperating Units: None. 

Man Years: 

Total: 0.6 
Professional: 0.4- 
Other: 0.2 

Project Description: 

Objectives : Extend definition of the interaction of plastic systems with the 
biological environment, emphasizing the kinetics of additive elution from 
polymers and absorption of body constituents. 

Methods Employed : Determination of concentration vs. time profiles of 
migrating species via quantitative analytical techniques. Parameters under 
investigation include fliiid composition and flow conditions. 

Major Findings : Refined analytical techniques enable evaluation of the 
di-2-ethylhexylphthalate-polyvinyl chloride system exposed to a soybean 
emiilsion "pseudo-serum." Preliminary runs on a simulated artificial kidney 
show promise. 

Significance : Physiologically compatible, stable materials with desirable 
physical properties are needed for many biomedical applications. Characteri- 
zation of desorption rates for additives from polymer system? and absorption 
of bodily constituents are important in determining the utility of implant 
materials . 



35 



Proposed Course : 

(1) Refinement of analytical techniques. 

(2) Kinetic studies in flow systems to define the rate-limiting steps, 

(3) Absorption studies including effects on physical properties. 
Honors and Awards : None . 

Publications: 



Boretos, J.W. and Gabelaick, H.L.: Letters to the Editor. Characterization 
of biomedical polymers. J. Biomed. Mater. Res . 7: 267, 1973. 

Gabelnick, H.L.: Biorheology. In Lapedes, D.N. (Ed. in Chief): McGraw Hill 
Yearbook of Science and Technology . New York, McGraw Hill, 1973, pp . 66-74- . 

and Litt, M. (Eds.): Rheology of Biological Systems . Springfield, 

111., Charles C Thomas, 1973, 319 pp. ~ 



36 



Serial No. DRS-BEIB-6 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Electrical and Electronic 
Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973, through June 30, 1974 

Project Title: Nuclear Magnetic Resonance Techniques for Biochemical 
Analysis 

Previous Serial Nximber: Same. 

Principal Investigators: Thomas R. Clem, Walter S.Fria\if, Edwin D. Becker 

Other Investigator: James A, Ferretti 

Cooperating Units: LCP-NIittlDD, PSL-DCRT 

Man Years: 



Total: 


4.0 


Professional: 


3.0 


Other: 


1.0 



Project Depcription: ' 

Objectives : Innovate and implement improved methods for structural j 

elucidation of organic molecules by means of nuclear magnetic resonance j 

with emphasis on 13c. m4v 

Methods Employed : Develop and evaluate techniques for improving sensitivity "^ 

and versatility, including use of a superconducting magnet, pulse train jjj 
excitation 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. ,„| 

Major Findings : NMR technique can be successfully extended to the , j 

characterization of nuclei other than-'-^Q, including ^\a a^d Br. : 

Significance : The system now approaching the status of a routine laboratory 

instrifflient, offers unprecedented capability for elucidation of organic 

molecule structure and, in particular, the location of -'-^c ®"^ al., atoms. '< 

The high field strength of the superconducting magnet enables finer 

resolution than is obtainable with most other 13q nMR apparatus. 



37 



Proposed Course : Modifications with a second superconducting magnet 

to enable experiments with full-time application to ^^q and related atoms j 

to extend capability to other nuclei, such as ^V^, 14fj, 15j^^ and 55|^_. 



Honors and Awards : None . 



Publications : None . 



i 



38 



Serial No. DRS-BEIB-7 

1. Biomedical Engineering and 
Instriimentation Branch 

2. Electrical and Electronic 
Engineering Section 

3. Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1973, through June 30, 1974 

Project Title: Television Image Processing Techniques for Biomedical Research 

Previous Serial Number: Same. 

Principal Investigator: William H. Schuette 

Other Investigators: James A. Dvorak, Leonard E. Grauer, Darrell V. Lewis, 

David R. Redwood, John M. Van Buren, Richard L. Webber, 
Willard C. Whitehouse 

Cooperating Units: LPD-NIAID, CB-IR-NHLI, EEG-NINDS, SN-NINDS, OMS-NIDR, 
ATM-CC 

Man Years: 

Total: 3.0 
Professional: 2.0 
Other: 1.0 

Project Description: 

Objectives : Develop and apply new and improved techniques for analyzing tele- 
vision signals in the context of medical research. Enhance effectiveness of 
television based systems for the collection and processing of biomedical data. 

Methods Employed : 

(1) A semiautomatic method calculates left ventricular volumes directly from 
televised fluoroscopy; ventricular silhouette tracings are electronically 
analyzed and volumes determined utilizing realistic geometrical assumptions. 

(2) A logarithmic television densitometer obtains the left ventricular net 
forward ejection fraction; the exponential decay rate of the washout curve 
following an LV X-ray dye injection is utilized to calculate the ejection 
fraction. 

(3) Television based apparatus analyzes changes in fluorescence occurring in 
exposed cortex during neurosurgery; fluorescence changes, related to metabolism 
over large areas and the activity from several regions are compared 
simultaneously . 



39 



(4) A quantum limited dental X-ray prototype has been successfully tested. 

( 5 ) A video system measures and digitally displays cell areas and volumes 
from image traces. 

(6) A technique for inserting analog data into the television format 
correlates auxiliary information with video signals. 

Major Findings : Image amplifiers enable low light level applications previ- 
ously reserved for photomultiplier tubes. The methods of (l) and (2) above, 
now in routine use in the catheterization laboratory, show excellent correla- 
tions, r = 0.98, in patients with normal ventricles. Analysis of televised 
fluorescence in conjunction with extracellular potassiujn ion concentrations 
reveals novel relationships between the kinetics of ion transport and metabo- 
lism. Video signals obtained for other purposes often produce valuable new 
quantitative data. Semiautomatic processing with analog circuitry and human 
involvement, at the proper level, can be more cost .effective than fully 
automated computer processing. 

Significance : These developments extend noninvasive testing and provide 
increased quantitative data for research and make treatment feasible which 
would otherwise be impractical. The televised fluorometer has launched new 
investigations on the metabolism of exposed human cortex. 

Proposed Course : Continue to work in established directions to improve 
available systems. 

Honors and Awards : None . 

Publications : 

Dvorak, J. A., Schuette, W.H., and Whitehouse, W.C.: A simple video method for 
the quantifying of geometric parameters of microscopic objects. J. Microsc . 
(in press) 

Levitsky, S., Schuette, W.H., Kempner, K.M., Sloane, R., Souther, S.G. , 
Mullin, E.M. , and Morrow, A.G.: Experimental and early clinical evaluation 
of heart tracking ( Radarkympgraphy ) as a noninvasive method for measuring 
myocardial contractility. Am. J. Cardiol . 32: 156-161, 1973. 

Lewis, D.C., O'Connor, M.L., and Schuette, W.H.: Oxidative metabolism during 
recurrent seizures in the penicillin treated hippocampus. Electroencephalogr . 
and Clin. Neurophysiol . ( In press ) 

Marcus, M.L., Schuette, W.H., Whitehouse, W.C., Bailey, J.J., Douglas, M.A., 
and Glancy, D.L.: Use of a video system in the study of ventricular fimction 
in man. Am. J. Cardiol . 32: 175-179, 1973. 

, , ) , and Glancy, D.L.: An automated method for the 



measurement of ventricular volume. Circulation, XLV: 65-76, 1972. 



40 



Schuette, W.H.: Video-log: A technique for recording analog signals in the 
television video format. Proceedings of the Eleventh Annual Rocky Mountain 
Bioengineering Symposium and Eleventh International ISA Biomedical Sciences 
Instrumentation Symposium, USAFA . ( In press ) 

Thompson, E.J., Wilson, S.H., Schuette, W.H., Whitehouse, W.C., and 
Nirenberg, M.W. : Measurement of the rate and velocity of movement by single 
heart cells in culture. Am. J. Cardiol. 32: 162-166, 1973. 



41 



Serial No. DRS-BEIB-8 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Electrical and Electronic 
Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973, through June 30, 197-4 

Project Title: Diagnostic Ultrasound 

Previous Serial Number: Same. 

Principal Investigator: James M. Griffith 

Other Investigators: Walter L. Henry, William R. Brody, P. David ]\^erowitz, 
Barry J. Maron, Stephen E. Epstein, Robert E. Goldstein 

Cooperating Units: CB-IR-NHLI, SU-IR-NHLI 

Man Years : 

Total: 3.0 
Professional: 1.5 
Other: 1.5 

Project Description: 

Objectives : Noninvasively obtain dynamic measurements of cardiac geometry 
and fiinction to quantitate wall thickness, transverse ventriciilar dimensions, 
and valve motions; to directly measure blood flow. 

Methods Employed : A gain switching technique was developed to increase the 
dynamic range of recorded information in one- and two-dimensional scans. 

Two probes were developed for use in dogs: (l) a pulse-echo probe, sutured 
directly to the heart wall, measures wall thickness and chamber size for 
clinical studies; (2) a cw doppler probe measures aortic flow. 

A real time two-dimensional sector scanner, previously reported, was improved 
to provide faster scan rates and wider view angles. 

Major Findings : Work completed during the past year has f\irther enlarged the 
amount of quantitative data obtainable from routine ultrasound studies. For 
example, the diagnosis of congenital heart malformations is very encouraging. 

Significance : Safe noninvasive methods for making quantitative measurements 
of cardiac dynamics is of substantial value for diagnostic and research 
purposes. 



A2 



Proposed Course : Refine and further develop present systems. It is believed 
that a number of significant techniques will yet develop; for instance, a 
range-gated doppler flowmeter optimized for cardiac geometry. 

Honors and Awards : None . 

Publications : 

Griffith, J.M. and Henry, W.L.: A real time system for two-dimensional echo- 
cardiography. In Proceedings of the 26th Annual Conference on Engineering in 
Medicine and Biology, 1973, Minneapolis, Minnesota . Arlington, Va., The 
Alliance for Engineering in Medicine and Biology, 1973, Vol. 15, p. 422. 

and : Video scanner-analog computer system for semiautomatic 



analysis of routine echocardiograms. Am. J. Cardiol. 32: 961-964-, 1973. 



43 



Serial No. DRS-BEIB-9 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Electrical and Electronic 
Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973, through June 30, 197^ 

Project Title: Measurement of Low Level, Rapid Chemical Reaction Rates by 
Laser Jump, Temperature Jump and Stopped Flow Techniques 

Previous Serial Number: Same. 

Principal Investigators: Michael Greifner, P. Boon Chock 

Other Investigators: None. 

Cooperating Unit: LB-IR-NHLI 

Man Years: 

Total: 1.0 
Professional: 0.75 
Other: 0.25 

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 photo- 
multipliers. ^node switching provides wide dynamic range without impairment 
of frequency response, linearity or accuracy. High intensity pulsed light 
sources improve the signal to noise ratio of nanosecond absorption measiire- 
ments. Signal averaging techniques recover low level signals otherwise 
obliterated by noise. 

Major Findings : Stopped flowmeters with increased sensitivity provide an 
order of magnitude improvement in absorption level detections over commer- 
cially available instruments. Higher 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 jimp apparatus 
and stopped flowmeters can provide information on the incremental, fast 
interactions between antibiotics with enzymes or proteins. 



44 



Proposed Course : Complete evaluation of stopped flowmeter reaction times. 
Test and evaluate temperature jump apparatus. Initiate investigation into 
laser jump technique feasibility. 

Honors and Awards : None . 

Publications: None. 



45 



Serial No. DRS-BEIB-10 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Electrical and Electronic 
Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973, through June 30, 197.; 

Project Title: Automatic Test Set for Evaluating Electrical Safety of 
Clinical Equipment 

Previous Serial Number: Same. 

Principal Investigators: Walter S. Friauf, Horace E. Cascio 

Other Investigators: Roland Corsey, Anthony J. Vita 

Cooperating Unit: ADM-CC 

Man Years: 

Total: 1.5 
Professional: 0.5 
Other: 1.0 

Project Description: 

Objectives : Improve performance and economy of routine electrical safety 
testing programs for hospital equipment and enhance the accuracy, reliability 
and safety of medical apparatus. 

Methods Employed : Design, construction, testing, and evaluation of an auto- 
mated test system that satisfies published criteria on electrical safety 
standards . 

Major Findings : Performance of the prototype test set has proven satisfactory, 
and formalized scheduled inspection routines have been inaugurated. A second 
generation unit featuring several refinements has been designed and built. 

Significance : Hospital electrical safety requires a great m^any routine tests 
at relatively short intervals which can be performed only with the aid of 
automatic test equipment. This is particularly true in a clinical research 
environment where a great variety of equipment is encountered and inconvenience 
to patients and medical staff must be minimized. 



46 



Proposed Co\irse : 

(1) Evaluate second generation unit. 

(2) Perform trend analysis on test data. 

(3) Disseminate information on the unit to other facilities and to potential 
manufacturers . 

Honors and Awards : None . 

Publication : 

Friauf, W.S., Cascio, H.E., and Jones, A.R.: Automated test set for checking 
biomedical equipment. Med. Electron. Data 4-: 5'4-60, 1973. 



47 



_ 



Serial No. DRS-BEIB-11 

1. Biomedical Engineering and ^ 
Instrumentation Branch ^ 

2. Mechanical Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973, through June 30, 197^ 

Project Title: Bioraechanical Concomitants of Head Injury /Head Injury Model 
Prograjn 

Previous Serial Number: Same. 

Principal Investigators: Ayub K. Ommaya, Lawrence E. Thibault 

Other Investigators: None. 

Cooperating Units: SNB-NINDS, BEIB-DRS, Department of Transportation, 
Armed Forces Radiobiology Research Institute 

Man Years: 

Total: 2.5 
Professional: 2.0 
Other: 0.5 

Project Description: 

Objectives : With animal and physical models attempt to validate finite 
element analytical efforts. Extend the physiological studies previously 
reported to larger primates with specific reference to the somato-sensory 
evoked response. 

Methods Employed : Experimental and analytic techniques guided by the state 
of the art in biomechanics. Computer analysis of electrophysiology changes 
related to mechanical trauma. Mechanical load measurement using implantable 
neutral density (with respect to brain tissue) transducers. 

Major Findings : The somato-sensory evoked response can be modulated by con- 
trolled inertial loading of the head. When rotational components of angular 
acceleration are minimized, analytical models predict reduced shearing 
strains and evoked responses show minimum changes. 

Significance : The evoked response technique should prove to be a significant 
clinical tool for diagnosis and management of head injuries. Correlations 
between changes in electrophysiologic parameters and mechanical loads should 
help establish national criteria for determining injury thresholds. 



48 



Proposed Course : Extend the physiological studies in order to gain insight 
into the sequellae of controlled forms of injury. Continue the analytical 
model validation effort. 

Honors and Awards : None . 

Publications : 

Gennarelli, T.A., Ommaya, A.K., and Thibault, L.E.: Comparison of transla- 
tional and rotational head motions in experimental cerebral concussion. In 
Proceedings of Fifteenth Stapp Car Crash Conference , November 17-19, 1971. 
Coronado, California. New York, Society of Automotive Engineers, Inc., 1972, 
pp. 797-803. 

, Thibault, L.E., and Ommaya, A.K.: Pathophysiologic responses to rota- 
tional and translational accelerations of the head. In Proceedings of 
Sixteenth Stapp Car Crash Conference, November 8-10, 1972, Detroit, Michigan. 
New York, Society of Automotive Engineers, Inc., Lawrence M. Patrick, 
Chairman, pp. 296-308. 

Ommaya, A.K., Gennarelli, T.A. , and Thibault, L.E.: Traumatic unconsciousness: 
Mechanics of injury to the brain in violent shaking of the head. In 
Proceedings of the American Association of Neurological Surgeons , 1973 . 
( In press ) 



^9 



Serial No. DRS-BEIB-12 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Mechanical Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973, through June 30, 1974 

Project Title: Atraumatic Electrical Sensing in Hmnan Brain Cortex 

Previous Serial Number: Same. 

Principal Investigator: Seth R. Goldstein 

Other Investigator: Edward M. Schmidt 

Cooperating Unit: LNLC-NINDS 

Man Years : 

Total: 1.6 
Professional: 1.0 
Other : 0.6 

Project Description: 

Objectives : Achieve stable electrode location with respect to an active 
neuron for reliable acute recording of brain cell activity within the piilsat- 
ing cortex at prescribed depths up to 0.5 cm with minimum tissue damage. 

Methods Employed : A conducting wire electrode is held within a gas bearing 
in the pulsating cortex at the desired insertion angle. A fine lead screw is 
actuated by gas thrust bearings to retain the "floating" action during elec- 
trode depth adjustment. 

Major Findings : The device has been successfully tested on a monkey; high 
quality recordings of neuroelectric potentials for prolonged durations have 
been produced. 

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 understand- 
ing of brain function. 

Proposed Course : Testing and evaluation with animals and humans, refinement 
of techniques and apparatus, if necessary; clinical applications; enlargement 
of device family for related types of measurement requirements. 

Honors and Awards : None . 



50 



I 



Publications : 

Goldstein, S.R. : Atraumatic recording from exposed pulsating human cortex — a 
new mechanism. In Proceedings of the 2$th Annual Conference on Engineering 
in Medicine and Biology 1972 , Bal Harbour, Florida, vol. lA- Arlington, Va. , 
The Alliance for Engineering in Medicine and Biology, Samuel P. Asper, M.D., 
Chairman, p. 190. 

and Salcman, M. : Mechanical factors in the design of chronic recording 



intracortical microelectrodes. IEEE Trans. BME. BME-20, 260-269, 1973. 



51 



Serial No. DRS-BEIB-13 

1. Biomedical Engineering and 
Instrumentation Branch 

2. Mechanical Engineering Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973, through June 30, 1974 

Project Title: Pregnant Sheep Hyperthermia: Effect of Elevated 
Body Temperature on Fetal Vitality 

Previous Serial Number: None. 

Principal Investigators: Gary K. Oaks, Howard D. Metz 

Other Investigators: Ronald A. Chez, Michael Epstein, Alan R. Fleischman, 
Robert Sefalo 

Cooperating Units: PRB-NICHHD, National Naval Medical Center 
Man Years : 



Total: 


1.5 


Professional: 


1.0 


Other: 


0.5 



Project Description: 

Objectives : Determine the effects of hyperthermia on the fetus by examining 
changes in umbilical blood flow, blood gas concentrations, and other vital 
processes . 

Methods Employed: Induce hyperthermia in pregnant sheep and measured blood 
gases, umbilical and uterine blood flow. The animal's body temperature is 
raised by modifying its environment to curtail transfer of endogeneous heat. 

Major Findings: Reproducible hyperthermia levels can be consistently produced 
by constraining the ability of the animal to control the elimination of meta- 
bolically generated heat. The environmental chamber designed for these studies 
has been tested and will be put into routine use. 

Significance : Elucidation of fetal disorders due to excessive mother body 
temperature in animals, upon extension to humans, can lead to improved prenatal 
and perinatal diagnoses and treatment. 

Proposed Course : Complete experimental protocols with sheep and extend to 
human cases. 

Honors and Awards : None . 

Publications : None . 

52 



DIVISION OF RESEARCH SERVICES 
Summary of Branch Activities July 1, 1973 through June 30, 197<4 

EMVIRO^MENTAL SERVICES BRANCH Vinson R. Oviatt, Chief 

I. SUMMARY 

The Environmental Services Branch devoted major program effort to assessment 
of chemical carcinogen hazards; procurement of laminar flow biological safety 
cabinets; and review of laboratory facilities working with potentially hazard- 
ous Class III, IV and "non-natural" organisms. All of these were in direct 
assistance to the intramural research programs and carried out in cooperation 
with other NIH program elements. Most notable review of laboratory facilities 
was in association with the NIAID for compliance with the "Memorandum of 
Understanding and Agreement" for the safe handling of Adenovirus Type 2 - SV-40 
Hybrids. 

A survey of chemical carcinogen usage was initiated in response to tentative 
standards under the Occupational Safety and Health Act. Preliminary data 
provided basic information on chemical carcinogen use in research environments 
to the DHEW panel of experts formulated to develop standards. The NIH response 
was the most comprehensive of any developed within DHEW. At NIH there are 
approximately 150 users of chemical carcinogens, 63 whom reported using one or 
more of the 14- designated chemical carcinogens of interest to the Department 
of Labor. An NIH program is now being formulated to deal with proper carcino- 
genic chemical identification, risk assessment, and control measures to be 
employed. Employee education will be included as a control measure. 

Procurement of laminar flow biological safety cabinets at NIH reached a crisis 
point d\iring the year because of unexpected demand for this safety device — 
not only at NIH where it was developed, but in outside laboratories. Seventy- 
five new LFBSC's were put in use with approximately 100 more on order at the 
end of the fiscal year. The NIH specification for the cabinets was modified 
three times during the year. These covered dimensional tolerances, human 
engineering factors, velocity standards, and test procedures. The office of 
Materiel Management was informed by GSA late in the year that NIH could proceed 
with the development of a Qualified Products List for this equipment. The 
first LFBSC's constructed to NIH specifications were purchased during the year. 

Major decontamination projects were those of the facilities at the Patuxent 
research facility vacated by NINDS and animal rooms in Building Jl for NCI 
which were associated with an Ectromelia outbreak. Safety cabinets and related 
equipment were tested both at the Middle America Research Unit in Panama, and 
the Rocky Mountain Laboratories in Hamilton, Montana. 

There was a marked increase in requests to ESB to share its expertise to the 
outside community. Professional and technical advice was provided to other 
governmental organizations of both this and foreign countries, the university 
research community and private institutions. Staff lectured at several univer- 
sities and one international techuical symposiimi on the many aspects of the 



53 



ESB program. The NIH Biohazard Safety Guide and the Laser Safety Manuals were 
developed during the year. The Branch provided technical assistance to the 
Assistant Secretary of Health, DHEW, by reviewing and assessing the health 
aspects of many guidelines proposed by the Environmental Protection Agency. 

Pollution control activities continued as a major Branch program. Pollution 
of the NIH stream on the Bethesda campus has apparently been brought under 
control, as major contaminating sources have been eliminated. Water pollution 
control activities at the NIH Animal Center continued. The Sewage Treatment 
Plant experienced operational difficulties during the year, as did the auto- 
matic water quality monitors. Noise control developed into a time-consuming 
program because of new federal regulations. The chemical waste disposal pro- 
gram was developed to the point that the NIH treatment facility is under 
contract for renovation. A contract was initiated for disposal of chemicals 
which cannot be handled on NIH premises. The 870 chemical fume hoods were 
surveyed under contract to the DOW Chemical Company. 

General environmental health projects continued with an emphasis on animal 
room facilities, food surveillance, and solid waste control. 

The contract to construct the Tri-Services Incinerator was cancelled and nego- 
tiations were begun with Montgomery County, Maryland, for the development of 
a Medical-Pathological Incinerator by the County to serve NIH and other medical 
research facilities within the County. Branch staff expended considerable 
time working with Montgomery County officials and the staff of their engineer- 
ing consultant firm. 

A variety of environmental studies was undertaken. The research contract with 
the University of Minnesota to study research water quality requirements was 
completed in June. Other projects included an assay of biological contamina- 
tion caused by small room humidifiers, analytical procedures for trace 
quantities of Freon 113 in biological materials, disinfection methods, and 
the handling and reprocessing of laboratory glassware. 

The training effort of the Branch was increased in several areas . A literature 
review entitled "Biological Laboratory Hazards" was developed and distributed 
quarterly to Laboratory and Department Chiefs at NIH. Approximately 150 
research and technical staff of various institutes attended seminars on The 
Theory, Operation and Use of the Laminar Flow Biological Safety Cabinet. Of 
particular note was a cooperative effort with other NIH safety groups in the 
development of a series of safety posters and accompanying information in the 
NIH RECORD. An NIH sponsored short course on Introduction to Biological Lab- 
oratory Techniques was offered to summer employees. ESB personnel received 
1,007 hours of training at designated short courses or classroom experience 
at local community colleges and universities. Three COSTEP trainees worked 
in the Branch. 

Improvement of human relations continued to receive Branch attention. The 
Branch Human Relations Committee was effective in restructuring both the 
employee appraisal of supervisors, and the mid-year employee appraisal tech- 
niques. The Committee was of valuable assistance in educational programs 
prior to the annual employee appraisal. ESB was fortunate in having a staff 
member selected as Chairman of the Division Human Relations Committee. 

54 



II. BRANCH PROGRAMS 



A. Objective 



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 coordinated 
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 equipment, and facilities. 
Consiiltation 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 (including air pollution) potentially or actually generated at 
NIH 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. 

4. General Sanitation and Sanitary Engineering 

The general sanitation and sanitary engineering program is concerned with 
basic environmental factors affecting the health of NIH employees, visitors 
and the quality of the research environment. These factors include food 
sanitation, water supply, solid and liquid waste disposal, housekeeping 
practices, pesticides, and water pollution control. 



55 



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 environ- 
mental 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 contam- 
inants . 

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 

Major program emphasis continued in the area of consultation with NIH research 
personnel in assessing potential biological hazard problems, equipment use 
and procurement. Laboratories working with potentially hazardous Class III 
and IV agents were surveyed. Most notable was the review of laboratory facil- 
ities for compliance with the NIAID "Memorandum of Understanding and Agreement" 
for the safe handling of Adenovirus Type 2 - SV40 Hybrids . 

The NIH Specification for Laminar Flow Biological Safety Cabinets was modified 
three times. These modifications covered the areas of dimensional tolerances, 
human engineering factors, velocity standards and test procedures. Materiel 
Management was informed by the General Services Administration that NIH could 
proceed with the development of a Qualified Products List for this equipment. 
When the QPL for the laminar flow biological safety cabinet is operational, 
procurement time for cabinets will be shortened by eighty to ninety days. 
ESB served as technical advisors to Materiel Management for the laminar flow 
biological safety cabinet testing and evaluation and in the review of procure- 
ment documents with respect to biological safety. The number of laminar flow 
biological safety cabinets in use at NIH increased from two hundred forty <bo 
three hundred fifteen. 

Major decontamination projects included nine laboratory rooms; a primate house 
and barn at the Patuxent research facility, which had been vacated by the 
NINDS research program; eighteen rooms in Building 14C, which were converted 
from conventional mouse colonies to barrier derived mouse production; and an 
animal room in Building 37, which was associated with an Ectromelia outbreak. 

The biowaste treatment system for the 5C corridor laboratory "isolation suite" 
in Building 36 was challenged with bacterial spores to determine the effective- 
ness of the treatment. This testing was perfonned after several modifications 
had been made to improve the overall operation of the system. 



56 



The Building 41 exhaust plenums were decontaminated for the Plant Engineering 
Branch to modify the filter banks and replace HEPA filters. Existing HEPA 
filters had been in use for approximately four years. Following the work, 
the installation was leak tested and certified. Filter frame holders in the 
exhaust plenum at MARU, Panama, were also modified and new filters installed. 
Testing of safety cabinets was performed at MAHU and at Rocky Mountain Lab- 
oratories, Hamilton, Montana, 

Requests for professional and technical advice from other governmental organi- 
zations and private institutions has shown a marked increase. Staff members 
are involved with committee work for such associations as the National Environ- 
mental Health Association and the Health and Safety Committee of the American 
College Health Association. 

A contract has been awarded for the construction of a decontamination chamber 
to be located on the third floor of Building 13- The facility will be used 
to decontaminate equipment to be repaired or surplused. 

The contract for testing and maintenance of the biological safety cabinets and 
other bio-control systems was continued. A contract was also negotiated for 
the development of the NIH Biohazard Safety Guide. 

2. Industrial Hygiene 

The Industrial Hygiene Program was responsible for initiating and collating 
the NIH response to the carcinogen control regulations as published in the 
Federal Register in January 1974- and in response to departmental directives. 
A questionnaire was devised and distributed to investigators by institute 
Scientific Directors. Reporting was greatly facilitated' by use of a Wylbur 
terminal. To achieve complete compliance next year with some of the regula- 
tions, it will be necessary to contract for laboratory surveys to provide ESB 
with discrete data. 

A major accomplishment was the completion of the chemical fume hood survey. 
Eight hundred and seventy hoods were surveyed under contract with the DOW 
Chemical Company. Their report was evaluated and work requests are in process 
to correct observed deficiencies. This survey will be performed annually in 
the future. 

The Laser Safety Manual will be completed. 

An increased number of noise evaluations were performed at the request of 
various institutes and divisions for the purpose of controlling occupational 
hazards and for assessing problems of interference with efficiency and perform- 
ance (a number of NIH employees have filed claims for hearing losses as a 
result of noise exposure). The energy situation has resulted in more tempera- 
ture, humidity and lighting problems being brought to ESB's attention both by 
the individuals concerned and the Employee Health Service. 

The problem of filtration of exhaust air to remove small quantities of iodine- 
131 from the air before its discharge to the outside received full attention 
this year. Design of one special installation in Building 7 for Dr. Robert 



57 



Purcell, NIAID, was completed. Work continues on finding a more general solu- 
tion for the many other investigators at NIH who function in limited space 
and with limited capacity exhaust systems. 

3. Hospital Environmental Control 

This program did not function as a planned operating effort for the first time 
in several years due to the resignation and subsequent abolishment of the 
hospital sanitarian position. Services to the Clinical Center continued on a 
request basis with most activities involving routine check of various steriliz- 
ing systems and request assistance to general problems relating to surveillance 
of humidifying and anesthesiology equipment, and surveillance of housekeeping 
procedures and sanitation problems in critical areas such as the operating 
rooms and intensive care units. 

4. General Sanitation and Sanitary Engineering 

A detailed sanitation survey was conducted for the Division of Pathology, 
Bureau of Biologies, to evaluate the animal room facilities for conformance 
to existing standards and the ability to meet program needs. Several less 
detailed surveys were conducted for other institutes to determine the degree 
of compliance with the existing NIH animal room standards. A study was con- 
ducted for the Veterinary Resources Branch, DRS, concerning cleaners and 
disinfectants for animal rooms. The information will be incorporated into a 
standard operating procedure for the Building 14 animal rooms. 

Food surveillance efforts continued on a routine basis. Surveys reflected a 
general upgrading of the GSI cafeterias with the installation of new equipment 
such as self-service beverage dispensers, refrigerated sandwich display boxes, 
and single service cup dispensers. 

Solid waste control remained a time-consuming effort. Although the Tri-Services 
Incinerator has been cancelled, ESB did provide input into the final phase of 
the impact statement via a study on noise from trucks and other sources with 
the cooperation of the Army Environmental Hygiene Agency. Although not useful 
for its intended purpose, the report will help in assessing the environmental 
impact of transportation noise related to the new County operated incinerator, 
the proposed alternate to Tri-Services. ESB has consulted on this alternative 
including reappraisal of the waste container to be used with the County's 
medical-pathological incinerator operation. As a result a one-way, plastic 
lined box was selected. The paper bag project, initiated several years ago, 
continued to make progress; there are now 125 bag holders in use outside of 
the Clinical Center. 

ESB continued to monitor and provide technical assistance to t?ie NIH Animal 
Center sewage treatment facilities. The sewage treatment plant has experienced 
several difficulties, the two most prominent being solids bulking and excessive 
sludge buildup. The Office of Engineering Services will contract with an 
engineering firm to propose solutions to these problems. The automatic water 
quality monitors experienced a number of breakdowns during the year, resulting 
in lost or unusable data, plus lost staff time in troubleshooting. 



58 



The greatly reduced number of complaints and ESB observations indicate that 
most of the water pollution sources have been brought under control with 
respect to the NTH stream on the Bethesda campus. Continued surveillance of 
mercury waste from NIH was conducted. 

An environmental analysis was made of a VEB proposed outdoor primate breeding 
facility at the site of the NCI Viral Oncology Unit, NIHAC. ESB has been very 
active in providing reviews of Environmental Protection Agency draft documents 
related to the environment for the Office of the Assistant Secretary for 
Health, DHEW. 

The ESB chemistry laboratory continues its work in the area of high purity 
water surveillance, special investigations and services. Work was completed 
on several projects. 

5. Environmental Studies 

The research contract with the University of Minnesota to study research water 
quality requirements is continuing satisfactorily and will be completed in 
June 1974- . The contract has resulted in new methodology in determining total 
solids, in high purity water, plus considerable data which will allow the 
Branch to reorient its program for the surveillance of high purity water systems. 
The recommendations in the final report will be integrated into program plans . 

Two short studies of biological contamination caused by small room humidifiers 
were completed. Results indicated that unless a very strict regimen is 
followed, these units can become an additional source of air contamination. 

A study of particular interest was development of an analytical procedure for 
trace quantities of Freon 113 in biological materials. This technique was 
applied in assisting Dr. Albert Z. Kapikian, NIAID, to identify Freon 113 
contamination of a viral antigen material to be given orally to a volunteer 
group . 

The Branch studies on Pseudomonas have resulted in over 100 requests for re- 
prints. Six requests for the 51 pyocin typing cultures were filled during 
the year. 

A series of studies are in progress on disinfection problems; the role of 
Pseudomonas, Serratia, Klebsiella and Herrellia in the hospital environment; 
the microbiology of parenteral infusions and sterilization .procedures for 
critical surgical equipment that are heat sensitive. 

The energy crisis of December 1973 provided an opportunity to study glassware 
handling on the reservation. The problem of sorting and separation has not 
yet been solved, nor has any effort been made to recycle non-contaminated 
glass. The study will continue on a more vigorous scale when the weather 
wamis up to permit proper sorting at the disposal site. 



59 



6, Training 

ESB is cooperating with other NIH safety groups, through the Biohazard Sub- 
committee on Information and Training, in developing a series of safety- 
posters and other information as am effort to raise the safety avrareness 
level of NIH employees. A literature review entitled "Biological Laboratory 
Hazards" is distributed quarterly in memorandum form to Laboratory and Depart- 
ment Chiefs at NIH and to other individuals interested in biohazard control 
at NIH and elsewhere. Seminars were presented during the year on The Theory, 
Operation And Use Of The Laminar Flow Biological Safety Cabinet , to approx- 
imately one hundred and fifty research and technical staff. 

The Branch offered a short course, sponsored by NIH, to introduce the summer 
employee to different biological techniques used in the laboratory. It was 
successfully completed by all twelve employees. 

Considerable amounts of time and effort are devoted to lectures and demonstra- 
tions for the nursing staff of the operating rooms. Clinical Center. Staff 
cooperated with the Veterinary Resources Branch, DRS, in one animal caretaker 
course presented to personnel from NIH, Walter Reed Medical Center, and Fort 
Detrick Cancer Unit. ESB is also cooperating with the Grounds Maintenance 
and Landscaping Section, FEB, OES, in providing a training course for the 
pest control employees and herbicide applicators. 

Lectures on various aspects of environmental health and sanitation were 
presented throughout the year including "Safety in the Laboratory", presented 
by the National Institute of Occupational Safety and Health. Other lectures 
were given at the University of Georgia, Indiana State University, The 
University of Michigan, and the University of Delaware. Assistance was given 
locally to the District of Columbia Department of Environmental Health and 
the Fairfax Hospital. The staff also participated in programs of several 
professional societies including the American Society of Microbiologists, 
American Hospital Association, American Public Health Association and the 
National Environmental Health Association. 

ESB personnel received 1,007 hours of training at designated short courses or 
in classroom experience at local community colleges and universities. ESB 
seminars were continued to provide "state-of-the-art" information to staff 
and other interested personnel. 

Three COSTEP trainees contributed to sanitation efforts at the NIH Animal Center, 
the solid wastes program on campus, and certain aspects of hospital sanitation. 

D. Problems 



The program for surveillance of the Clinical Center's environment and environ- 
mental control services to its staff was largely curtailed with the resignation 
of the Hospital Environmentalist and abolishment of the position to meet 
reduced position quotas. A realignment of the program to provide "emergency" 
type services was initiated within the Branch's staff capabilities. 



60 



Air handling systems, construction and architectural details of some of the 
older NIH laboratory buildings make them unsuitable for hazardous biological 
and chemical work from a safety viewpoint. In addition, the research is 
vulnerable to extraneous environmental contamination. This situation has 
become more critical due to space shortages. As a result, some laboratory 
work was relocated on a temporary basis to completely unsuitable space. An 
example of this is location of laboratories in the 13 North Patient Care Area. 
This space is in close proximity to patients and totally unacceptable with 
respect to the air handling and other laboratory requirements. 

Staff reports indicate an increasing degradation of environmental sanitation 
of the NIH buildings and grounds. Buildings in particular need of improved 
sanitation practices are 6, 10, and 13. Basic problems are associated with the 
lack of adequate numbers of staff for the central service organization; i.e., 
housekeeping, plant maintenance and buildings and grounds. 

E. Program Plans 

Increased contracting will be utilized to accomplish Branch objectives in 
FY 1975. In particular, a service contract will be executed to help assure 
compliance with the OSHA chemical carcinogen regulations and infection control 
guidelines. A similar service contract will be executed to provide assistance 
and surveillance of biological laboratories working with Class III agents. 
Two other service contracts will relate to stream pollution control programs 
on Broad Rim at NIHAC. One contract calls for the maintenance and service of 
the automated water pollution monitors, and the second will assess the sampling 
activities of ESB and provide a water quality index on which future pollution 
evaluations will be based. Contracts for monitoring chemical fume hoods and 
laminar flow biological safety cabinets are continued. ; 

ESB will initiate an Emergency Issuance Exchange Program for laminar flow 
biological safety cabinets about mid-fiscal year 1975 with an initial purchase 
of eight cabinets. Emergency need for these cabinets will be justified by the 
I/D Scientific Director to the Director, DRS, before a cabinet will be issued. 
This program should help eliminate the six-month waiting period before a 
cabinet is received, when the investigator may continue working in either 
marginal equipment or on the open bench. 

Posting laboratories with biohazard signs will be updated in the coming year. 

Three administrative actions are planned. They are: return to the management 
by objectives system at the staff, section and Branch level; revision of the 
Branch data reporting system; and establishment of Branch operation procedures 
relating to the day-to-day technical programs of ESB. 

F. Publications 



Oviatt, V.R. : Environmental Control. The Hospital Engineering Handbook , 
Chapter 7, Chicago, Illinois, pp. 101-116, March 1974. 



61 



Gates, A.S., Jr., Wil.kinson, T.K.: Disposal of Exhaust Air From Buildings. 
Proceedings of the 26th Annual Conference on Engineering in Medicine and 
Biology , Minneapolis, Minnesota. 15:220, 1973 • 

Karamian, N.A. : Improved Separatory Funnel. Analytical Chemistry . 
-45:2154-2155, 1973. 

Karamian, N.A. : Polytetrafluoroethylene Tubing. American Laboratory . 
5:11-U, 1973. 



62 



DIVISION OF RESEARCH SERVICES 
Sum m ary of Branch Activities July 1, 1973, through June 30, 1974 

LIBRARY BRANCH Ruth C. Smith, Chief 

I . SUMMARY 

The review of personnel and services in all areas of the Library, initiated 
in May when the Branch Chief entered on duty, was continued. A substantial 
acquaintance with the entire Library operation was achieved. Some Library 
activities were identified to be given priority for development, improvement 
or expansion for more effective Library support of the NIH research effort. 

The suit of Williams and Wilkins Company against the Government for alleged 
copyright infringement relating to the photocopy service of the NIH Library 
and NLM was decided by the Court of Claims in favor of the Government in a 
four to three decision. The publishing company is appealing the Court of 
Claims decision to the Supreme Court. 

The Library Advisory Committee met three times during the year. Under the 
Chairmanship of Dr. John S. Finlayson, BB, the membership remained the same, 
except that Dr. Stanley A. Robrish, NIDR, replaced Dr. Howell 0. Archard. 

The monthly listing of books, journals, and other literature added to the 
Library's collection is now issued as a memorandum from the Librarian. 
Translated articles are also listed. 

A Scope and Coverage Committee was appointed to draw up a plan of action to 
formulate a Library policy for scope and coverage of literature acquired for 
the Library collection. The first step, delineation of current B/I/D 
research and administrative needs through analysis of published programs, 
has been completed. 

Completion of a study on the comparable value of a card catalog vs. a book 
catalog for use in proximity to the book collection on the Lower Level was 
followed by an investigation of costs for duplicating cards in the Library's 
catalog. 

Job restructuring was initiated in the Library as an outgrowth of a recom- 
mendation by the NIH Job Restructuring Team. The objective is to establish 
a career ladder of bridge positions whereby a qualified nonprofessional 
Library Technician could progress in a planned program of on-the-job and 
academic training to a professional position of Technical Information 
Specialist. 

A new position was created to provide special attention to nonprint media 
resources. A nonprint collection will be organized, developed, and operated 
for NIH investigators. 



63 



Site surveys of automated circulation procedures in area libraries and litera- 
ture studies have been made by Library staff. A management study has been d 
proposed to determine the feasibility of implementing an automated system in 
the Library's Circulation Unit, 

The Library participated in the NIH celebrations of Black History and Native 
American Weeks. The Branch Chief, a member of the NIH Minority Cultural 
Program Committee, served as a session Mistress of Ceremonies during Black 
History Week. Exhibits prepared by Library staff for each program were 
displayed in the outside corridor. High school students participating in 
the programs were given tours of the Library. | 

An effective training program for professional and all other staff members 
contributed to higher quality service to the NIH investigators, to keeping 
abreast of new developments in Library science, to administration and human 
relations, and to maintaining employee interest in further training. 

A "brown bag" lunch discussion meeting was held by the Human Relations 
Committee. The Committee also launched a successful drive in the Library 
for food contributions for an employee on extended leave due to illness. 



64 



.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; provi- 
sion 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 Imowledgeable of current developments in manual and machine 
methods of comraunieation and information retrieval, and is alert to adjust- 
ment of procedures for improved Library services. 

B. Current Programs 

Technical Services 

The Acquisitions staff provides for the acquisition of books, journals, 
technical reports, and nonprint materials by purchase, gift, and exchange 
which have been selected as pertinent to the scope of the Library. The 
staff is responsible for the maintenance of accession records through input 
to automated systems used by the Library and for the preparation of completed 
journal volumes for commercial binding. Computer printout includes daily 
and monthly cumulated listings of current journals and their holdings and 
weekly listing of books on order or in preparation. 

The Cataloging staff organizes the acquired literature through classification, 
cataloging and subject heading, and processes it for inclusion in the collec- 
tion. The staff is responsible for the maintenance of the Library's catalog 
and the maintenance of catalog records for journals through input to the 
automated systems. 

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; issues Page- 
masters; and makes assignments to locked study carrels. 

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 it3 use. 



65 



The Stacks and Copy Service staff maintains the stacks, carrels, reference 
and Reading Room areas and reshelves 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. 

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, com- 
puterized information retrieval systems, and clearinghouses. The Reference 
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 litera- 
ture searches as requested. They serve as selectors for Library acquisitions 
by continually searching for literature pertinent to the scope of the Library. 
They also maintain the collection of basic Reference Books. The Section 
staff provides bibliographic assistance with experienced searchers to conduct 
requested medical, chemical and biological 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). 

Translating Service 

The Translation Unit provides oral, recorded, and written translations as 
requested. Oral translations are emphasized in-house, and a written trans- 
lation service is provided through contractual firnis, 

C. Program Progress and Accomplishments 

Technical Services 

Several steps were taken to provide more effective assistance to the Library 
clientele in locating literature. The Library's catalog was separated into 
two sections, an author/title section and a subject section, for easier use. 
Plans were completed for the establishment of a duplicate catalog near the 
book collection on the Lower Level to provide needed information on location. 
An outline of the Library of Congress classification schedules covering 
subject areas pertinent to NIH research interests was posted on the Lower 
Level bulletin board adjacent to the book collection. 

Significant progress was made in job restructuring due to cooperative efforts 
of members of the NIH Job Restructuring Team, the Library's Personnel Gener- 
alist and Library m.anagement. The objective was development of a planned 
progression of career ladders with on-the-job and academic trainir^ whereby 
a qualified Library Technician could move over a period of years to a profes- 
sional position as Technical Information Specialist. Further work on the 
project has been postponed until a proposal for a major reorganization of 
the Section is approved. 



66 



All current and noncurrent journals in the Library's collection are listed 
together with their holdings beginning with the March issue of the PHILSOM 
printout. Organizing and coding the holdings input for the noncurrent 
journals required one year to complete. 

The FY 1974- contract for journal subscriptions was again awarded to the 
F. W. Faxon Company. The DHEW binding contract was awarded to a new company, 
Wert Bookbinding Inc. of Middletown, Pennsylvania. This required recoding 
the binding data changes for input to the PHILSOM journal control system to 
obtain computer-produced Binding Control Slips compatible for the new binder. 

The Library provided professional cataloging assistance to the Library 
Technician in charge of the Division of Research Grants Library. 

Representatives from several New York libraries which are instituting an 
independent network using the Washington University Medical School Library's 
PHILSOM journal control system visited the NIH Library in October and 
November. They were interested in observing the PHILSOM system in action 
and discussing system-related problems encountered by the Library. The 
visitors represented the Medical Library Center of New York, Cornell 
University Medical College Library, and the Library of the College of 
Medicine and Dentistry of New Jersey at Newark. 

Readers Services 

Registration for the new NIH Library Identification Cards began in mid- 
summer. After September 5, the blue ID Card was invalid and NIH employees 
were required to use the new red Card to obtain Library services. 

The Library operated throughout the year with insufficient equipment for 
effective Library Copy Service. The equipment installed in FY 1973 on a 
90-day trial period proved inadequate for required continuous use. With 
one request disapproved by DHEW, it is hoped that a new justification for 
obtaining additional equipment will be approved so that this important 
service to NIH research may be efficiently continued. 

New drawers were installed in the Circulation Desk to accommodate the trays 
containing the book and journal charge files placed on open desks when the 
request form was increased in size. Easier access to the files was pro- 
vided the Circulation Desk staff in responding to inquiries and performing 
charging procedures . 

The entire book collection and a portion of the journal collection on the 
Lower Level were shifted to relieve crowded sections and make possible 
shelving of newly acquired and returned vol\jmes. This project was given 
priority by the new supervisory Library Technician in the Stacks and Copy 
Service Unit serving as Acting Head during the extended illness of the 
Unit Head. 



67 



Effective in August, the National Library of Medicine reduced the number 
of interlibrary loan requests it will accept from the NIH Library from 
fifty to twenty per day. An NIH Library employee was regiilarly scheduled 
50-60^ of his time to help process NIH Library requests at NLM. 

Due to the energy crisis, the Library was requested by NIH Administrative 
Services to use NIH Vehicle Dispatch for pickup and return of interlibrary 
loan material and for pickup of priority new books from area libraries and 
bookstores. Use of government automobiles by Library messengers is limited 
to pickup and delivery to the National Library of Medicine, Division of 
Computer Research and Technology and pickup from the Library's book boxes 
on the reservation. 

The Section was given the responsibility for a new Library activity, the 
organization, development and operation of a nonprint media collection to 
support NIH research. A Librarian was assigned in March and progress was 
made in determining the basis of the new service. 

A study of the use of the coir-operated copying equipment located in the 
Library indicated that a considerable number of NIH employees use these 
machines in the evenings and weekends when the Library Copy Service is 
not in operation. 

Reference and Bibliographic Services 

A Reference Assistance Desk was reinstated in the Lower Level Reading Room 
area to receive reference inquiries from Library users. This station 
eliminates the need to go to the Upper Level for assistance. An uptrend 
in reference service continued during the latter part of the fiscal year. 

Approximately seventy NIH investigators responded to the Library's announce- 
ment in the NIH Record of its MEDLINE orientation/demonstration. Sessions 
were conducted by the Library searchers in July and August. 

The n\imber of requests by NIH investigators for automated bibliographic 
searches in the biomedical field continued to increase. In addition to 
medical bibliographies obtained through National Library of Medicine's 
MEDLINE, the Library now provides NIH scientists with bibliographic 
searching services, both recurring and retrospective, in chemistry through 
Chemical Abstract's automated system CBAC (Chemical and Biological Activi- 
ties ) and current awareness in biology and related fields through Biological 
Abstract's BIOSIS system (BioScience Information Service). The Library's 
professional staff prepares individual profiles indicating the necessary 
subject parameters for each request. 

Since MEDLINE searching requests continue in high demand, arrangements were 
made with the National Library of Medicine for a second access code to its 
computer through the NIH Library's V/YLBUR terminal at minimal fee. The 
Technical Services Section scheduled use of this terminal to avoid conflict 
with WYLBUR acquisition and cataloging programs. Technical Services Section 
is able also to access NLM's CATLINE and SERLINE via this terminal for 
cataloging and acquisition information. 

68 



The Section Chief participated in NIM's Region IV IjIEDLINE Workshop on 
November 1-2, speaking on a panel on "Analyst-Requester-Data Base Interpreta- 
tions . " 

Translating Service 

Contact translating services for written translations, which are not now 
limited by the Library's budget, increased substantially in the first com- 
plete year of direct charges to the B/I/D's. Quality control for the 
completed translations is provided by the Library. Oral translations con- 
tinue to be emphasized in- house. 

Training 

The FY 1974 Branch Training Program was developed through individual dis- 
cussions between the Section Chiefs and their employees. Proposals were 
made for beneficial employee development in the present job and for more 
effective use of the employee in the Library. Some tlriree hundred fifty 
man-days were devoted to employee participation in academic, administrative, 
technical and in-Library training courses and workshops. One Library 
Technician received the Certificate of Accomplishment for Library Techni- 
cians granted by the U. S. Department of Agriculture Graduate School upon 
completion of an organized course of several years' study. One employee 
continued special training relative to the Basic Adult Education program. 
Two employees were enrolled in the NIH/FCC Upward Mobility College and 
one in Federal City College. 

Exhibits 

Exhibits prepared by the Library staff and displayed during the year covered 
the following topics: Library Services, History of the Public Health 
Service, What is CBAC?, Acupuncture, Black History Week, Native American 
Week, and National Library Week. Assistance was received from the Medical 
Arts and Photography Branch, and Mrs. Katl-ileen Snowden, Veterinary Resources 
Branch, loaned unusual wood carvings. Jewelry, and some rare historical 
journals for the Black History Week Exhibit. 

D. Problems 

Downtime and poor product quality of the present photocopy machines con- 
tinue. Past efforts to obtain new machines to meet the heavy demand have 
been rejected. Additional justifications for the requested equipment have 
been submitted. 

The level of the humidity on the lower level of the Library detrimentally 
affects the Library's main collection of books and journals. Higher 
humidity developed yrhen the chilled water in the cooling system was cut 
off duririg the energy crisis. 

Increased efforts are planned to resolve or eliminate personnel problems 
that remain in some Sections. 



69 



E. Program Plans 

Completion of a Scope and Coverage Statement will provide much needed govern- 
ing rules for developing the Library's book and journal collections. 

When approval of the planned reorganization of the Technical Services Section 
is received, careful attention will be given to orienting and training the 
staff in the substantial procedural changes to effect an orderly transition. 

Development and implementation of an automated circulation system will provide 
a more efficient service to Library clientele and will provide better control 
of the Library's collections. 

After establishing specific requirements of NIH researchers, a nonprint media 
collection will be developed to expand the present microfilm and microfiche 
holdings of the Library. Equipment needed in its use will be acquired, such 
as projectors, screens, playback units, tapes, filmstrips, and slides. 

Conversion of the subject headings used in the Library's catalog to identify 
and locate medical books and journals held in the collection will provide 
the investigator with the specialized medical terminology used by the 
National Library of Medicine. Library of Congress headings will continue 
to be used for material in other subject fields. 

Anticipated completion of a duplicate card catalog adjacent to the book 
collection on the Lower Level will facilitate access to the main book and 
journal collections. 

Arrangements will be made with the National Library of Medicine for a second 
MEDLINE terminal to meet search demands and to use CATLIInIE in converting to 
NLM's medical subject heading (MeSH) system. 

F. Publications 

Smith, Ruth C: SHARP: Experiences in Library Automation. Special 
Libraries 65: 61-65, 1974. 



70 



DIVISION OF RESEARCH SERVICES 

Summary of Branch Activities July 1, 1973 through June 30, 1974 

MEDICAL ARTS & PHOTOGRAPHY BRANCH Mr. Arthur F. Moore, Chief 

I. SUMMARY 

Demands for MAPB services remained high. With a completely renovated Photo 
Lab, requests were serviced within five days and the Branch is committed 
to the reduction to seven days for photomicrograph and photomacrograph 
services by the end of FY - 75. The newly named and reorganized Design 
Graphics Section has cut production 10 percent in reprint material, however, 
design and delivery of exhibits increased 100 percent. Medical Illustration 
continues a substantial steady output. MAPB increased its use of outside 
contract services by 26 percent. With new equipment and facilities. Branch 
continued to improved and broaden its skills to meet increased program 
demands with dispatch and high morale. 



71 



f 



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, commmiicating 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. Ciirrent 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; medical models, and computer-generated graphics. 

C. Program Progress and Accomplishments 

1. Service Time Acceleration and Graphics Program 

The demand for MAPB services remained high. In the Photo Lab, the posted 
turn- around- time for requests is five working days, however, 20 percent 
of the work was done in less time on an emergency basis. The scientific 
photo unit tiim-around-time for finished product was 15 workdays with a small 
amount of work completed more rapidly on emergency demand. This delivery 
time is excessive and the Branch is committed to reducing the wait from 15 
to at least 7 days for scientific photography by the end of FY - 75. 

There was a decided demand for more color photography. Black & white 
photography continued at the same level. 

Requests for Medical Illustration remained at a high level. 

As a result of DHEW ordered cutback in informational materials, production 
of booklets, brochures, pamphlets, etc., dropped approximately 10 percent. 



73 



This is reflected primarily in the reworking of reprint material. At the 
same time, approved requests for design and construction of exhibits was 
up 100 percent. 

In the area of Design Graphics, an independent study of all the NIH graphics 
was conducted by the National Endowment for the Arts. Their findings con- 
cluded NIH graphics lacked coordination with a resultant loss of image to 
NIH and its component Institutes. 

The Branch took positive steps to rectify this situation by initiating a 
major ongoing plan to develop a well coordinated graphics program to more 
effectively communicate work being done at the NIH to the scientific 
community and the public. 

2. Operational Improvements 

The General Illustration Section was reorganized and renamed the Design 
Graphics Section to more clearly describe its overall functions to the 
prospective NIH user. Two of the three units, Graphics and Drafting, were 
combined under the Graphics Unit to avoid duplication, to gain uniformity 
of production and to enrich those jobs in the drafting area which, in recent 
years, have become so simplified as to reduce the work to little more than 
preplotted tracings. 

A complete renovation of the Photographic Laboratory spaces was completed, 
with installation of new highly technical equipment. This allows for in- 
creased production, quicker response time, improved quality and morale among 
the employees . 

Photographic end-product prices were revised to reflect a more accurate 
balance of profit and loss margin. The Section operating costs, reflected 
in the revolving fund were within 1 percent of the break-even point. Total 
revenue was in excess of $4-04,000. 

3. Service Contracts 

There was a 26 percent increase in outside contracting. With niimbers of 
Branch personnel remaining static, this figure represents a substantial 
increase in demand for MAPB services from the NIH community. 

During FY - 1974, the Branch streamlined contract service billing procedures, 
processing them in half the time previously required. However, these actions 
have only partially accelerated payment to service suppliers which remained 
embarrassingly slow. 

4 . Training 

Thirteen members of the Branch attended out-of-the-area professional 
multiple-day seminars. In addition, 24 employees attended 43 separate formal 
training courses. 



74 



5. EEO Developments 

Heavy emphasis was placed on continued familiarization of Branch employees 
with the EEO. This was accomplished with groups of employees in meetings 
with EEO-HRC representatives. Many suggestions were made directly to the 
EEO officers by the employees and many were implemented. Similar meetings 
were held with first line supervisors, and EEO-HRC representatives. Eight 
employees from the four sections of the Branch attended the two-day DRS-EEO 
Seminar in May. 

6. Labor Relations 

A new two-year labor management agreement was negotiated between the MAPB 
and AFGE Local 24-19. Negotiations were conducted in a cooperative manner 
and the MAPB has had no problems working within the agreement. The MAPB 
considers it an honor to have both the President and Vice-President of 
AFGE Local 24-19 on its staff. 

D. Problems 

The Branch was increasingly dependent on outside quality contractors to meet 
the demands of the NIH commiinity. MAPB has identified a number of purveyors 
of high quality services, however, one-by-one these contractors refused to serve 
the Branch because of the long time it takes the NIH to pay them for work done. 
This situation leaves the MAPB increasingly vulnerable in meeting the mounting 
demands from its clients. 

There is also a critical need for the NIH community using MAPB services to 
allow more lead time for planning and execution of their audio-visual material. 
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 the NIH Graphics Program. 
It will continue to improve, enlarge, and extend its services and will seek 
more persuasive ways to acquaint the NIH community with its skills. The 
Branch will continue to emphasize the necessity of early counsel and planning 
for optimum results. 



75 



/ V 



DIVISION OF RESEARCH SERVICES 

Summary of Branch Activities July 1, 1973, through June 30, 1974 

Veterinary Resources Branch Dr. Robert A. Whitney, Jr., Chief 

I . SUMVIARY 

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. 

ATRB 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 six 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, 
of most significance, contracting. 

The Rodent and Rabbit Pi-oduction Section was reorganized and renamed the 
Small Animal Section. The new organization is designed to be more efficient 
in responding to BID requirements for rodents and rabbits produced intra- 
murally and from contract sources. 

A Catalogue of NIH R odents was published. Characteristics of more than 
100 strains and stocks of rodents and rabbits maintained in the VRB genetic 
repository are described in loose-leaf notebook form. Approximately 150 
breeding nuclei of VRB strains of mice were provided to the international 
biomedical research community.. 

Investigators ' requirements for VRB produced rodents and rabbits increased 
and total issues remained at about 500,000 despite a reduction in permanent 
personnel; however, an imbalance of temporary employees was utilized in some 
areas to maintain adequate production levels. Issues of noninbred animals 
from contract sources decreased. 

The importance of maintaining the genetic pool of VRB noninbred stocks was 
demonstrated to be essential for the continuance of effective testing of 
biologies. VRB colonies of mice now originate from hysterectomy-derived, 
barrier -maintained breeding stock. New pathogen-free colonies were 
established this year and the old conventional colonies phased out . 

While rodent, rabbit, and cat production dropped, laboratory reared dogs, 
timed-pregnant nonhuman primates, and ungulate production increased. 
Contracts were used to supplement canine, primate, and ungulate production 
as well as rodent production. 

Cutbacks in rhesus monkey exports from India in 197-4 prompted VRB to initiate 
domestic breeding programs. A new facility at Perrine, Florida, was obtained 
from the Environmental Protection Agency and is being stocked with over 700 



77 



rhesus breeders. Contracts are also being negotiated to initiate other 
domestic breeding colonies to produce 500 or more rhesus monkeys per year for 
use in NIH intramural research. 

Tissue culture and media production decreased 6 percent. Glassware issues 
decreased 12 percent. Personnel reductions and increased use of disposable 
supplies contributed to this reduction, which was largely due to the decision 
to stop supplying two major NCI contractors with media. 

Surgical activities and support have stabilised at 800 procedures per year. 
Surgical facilities are now used at maximum capacity. 

Experimental animal holding for dogs, which has long been over capacity, was, 
in part, contracted. With the Phase I renovation of Building 14-D, protected 
facilities are available for holding 1,000 nonhuman primates. Over 1,700 
primates will be held in this building on completion of Phases II and III 
renovations. 

The Animal Disease Investigation Service was reorganized to ensure rapid 
response to requests. The number of calls made to the BID's increased by 
22 percent, from 150 to 183. 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, well received by the BID investigators, 
has gradually increased in scope. It has been mutually beneficial to 
investigators and to the VRB professional staff in providing an overview of 
laboratory animal facilities and practices at NIH. 



^ 



78 



II. BRANCH PROGRAMS 

A. Objectives 

The primary objectives of the Veterinary ResoTirces Branch are: 

1. Issuance of research animals, animal biologies, tissue cultiires, tissue 
ciilture 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 and roentgenography and other special procedures. 
4-. 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 cons\iltative services on animal health and husbandry, use of 
experimental animals, tissue ciiltures, and bacteriologic media. 

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 pathogenfree 
(SPF) rodents are produced for intramural research programs requiring them and 
for replacement breeders to enhance the health status of production and genetic 
colonies. 

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 immunizations, 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 modem 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. 

79 



3. Tissue Cul.ture and Media Production 

Several continuous cell line tissue cultures are maintained, propagated, and 
produced in large volxmes 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- 
teiTO 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 Buildings lA-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, & 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 veterinarians assigned to the 
section 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 investiga- 
tors 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. No gain is projected for 
the next year unless constraints in space and personnel are resolved. 

Experimental surgery continues to be complex with numerous thoracic, cardio- 
vascular, 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. 

30 



i 



^ 



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, 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 
comprehensive review of its animal care programs with evaluations and 
recommendations for improvement. Consultative services on use of tissue 
ciiltiires 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 

About 500,000 VRB-produced rodents and rabbits were issued to investigators, 
equivalent to the number produced last year . Guinea pig and rabbit production 
decreased, rat and hamster production remained unchanged, but there was an 
increased requirement for and production of VRB inbred and noninbred mice. 
The total demand for VRB strains and stocks of mice was not satisfied by 
current production levels. 

Conventional mouse production colonies were phased out and new pathogen-free 
colonies established from hysterectomy-derived breeding stock raised in the 
barrier. The new pathogen-free colonies were initially established in a 
"clean conventional" building and the old conventional colonies moved to the 
rabbit building while the former mouse production wing was decontaminated, 
painted, and converted to a "clean conventional" building. The pathogen-free 
inbred mouse production colonies were then moved back into the decontaminated 
building. Most investigator responses to the higher quality mouse were 
favorable; however, a few are dissatisfied with changed that resulted in 
alterations in baseline data. Inbred mouse strains have not adapted to the 
barrier and are being isolated while attempts are made to hysterectomy derive 
them directly into a "clean conventional" area. 

Commercial sources of noninbred mice have proved unsatisfactory for testing 
certain biologies; therefore, FDA has provided temporary positions to 
increase General Purpose and NIH mouse production. The Frederick Cancer 
Research Center (FCRC) continues to rely on VRB foundation colonies as the 



81 



genetic base for their rodent colonies. Pedigreed mouse and rat strains are 
now provided exclusively from a barrier to reduce the possibility of contami- 
nation to their colonies. The demand for noninbred mutant "nude" (athymic) 
mice is increasing due to its immunologic deficiency. Production of this 
mouse, which is difficult in conventional colonies, has been excellent under 
barrier and "clean conventional" conditions. 

The pathogen-free rat colonies in the barrier continue to have excellent 
health and reproductive performance although it has been over five years 
since they were initially hysterectomy derived. The Osborne Mendel and F3^4/N 
clean conventional production colonies were contaminated with Sendai virus, 
relocated in a conventional area, and decontaminated rooms were restocked with 
barrier animals. The new colonies are Sendai free. 

A major effort was made to hysterectomy derive inbred guinea pigs and 
establish foundation colonies in the barrier. Over 300 term feti have been 
taken by hysterectomy derivation into germfree and pathogen-free isolators. 
Maintenance of the young under isolator-defined flora conditions has been 
successful, but establishing a viable nucleus in the barrier has not. Various 
combinations of bacteria are being tried to establish an acceptable intestinal 
flora and various dietary regimes are being used to establish nutrient require- 
ments, growth, and survival rates. 

Vegetable supplementation (kale) was eliminated from the diet of the guinea 
pig production colonies without a noticeable effect on productivity. 
Simultaneously, the amount of drinking water provided daily to the guinea 
pigs was increased. Hartley guinea pigs from Edgewood Arsenal were removed 
from the proposed clean conventional production wing ¥/hen found serologically 
positive for Sendai, GDVII, SV5 and H-1 viruses. They continue to show good 
reproductive performance on an autoclavable open formula diet . 

A nucleus of pathogen-free rabbits obtained from Edgewood Arsenal are serving 
as foster mothers to establish pathogen-free colonies of NTH rabbits in a 
clean conventional environment. The colony has remained free of Pasteurella 
and Bordetella infections as well as internal and external parasites; however, 
Tyzzer's disease has been diagnosed. The C-6 deficient and Netherlands Dwarf 
rabbits have been successfully established in the new environment as well as 
most of the defined allotype strains which are being inbred. A small nucleus 
of the noninbred NIH New Zealand White rabbit is also being hysterectomy 
derived and foster nursed to retain the genetic base of that colony in a "clean 
conventional" environment. 

Rabbit production was decreased to a maintenance level with the initiation of 
a contract to provide noninbred New Zealand White rabbits . Tecljiiques are 
being studied to develop a better defined pathogen-free rabbit . 

The Rodent and Rabbit Production Section was reorganized and its name changed 
to the Small Animal Section. Under the new organization there will be a 
building supervisor in animal care areas, a cagewash unit, an ordering and 
contracts office, an administrative assistant, and a professional services 
group. The Genetics Unit was eliminated as an organizational entity; however, 



82 



the role of strain maintenance is expected to be enhanced because of the 
^ additional time that will be available to the geneticists for technical matters. 

b. Large Animal Production 

The canine breeding colony currently consists of U3 bitches and 11 dogs. 
Culling continues to be directed towards eliminating poor producers and 
animals with hip dysplasia. The last of four inbred lines of foxhounds was 
established. The inbreeding colony currently 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 crossbreeding the 
lines. 

A contract was established to breed and provide purebred foxhounds for NIH 
research at a rate of 400 to 600 per year. Availability of purebred stock 
from NIHAC and contract sources has reduced the need to rely upon random 
source foxhounds and permits elimination of random source mongrel dogs as 
standard NIH research animals. 

The cat breeding colony was reduced from 25 to 13 queens and six toms. The 
projected rate of issue is approximately 150 cats. 

The goat breeding herd was expanded from 10 to 16 does and one buck. Goats 
produced from the breeding herd will be held until approximately one year 
of age before issue. 

f c . Nonhuman Primates 

A nonhuman primate breeding colony was established at Perrine, Florida. At 
capacity, it is expected that the colony will contain about 700 adult female 
■ rhesus monkeys as well as their neonatal offspring. The facility will have 
been stocked with at least 250 breeders by the end of FY 1974- • Production 
from the colony will upgrade the quality of rhesus monkeys for research and 
supplement embargoed supplies of rhesus obtained from the wild. 

The timed-pregnant rhesus monkey breeding colony has continued to grow from 
165 animals to 270 animals, including 40 rhesus monkeys assigned to NINDS 
which are also managed as a timed -pregnant breeding, colony. Currently, there 
is a contract with Gulf South Research Institute to provide from 80 to 100 
timed -pregnant rhesus monkeys in addition to the VEB breeding colony. The 
TOB breeding colony is newly developed and, over the past year, 120 pregnant 
animals were produced and assigned to BID investigators, in addition to 28 
timed-pregnant animals delivered by contract. A new contract for timed- 
pregnant baboons is planned to provide another animal model for pregnancy and 
perinatal research. 



S3 



2. Research Animal Procurement and Conditioning 

a. Rodents and Rabbits 

The total purchase of rodents and rabbits from contractors decreased from 
132,500 in FY 1973 to approximately 90,000. There was a decline in acceptance 
of nonlnbred mice, rats, and hamsters from contract sources. A contract for 
Hartley guinea pigs was initiated. However, the contractor was not able to 
provide sufficient animals to meet NIH requirements. A contract for New 
Zealand White rabbits was initiated which, thus far, is providing acceptable 
quality and service. An itemized list of animals purchased on contract are 
as follows : 

Hartley Guinea Pigs — Carworth 2,500 

Rabbits— Lab-Rabs 2,500 

Sprague Dawley Rats — Taconic 35,000 

Hamsters — Lakeview 9,000 

Swiss Mice — Taconic 4-0,000 

In addition, VRB arranged for the Frederick Cancer Research Center to supply 
NIH investigators over 1,300 Hartley guinea pigs, 500 inbred guinea pigs, 
2,500 inbred mice, and 150 rabbits. 

b. Large Animals 

Random so\irce mongrel dogs and random source foxhounds are purchased after 
30 days of conditioning by the vendor. Illness and losses among animals have 
been minimal. The trend in issues of random source dogs of both types 
declined. Estimates indicate that approximately 800 to 1,000 random source 
dogs (mongrel and foxhound) -vidll be issued. The contract requirements for 
mongrel random source dogs will be reduced from an estimated 1,04-0 (FY 1973) 
to 150 (FY 1974). 

Requests for random source cats appear to be increasing slightly. Projected 
issues are 700 to 800. 

A.pproximately 550 ungulate animals will be purchased, quarantined, conditioned, 
and issued. In addition, some 50 domestic fowl including ducks, chickens, and 
turkeys will be utilized. 

The primate quarantine facility entered its second year of operation and is 
currently filled to capacity. An effort has been made to procure as many 
large, stock rhesus monkeys as possible so as to be able to fill the needs for 
breeding stock at Perrine, Florida, and Gulf South Research, and to supply 
basic NIH needs. 

Rhesus ( Macaca mulatta ) monkey issues are estimated at about 3,575 which 
represents an increase of about 875 over last year. 



84 



other species of monkeys and apes (M. fascicularis , M. nemestrina , 
f Erythrocetius patas , Saimiri sciureus , Cebus albif rons/apella , Cercopithecus 
athiops , Papio spp . , Aotus trivirgatus , Saguinus oedipus , Callithrix sp . , and 
Pan sp . ) contributed small numbers to the overall quarantine and conditioning 
program . 

3. Tissue Culture and Media Production 

Based on the first seven months of FY 1974-, the number of requisitions 
processed for tissue culture and media will total 13,000; a decrease of 
6 percent from last year. The volume of media produced will be 63,000 liters 
of bacteriologic media and 65,000 liters of tissue culture media for a total 
of 128,000 liters. This total represents a 12 percent decrease over last 
fiscal year, and primarily results from a policy decision to no longer supply 
tissue culture media on a routine basis to NCI contractors. 

Issues of blood agar plates of all types, including horse, sheep, and human 
blood plates will total 148,000 this year, a 1 percent increase. In addition 
to blood agar plates, there will be another 378,000 plates of other types for 
a total of 526,000 plates for the fiscal year. This is a 26 percent increase 
over last fiscal year. 

Issues of tissue culture cells as cell suspension increased 10 percent to a 
projected total of 206 liters of suspension. This is indicative of a trend 
toward cells in suspension rather than tubes or bottles of cells. 

J Tissue culture cell freezing and storage services continued to show increasing 
' popularity with NIH investigators. A projected total of 3,000 ampules of 
cells will be frozen and over 2,300 ampules of cells were maintained in the 
frozen cell bank to support research programs. This represents a significant 
increase of 42 percent over last fiscal year. 

Renovations to provide filtered air to the room housing the automatic media 
bottle filling system are expected to extend aseptic bottling to sterile 
tissue culture media. This system should eventually lead to almost total 
automation of media dispensing for both bacteriologic and tissue culture 
media . 

Construction of a separate sterile filling room to house an existing automatic 
tubing machine has provided a much more efficient operation for this important 
aspect of media production. It is now possible to carry out sterile 
production in tubes simultaneously with other types of production. 

Further automation of the labeling system is expected to greatly reduce time- 
consuming manual application of lables to bottles. The new system will be 
tied in with the existing bottle conveyor after minor problems of synchro- 
nization and label specifications are solved. 

Several improvements to provide better working conditions were accomplished. 
H An air-conditioned employee lunchroom, which also serves as a Section 
I conference room, was provided. Improved lighting of a windowless main 

^L 85 



corridor consideraLly brightened an otherwise dark and dreary area, as well 
as making the area safer. Plans for painting and installation of improved 
air-conditioning for several high-heat -load work areas are underway. 

4. Processing Glassware, Animal Cages and Miscellaneous Items 

Projected glassware issues to the I/D's totaled 8,124,000 pieces; a decrease 
of 14 percent over last fiscal year. A projected total of 244,000 cages, 
racks, and associated pieces of equipment were processed, not including 
carpets washed for the Clinical Center. 

New detergent controls were purchased for cagewashing and glasswashing machines. 
Hopefully, these controls -will reduce the amount of detergent used and also 
provide more accurate dispensing. 

Two new electric dryers were purchased and are awaiting installation. These 
dryers will be located near the pipette washers and will be used to dry 
pipettes. The relocation of these dryers will greatly reduce the handling and 
transporting of washed pipettes. 

5. Animal Biologies Production 

Domestic turkeys and ducks vrere used in small numbers to produce normal blood 
and antisera for specific research projects. 

The canine blood donor colony, which consists of 258 dogs, produced an 
estimated 3,200 units (l unit=500 ml) of blood. 

The RIF-free avian activity was phased out early in the fiscal year. 

Biologies production from ungulate animals was stable. Projected production 
includes 1,500 liters of ungulate blood. The size of the ungulate herd main- 
tained for all purposes increased from 515 to 550. 

6. Genetic Repository and New Animal Models Program 

Catalogue of NIH Rodents was published. It describes characteristics of the 
over 100 stFains and stocks of rodents and rabbits maintained. These colonies 
represent the most diversified, multispecies collection maintained in any one 
facility. In addition to supplying animals for intramural investigators, 
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 150 investigators were provided with 
litters of Inbred animals to start colonies and several hundred noninbred 
animals were provided as breeding stock. Several commercial producers were 
also provided with breeding stock. Requests were particularly numerous for 
the hypertensive rat; nude, athymic mouse; and inbred guinea pigs. 

A program to assist investigators in obtaining nev/ 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 

86 



in a particiilar research problem were adapted from nature. New models are 
hysterectomy derived and foster nursed or hand nirrsed prior to Introduction 
into the NIH colonies. Three new strains were added to the repository at the 
request of NIH investigators . They are : 

Inbred Mice: BALB/cCr 
Inbred Rats: Lou/c/WsL 
Lou/m/WsL 

The new BALB/c subline was requested by NCI to support production at FCRC. 
NCI also requested establishment of the additional rat strains and some NCI 
contract programs are calling for use of A/RB colonies as the genetic base. 

7. Experimental Surgery, X-ray, and Related Activities 

a. Building 28 Facilities 

The surgical facilities are primarily available to BID investigators; 
however, surgery was frequently performed by veterinarians assigned to the 
Section at the specific request of investigators. Assistance to investigators 
was provided in anesthesiology, surgical support, diagnostic radiology, and 
postoperative care of animals. 

Surgical facilities in Building 28 were used at maximum capacity. No 
projected increase is anticipated next year due to limitations of building 
size and room arangement unless the siirgery suites are moved to Building 14E. 
There was also a marked increase in the time devoted by Experimental Surgery 
Unit personnel in providing better technical and professional assistance to 
investigators conducting research in this s\irgical facility. 

b. Animal Center Ungulate Surgery 

Activities in ungulate surgery declined from previous levels. Projects 
utilizing sheep for intrauterine fetal surgery are expected to be markedly 
decreased and, possibly, cease. Breeding continued to develop foior inbred 
lines of immunologically distinct miniature swine. Five sows produced 20 
progeny this year. A project concerning the possible teratologic effects of 
feeding blighted potatoes to pregnant sows involves a small swine breeding 
program and surgery. 

Radiographic procedures remained constant with 250 exposures projected. 

8. Experimental Animal Holding 
a. Primates 

Renovations were completed for Phase I of Building 14-D with a capacity of 
over 800 primates. Heavy demands by BID investigators for this space totaled 
approximately 1,100 primates. To meet these requirements, completion of 
renovations of Phase II and III are mandatory for the beginning of FY 1975. 



87 



This coincides with the programmed renovations of the BoB portion of Building 
I4.D so that a complete primate research holding facility will be available to 
meet the needs of NIH. A total capacity of 1,750 simian primates assigned to 
specific research projects will establish this colony as one of the largest 
primate facilities in the United States. Isolation facilities permitting 
infectious disease studies in up to 700 animals will also be provided by the 
renovation . 

b . Canine 

The population of long-term dog holding leveled at approximately 350 dogs 
per month. This was achieved through a contract to hold dogs off the 
Bethesda campus when only infrequent investigator manipulation is required. 
This permitted a more suitable canine density population per kennel to achieve 
better animal care management. The south wing of Building I4E was equipped 
with 22 individual dog runs which currently hold dogs on atherogenic diets. 

c . Ungulates 

Several species of ungulates were held under observation for NIH investigators 
during investigative studies. Physiological sampling and specimen collections 
were provided in association with these studies. 

9. Animal Nutrition 

VRB-developed open formula rations for rats, mice, and rabbits were used 
increasingly throughout NIH during the past year without any reported problems 
from investigators. Purchase of the rabbit ration was approximately 50 percent 
above the estijiiated yearly requirements. Based on dollar value, approximately 
70 percent of the animal feeds used by NIH are presently purchased via 
advertised contracts for open formula rations while 30 percent are purchased 
via negotiated "sole source" contracts. Prior to initiation of the nutrition 
program, this ratio was 30 to 70 percent for feeds purchased via advertised 
and negotiated contracts, respectively. An estimated $4-0,000 per year was 
saved as a result of the increased use of advertised contracts. 

A contract was established with an independent laboratory to conduct estrogen 
assays and a limited number of nutrient analyses on samples collected from 
feeds manufactured for NIH contracts. Objectives were attained without any 
major problems. The estrogen assay results were uniform while the nutrient 
analyses indicated considerable variation in the nutrient concentration among 
production batches of animal feeds. The requirements of this contract were 
expanded to include nutrient analyses on every sample of feed submitted for 
estrogen assay. A contract was established to conduct various nutrient 
analyses on experimental laboratory animal rations. Data obtained from this 
source was the basis for establishing vitamin levels in open formula auto- 
clavable rations . 

Data was accumulated indicating it is not advantageous to feed rats and mice 
rations containing more than 16 to 18 percent protein for maximum reproductive 
performance. This is important since ingredients containing high quality 



proteins are not readily available and the current cost of each percent of 
protein is approximately $12 per ton of finished product. 

Considerable progress was made toward formulating autoclavable rations for 
rats, mice, rabbits, and guinea pigs. Vegetable supplementation of the 
production colonies of guinea pigs was discontinued. 

An increasing number of NIH investigators asked for assistance in 
formulating and/or obtaining rations for special research projects and in 
various nutritional studies with rats, mice, and primates. 

10. Animal Health 

a. VEB Animal Health Problems 

An enterocecocolitis was recognized as a new disease problem in weanling age 
rabbits in C wing, causing over 10 percent of fatalities. Ciilture results 
indicate that the disease is caused by overgrowth of Escherichia coli. 
Whether this strain of E. coli is particularly pathogenic for rabbits or is 
simply over -populating the intestines of rabbits held in an unusually clean 
environment is not known. The rabbits in C wing are free of a number of 
common bacteria of rabbits, including the respiratory pathogens Pasteurella 
multocida and Bordetella bronchi septica . Pneumonia caused by these agents is 
still a problem in the few remaining "conventional" rabbit rooms (11.5 percent 
of fatalities). Neonatal deaths accounted for more than 30 percent of losses 
in rabbits. Findings indicated that moat deaths were due to failure of the dam 
to properly feed or ^are for her offspring. 

Strongyloidosis occurred for the first time in the history of the rabbit 
colony. The ova and larvae of S. papillosus were detected in a composite 
fecal sample from one room during the weekly coccidiosis surveys. Although 
an attempt was made to eradicate the disease by frequent testing and killing 
of affected animals, within three weeks the disease cropped up in cages widely 
scattered in the room. The entire room of animals was sacrificed to prevent 
spread to other rooms. The significance of these findings from an epidemio- 
logic viewpoint is that S. papillosus is a common parasite of sheep, and 
sheep were introduced into the building five months before the outbreak. 
Five sheep were tested and found to be shedding ova. 

Efforts to produce guinea pigs with limited microflora in the barrier 
facilities continued to be thwarted by fatal enterocecocolitis and deaths of 
undetermined cause. As in rabbits, the enterocecocolitis is caused, apparently, 
by imbalances of intestinal microflora. 

Hemothorax continues to occur in relatively low incidence (6.9 percent of 
fatalities) in the barrier-maintained mouse colonies. As previously described, 
the disease appears to be a noninfectious condition of male mice characterized 
by myocarditis and prolonged bleeding time. In contrast to the first outbreak, 
which involved 10 to 12 week old GP mice, the disease is now recognized in all 
strains at four to six months of age. Efforts to reproduce the disease 
experimentally by feeding vitamin K deficient diets have been unsuccessful. 



89 



The major disease problems in nonhuman primates again were those which 
typically occur following shipment. In animals that died, 4-1.5 percent had 
colitis, usually hemorrhagic, and 26.2 percent had pneumonia. Bacteriologic 
studies indicated that the colitis was caused, for the most part, by 
Shigella sp . 

Tyzzer's disease was found in only four rabbits, the lowest incidence in 
many years. This probably was the result of reduced colony size and the 
reestablishment of the colonies from cesarean-delivered stock in unusually 
clean quarters. Since its causative agent is a spore former, it is likely 
that the disease will become established in the colony again. A method to 
detect serum antibody to this disease using the indirect fluorescent antibody 
technique was developed, thus permitting more detailed studies of the natural 
history of the disease and its pathogenesis. Already it has been shown in 
limited studies that the agent in rabbits appears immunologically indistin- 
guishable from the agent of Tyzzer's disease in foals. The latter agent was 
first isolated by GPS staff this year when assistance in dealing with a new 
disease of foals was urgently requested by the staff of the University of 
Kentucky. 

Fecal culturing for Myc ob ac t er ium paratuberculosis in the goat herd was 
continued. The incidence of Johne's disease declined from 21 cases in 1972 
to two in 1973. Culturing will continue for at least another year. 

Initial screening of the sheep flock for Q fever was completed . None of the 
71 sheep tested were considered to have active Coxiella burnetti infection. 
Testing will be performed on a continuing basis. 

Brucellosis testing was continued in the swine herd, and no new cases were 
detected. Testing will be continued for about six months. Thereafter, only 
new acquisitions will be tested during the quarantine period. 

Urolithiasis was diagnosed in 15 goats (wethers). Four of the cases were 
fatal. The disease is thought to be associated with the exclusive feeding 
of grain concentrates. 

b. BID Animal Health Problems 

The most serious animal disease problem in the NIH laboratories was an 
outbreak of ectromelia (mouse pox), the second such outbreak in NIH history. 
The first occurred in I960. This disease is highly contagious and is feared 
in animal colonies and research laboratories because of the difficulty in 
eradication and because both the enzootic and epizootic forms of the disease 
wreak havoc with animal experimentation. This disease was introduced into an 
animal room in the NCI's Building 37 in mice received from England. Those 
mice are believed to have been infected just before shipment to the USA when 
they were inoculated with tumor cells contaminated with the causative virus. 
Fortunately, within several weeks after the mice were received at NIH, warning 
came from England that they might be infected. In brief, the affected area 
in Building 37 v/as placed under quarantine, the diagnosis was confirmed by 
serology and virus isolation, the infected and known exposed animals were 



90 



sacrificed, a large number of mice housed nearby were vaccinated, a serologic 
monitoring program was initiated. A variety of other measures were talcen to 
prevent the virus from leaving Building 37 in animals or on inanimate fomites. 
No new cases of mouse pox have been detected since the disease was discovered. 
As a result of the outbreak, the NIH's policies governing the importation of 
mice and products of mice, including tumors, are undergoing revision. 

Salmonellosis was introduced into a room of guinea pigs in the National 
Institute of Dental Research (NIDR) in a shipment of Hartley guinea pigs from 
a commercial supplier. After the animals were received, NIDR was notified by 
the supplier that the animals might be infected. The guinea pigs were cultured 
and found to be infected with a Group B Salmonella sp. The animals were 
sacrificed. Thirty-one of the 100 cages of inbred guinea pigs in the same 
room were cultured and found negative. Follow-up testing was recommended, 
but has not yet been solicited. 

11. Animal Disease Investigation Service 

The Animal Disease Investigation Service was reorganized during the year to 
insure rapid response to requests. The number of calls made to the BID 
increased by 22 percent, from 150 to 183. 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. This service, well received by the BID investigators, gradually 
increased in scope. It has been mutually beneficial to investigators and to 
the VRB professional staff in providing an overview of laboratory animal 
facilities and practices at NIH. 

D. Problems 



Problems of Animal Disease are referred to in Part II, C, 10, a and b. 

There is a serious understaffing problem in spite of contracts initiated to 
reduce in -house production. Some sections are forced to rely on temporary 
employees to meet the work load. Temporary employees are concentrated in the 
cagewash unit of the Small Animal Section, creating severe shortages when they 
are terminated in June. As a resiilt of the manpower shortage, many employees 
are required to work unreasonable overtime and several necessary activities, 
such as increased inbred mouse production, were postponed. 

There was a large revolving fund deficit for rodent and rabbit production. 
This indicates the need for financing research and development, strain 
development, and genetic repository activities from sources other than 
animal issues. 

The contract supplier of Hartley guinea pigs was unable to supply animals to 
meet many requests by investigators. The colony was sold to another firm in 
the middle of the contract term. The original supplier was obliged to comply 
with the contract and continue production to meet NIH demands, but was 
usually unable to deliver animals requested. 



91 



A VEB employee retired on disability with emphysema which was claimed to he 
aggravated by the use of peracetic acid for disinfection of isolators and 
germfree equipment. Precautions are now taken to minimize exposure of 
employees doing germfree work to peracetic acid. 

Lack of adequate space for personnel and for efficient utilization of 
equipment continues to be the major problem facing the Media Unit. In spite 
of several attempts to renovate existing space, overcrowding prevents 
necessary expansion in media storage at cold room temperatures and further 
automation of tubing, bottling, and plate pouring operations. The increase 
in volume and complexity of individual requests for media makes additional 
space mandatory if these demands are to be met without greatly increased 
backlogs in production. 

Shortages of some material and supplies used daily in media production, and 
brought on by current shortages caused problems of varying degree . Agar 
supplies, for instance, have become very erratic and have made changes in 
production necessary to cope with the situation. 

The supply of membrane filters for sterilization of tissue culture media 
has become a problem due to difficulties in meeting the justification 
required by procurement for a membrane fulfilling the specifications needed 
for media production. 

The unit continued to have difficulty in supplying the daily demands for 
glassware trays for return of dirty glassware. Periodic repeat orders of 
300 new trays seem to relieve the situation for short periods of time, but 
demand still exceeds supply. During FY 1973 and 74-, 600 new trays were put 
into the system and plans to add 300 more trays are now being made. 

Transportation of glassware to the outlying buildings and return of dirty 
glassware for processing continues to be a problem. Irregular pickups of 
dirty glassware causes needless fluctuations in work load; some days almost 
no glassware is returned and on other days there is too much to be processed 
efficiently. On slow days new glassware must be placed into circulation to 
meet demands when a more regular rate of retiirn might conceivably lessen the 
need for endless supplies of new glassware, Recent publicity regarding the 
impact of the energy crisis on disposable types of glassware and plastic 
labware hopefully will increase awareness of researchers and elicit more 
cooperation. 

Availability of quality, blood group CEA 1, 2, & 3 negative, microfilaria 
negative, dysplasia-free dogs as additions to the breeding colony will 
continue to be extremely limited. The rigid selection requirements retard 
full development of the breeding colony. 

The sheep flock (donors and stock animals) is restricted from expanding to 
meet overall BID requirements because of the increasing numbers of sheep 
being housed for NHLI and NICHD programs. While the vast majority of the 
NHLI flock IS maintained under contract at Luray, Virginia, the NIHAC provides 
short-term housing for a substantial and increasing number of sheep coming 
from or returning to the -contractor and Bethesda. 



92 



While there appears to be a real need to provide facilities for breeding and 
holding swine, the BID's involved failed to provide sufficiently detailed 
POR's to enable the Section to formulate plans to meet the requirements. 

Establishment of two large pasture areas for goat and burro breeding is 
behind schedule due to design and contracting problems . 

While the supply of rhesus monkeys from India remained constant through 
FY 1974^ difficulties were experienced in obtaining adult females suitable 
as breeders. It was, therefore, necessary to purchase large stock (3.7 to 
4.6 kg) rhesus monkeys which are in reality subadults. Only 25 to 30 percent 
of the animals received are eventually selected as potential breeders, 
however, because each shipment of monkeys consists of 50 percent males and 
20-25 percent of the females are unsuitable. Consequently, in order to 
provide the Perrine breeding colony with 500 potential breeders (females), 
more than 2,000 monkeys must be processed. It has also been found necessary 
to condition large stock monkeys for 90 to 120 days prior to shipping to 
Perrine or issuing to BID's. As a result, space for quaranting small stock 
rhesus monkeys was restricted, and some BID's were required to use large 
instead of small monkeys. 

Contract prices for a variety of animals and products increased. The cost 
of random source foxhounds increased by a modest 4- percent, that of random 
source cats increased by 19 percent, and monkey costs increased by 30 percent 
for small and 36 percent for large stock rhesus. Feed costs escalated by 
30 percent for dog food, 20 percent for livestock grain concentrates and 
10 percent for monkey chow. 

E. Program Plans 

The program to free all rodent strains and stocks of disease through 
hysterectomy derivation will continue. Improved techniques will be developed 
for applying this practice to guinea pigs and rabbits. This requires a 
cooperative effort in areas of nutrition, microbiology, and genetics and 
development of methods for hand and foster nursing these species and for 
acclimating the animals to a pathogen-free environment . 

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, using YRB colonies as the genetic base. An improved quality 
control program for contract animals will be initiated. New strains of 
rodents will be added to the repository that have significant potential for 
research. The National Research Council has been- asked to establish criteria 
for evaluating the importance of maintaining each new strain. 

Studies to define the major nutrient requirements of different species and 
strains of inbred rodents will continue. It is essential to the establishment 
of SPF colonies of rabbits and guinea pigs that the present autoclavable 
rations for these species be improved. 

Availability of feed ingredients presently used in formulation of laboratory 
animal rations is a major concern. Accordingly, studies to evaluate some 
lower quality, more readily available Ingredients will be developed. 

93 



Efforts will continue to develop open formula rations purchaseable through 
advertised contracts to replace closed formula rations p^orchased through 
negotiated, sole source contracts. 

Continued expansion of the canine breeding colony hy purchase of quality dogs 
will be pursued. The feline breeding colony was relocated from Building T-8 
to Building 102. This move provides sufficient space in the former location 
to house a total of 160 bitches and their progeny. Contract production of 
purebred foxhound puppies (approximately 600 per year) will be continued. 

The dairy goat and burro breeding herds will be expanded during FY 1975 or 
as soon as appropriate fencing is installed around existing pasture land and 
shelters are erected. 

Further definition of the blood gi'oups of dogs in the canine donor and 
breeding colonies will be undertaken when "typing" antisera becomes available 
from outside sources. 

The feline breeding colony (approximately 20 cats) will fill special requests 
for defined cats, timed-pregnancies, and neonates. 

Emphasis on supplying the Perrine facility with a full complement of rhesus 
monkey breeding stock will continue. Anticipated achievement of this objec- 
tive is mid-FY 1975, when the NIHAC program will be readjusted to provide 
holding space for young monkeys produced by the Perrine facility, and for 
conditioning replacement breeding stock for both Perrine and contraGtor( s). 

Leasing 200 acres of pasture and several buildings adjacent to the Animal 
Center will provide space for sheep, swine, and biirros. Improvement of 
existing structures, installation of fences and purchase of temporary 
farrowing/swine holding buildings must be vigorously pursued if effective 
use is to be made of the property during FY 1975. 

In order to meet the increasing demands of the research community in the face 
of manpower reductions, continued efforts will be made to expand or improve 
automation. Improvements in the area of plate production of solid media are 
.needed to keep pace with increasing demand for this service. 

Continued efforts to expand quality control testing of all media will be 
concentrated in the area of automated testing of such parameters as glucose 
content, sodium ion concentration, etc. Extension of quality control testing 
to more bacteriologic media is planned as personnel and space needs are met. 

A concerted effort to locate a supplier of deionized water will be made this 
year. Due to manpower reductions, it is no longer possible for Glassware Unit 
personnel to keep up with the constant regeneration of the large mixed bed 
deionizers. 

The total impact of the energy shortage on plastic and disposable laboratory 
glassware is unknown and, therefore, its effect on program planning is 
difficult to predict. It seems logical that despite the promising immediate 
outlook for continued supplies, eventual shortages may occur. 

94 



Plans are underway to design and implement a new form for glassware issue to 
eliminate unnecessary paper work, provide information as to quantities and 
types of glassware issued and a record of glassware ordered for the requestor. 
Present methods do not give any permanent record of orders received. 

F. Publications 

Bohner, H.J. and Miller, C.E.: Studies on rearing the Hamster Germfree. In 
Heneghan, J.B. (Ed.): Germfree Research Biological Effects of Gnotobiotic 
Environments . New York, Academic Press, 1973, pp. 619-622. 

Ganaway, J.R. : Bacterial, mycoplasma, and rickettsial diseases. In Wagner, J. 
and Manning, P. (ed.): Biology of the Guinea Pig . New York, N.Y., Academic 
Press, in press. 

Ganaway, J.R., Allen, A.M., Moore, T.D., and Bohner, H.J.: Natural infection 
of germfree rats with IVbrcoplasma pulmonis . J. Infect. Pis . 127: 529-537, 1973, 

Goldman, P.M. and Moore, T.D.: Spontaneous Lancefield group G streptococcal 
infection in a random source cat colony. Lab. Anim. Sci . 23: 565-566, 1973. 

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 ., 2-4: 318-325, 1974. 

Knapka, J.J., Smith, K.P., and Judge, F.J.: Effects of open and closed formula 
rations on the performance of BALB/cAnN, C57BL/6N, and Swiss Mice. Lab. Anim . 
Sci . , in press. 

Moore, T.D., Allen, A.M., and Ganaway, J.R. : Latent Pasteurella pneumotropica 
infection of the gnotobiotic and barrier-held rats. Lab. Anim. Sci . 23: 
657-661, 1973. 

Potkay, S., Bacher, J.D., and Pitts, T.W. : Feline infectious peritonitis in a 
closed breeding colony. Lab. Anim. Sci . 2-4: 279-289, 197-4. 

Potkay, S. and Gilmore, J. P.: Autoregiilation of glomerular filtration in 
renin-depleted dogs. Proc. Soc . Exp. Biol. Med . 143: 508-512, 1973. 

Strandberg, J.D. and Goodman, D.G.: Animal Model: canine mammary neoplasia. 
Am. J. Pathol . , in press . 

Whitney, R.A., Jr., Johnson, D.J., and Cole, W.C.: Laboratory Primate Handbook . 
New York, Academic Press, 1973, 176 pp. 



95 



Serial No. DRS-VRB-1 

1. Veterinary Resources Branch 

2. Comparative Pathology Section 

3 . Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973 through June 30, 197^ 

Project Title: PATHOLOGY OF ADJUNCTr/E EFFECT OF IMMUNOSUPPRESSION AND 
THYMECTOMY ON CANINE PULMONARY ALLOGRAFTS 

Previous Serial Number: DRS-VRB-3 

Principal Investigator: Dawn G. Goodman 

Other Investigators: Richard Scott, NHLI 
Tom Bowles, NCI 
Glenn Gaelhold, NCI 
Paul Chretien, NCI 
Thomas Moore, DRS 

Cooperating Units: Surgery Branch, NCI 

Special Programs and Resources Branch, NHLI 

y^m Years : 

Total: 1.0 
Professional : . 5 
Others: .5 

Project Description: 

Objectives : To evaluate the role of thymectomy on decreasing the iminune 
response using the K-9 lung allograft as a model. 

Methods Employed : Dogs which are 4- years or older and weighing 15 kg. or more 
are used. Fifteen dogs have been thymectomized as puppies. Four groups of 
dogs are used: 

1. Controls — no immiinosuppression or thymectomy 

2. Standard immunosuppression (prednisone and azothioprine ) 

3. Standard immunosuppression plus thymectomy (performed at age 4--6 months). 

4. Thymectomy without immunosuppression. 

Ifejor Findings : There are difficiilties with surgical techniques and post- 
operative survival, particularly with the thymectomized dogs, which necessitate 
using larger numbers of dogs than previously anticipated. 

Proposed Coiirse : Continuation 

Honors and Awards : None 

Publications : None 



97 



Serial No. DRS-VRB-2 

1. Veterinary Resources Branch 

2. Small Animal Section 

3 . Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1973 through June 30, 1974 



Project Title: DIFFERENT LEVELS OF DIETARY PROTEIN FOR LABORATORY RATS 
Previous Serial Number: DRS-VRB-4 

Principal Investigators: Anton M. Allen 

Joseph J. Knapka 

Other Investigator: K.P. Smith 

Cooperating Units: Comparative Pathology Section, VRB, DRS 

J/fen Years: 



Total : 


1.0 


Professional : 


.5 


Other : 


.5 



Project Description: 

Objectives : To evaluate the effect of various levels of dietary crude 
protein on the reproductive performance, various physiological systems, 
pathology and longevity of noninbred 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 : Evaluation of reproductive data has shown a decrease in the 
level of dietary protein from 24 to 16 percent had no significant effect on 
the number of offspring weaned. Analyses of pathological data are presently 
in progress. 

Proposed Coiirse : Continuation 

Honors and Awards : None 

Publications: None 



98 



Serial No. DRS-VRB-3 

1. Veterinary Resources Branch 

2. Small Animal Section 

3 . Bethesda 



PHS-NIH 

Individual Project Report 

July 1, 1973 through June 30, 1974 

Project Title: GENETIC ANALYSIS AND ANIMAL MODEL DEVELOPMENT 

Previous Serial Nimiber: DRS-VRB-5 

Principal Investigator: C.T. Hansen 

Other Investigators: K.P. Smith 
W.J. Hinkle 
W.J. McEleney 

Cooperating Units: Laboratory of Bacterial Products, BoB 
Laboratory of Immunology, NIAID 
Laboratory of Pathology, GLC, NCI 



Man Years : 

Total : 

Professional : 
Others : 

Project Description: 



Objectives : 1 ) 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 and Major Findings : Comparisons of reproductive performance 
of 17 inbred strains of rats between conventional and SPF conditions show a 
20 percent average increase in the SPF environment over that of the conven- 
tional environment. The major difference between the two environments was a 
marked reduction in neonatal loss in the SPF environment . 

A study has been undertaken to determine if genetic variation still exists 
within long inbred strains of mice. The response to selection for increase 
in body weight between three and six weeks of age was compared in progeny 
produced by inbreeding and outbreeding within two inbred strains and one 
outbred stock. Sufficient results have not yet been accumulated to indicate 
any significant results . 

Comparison of tumor frequencies between conventional and SPF inbred strains 
suggests for the most part that establishing these animals in an SPF 



99 



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 manmary 
tumors occurs at a somev/hat 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 fonn of inheritance. A series of diallel crosses between 
a niimber 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 fifteenth generation. 
Sensitivity has increased to 85 percent in the sensitive strains and decreased 
to 3-5 percent in the 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 syston 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 has been established. This 
animal is very unique in that the thymus fails to develop with the result 
that half of the immune mechanism is absent. Tlie potential of this animal 
for immunological and cancer research is considerable. The project consists 
of two phases. First, to develop techniques and procedures for Iso'ge-scale 
production since It is extremely susceptible to various infections. Second, 
to establish this gene on a niimber 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. 

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. 

Proposed Course : Continuation 

Honors and Awards : None 

Publications : None 



100 



Serial No. DRS-VRB-4 

1. Veterinary Resources Branch 

2. Small Animal Section 

3 . Bethesda 



PHS-NIH 

Individual Project Report 

July 1, .1973 through June 30, 1974 



Project Title: DEVELOPMENT OF DIETS FOR LABORATORY ANIMALS 

Previous Serial Number: DRS-VRB-6 

Principal Investigator: J.J. Knapka 

Other Investigators: F.J. Judge 
K.P. Smith 



Cooperating Units: 


None 


Man Years: 




■ Total: 


2.0 


Professional : 


.5 


Others: 


1.5 



Project Description: 

Objectives : 1 ) To formulate and evaluate open formula rations designed to 
improve the nutritional status of laboratory animal colonies, 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 : Data have accumulated which indicate differences in crude 
protein and crude fat requirements between various strains of inbred mice. 
These data also show reproduction is not affected when the dietary crude 
protein level is reduced from 24 to 8 percent. A significant protein x fat 
interaction indicated maximum reproduction in mice colonies is dependent on 
the dietary ratio of these major nutrients rather than the concentration of 
each nutrient per se. 

The problems associated with ascorbic acid stability in autoclavable open 
formula guinea pig rations appear to be resolved. Guinea pigs have been 

101 



maintained on these rations for up to six months without showing any clinical 
signs of scurvy. Considerable progress has been made in the development of 
autoclavable open formula rations for rats, mice, and rabbits. 

Significance : The development of open formula rations for NIH production and 
research animal colonies is advantageous because l) production of rations is 
not restricted to a single mill in the event of a fire or bacterial contami- 
nation, 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 requirements of the strain of 
animal involved. 

Proposed Course : Continuation 

Honors and Awards : None 

Publications : 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/cAnN, C57BL/6N, and Swiss Mice. Lab. Anim . 
Sci. , in press . 



i 



102 



Serial No. DRS-VRB-5 

1. Veterinary Resources Branch 

2. Comparative Pathology Section 

3 . Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973 through June 30, 1974 

Project Title: TYZZER'S DISEASE 

Previous Serial Number: None 

Principal Investigator: James R. Ganaway 

Other Investigators: Anton M. Allen 
Thorns D. Moore 

Cooperating Unit: University of Kentucky (Dr. T.W. Swerczek) 

Man Years: 

Total: 1.0 
Professional : 1.0 
Others : . 

Project Description: 

Objectives : To characterize the etlologlc agent . To study the pathogenesis 
of the disease through experimental transmission studies. To recommend 
measures for the control and/or prevention of the disease . 

Methods Employed : Microbiology and pathology. 

Major Findings : The disease continues to occur enzootically In the NIH 
rabbit production colony. Studies designed to elucidate the biology of the 
etlologlc agent, Bacillus plllformls , continue. We have confirmed the 
diagnosis of Tyzzer's disease in foals, this being the first knowledge of 
the spontaneous occurrence of this fatal disease in this species (collaborative 
studies with Dr. Hall, University of Connecticut and Dr. Swerczek, University 
of Kentucky). We have Isolated the agent from the liver of a foal which died 
of the disease. The developmental and morphologic properties are similar to 
the agent Isolated from laboratory rabbits with Tyzzer's disease. Serological 
studies using the fluorescent antibody technique indicate that the Isolants 
from each of these two divergent species are closely related if not identical. 

Significance : This disease was known to occur only in laboratory mice prior 
to 1965. As a result of our having described this disease in epizootic form 
in the NIH laboratory rabbit colony and, further, by providing basic criteria 
necessary for diagnosis, the disease is presently recognized as a major cause 
of epizootic fatal disease in rats, mice, hamsters, gerblls, rabbits, cats, 
muskrats, wild hares, subhuman primates, and horses. Tyzzer's disease is 

103 



recognized as one of the major diseases of laboratory animals which complicates 
and interferes with biomedical research. 

Proposed Course : Continuation 

Honors and Awards : None 

Publications: None 



10^ 



Serial No. DRS-VRB-6 

1. Veterinary Resources Branch 

2. Comparative Pathology Section 

3. Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973 through June 30, 1974 

Project Title: A COMPARISON OF THE EFFECTIVENESS OF SUTURE MATERIALS ON 
BRONCHIAL STUMP CLOSURE FOLLOWING PNEUMONECTOMY 

Previous Serial Number: None 

Principal Investigator: Richard Scott, NHLI 

Other Investigators : Dawn G. Goodman 

Glenn Gaelhold, NCI 
Paul Chretien, NCI 

Cooperating Units: Surgery Branch, NCI 

Special Programs and Resources Branch, Division 
of Lung Diseases, NHLI 

Man Years: 

Total: 0.5 
Professional: .25 
Other: .25 

Project Description: 

Objective : To compare the effect of three types of suture material: silk, 
chromic gut, and wire staples on closure of the bronchial stump following 
pneumonectomy . 

Methods Employed : Random source dogs are used. Pneumonectomies are performed 
and the bronchial stump is closed with either silk, chromic gut, or wire staple 
sutures. The dogs are sacrificed 14- days postoperatively. The tensile strength 
of the suture line is evaluated. Then the bronchial stump is cultured for 
bacteria and evaluated histopathologically. 

Major Findings : Histopathologically, the wire staples were found to cause very 
little tissue reaction, the chromic gut to be intermediate and the silk to cause 
the most severe reaction at 14- days postoperatively. However, all three were 
equally effective in obtaining adequate closure of the bronchial stump. 

Significance: Suture materials have never been evaluated with regard to 
closure and healing in the bronchi. 

Proposed Course : Continuation 

Honors and Awards : None 

Publications : None 

105 



Serial No. DRS-VRB-7 

1. Veterinary Resources Branch 

2. Small Animal Section 

3. Bathe sda 



* 



PHS-NIH 

Individual Project Report 

July 1, 1973 through June 30, 1974 



Project Title: SELECTION FOR 6-WEEK WEIGHT IN INBRED AND 
NONINBRED STRAINS OF MICE 

Previous Serial Number: None 

Principal Investigator: K.P. Smith 

Other Investigator: C.T. Hansen 

Cooperating Units: None 

Man Years: 

Total: 1.0 
Professional: .5 
Others : . 5 

Project Description: 

Objectives : 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 
(C3H+/HeN and NGP) and one noninbred (GP). There are 72 mating pairs per 
strain. In each strain there are three groups: 1) 12 pair of brother x 
sister matings, 2) 24- pair of random matings, 3) 36 pair of random matings 
which are selected for six-week body weight. The experiment will include 
six generations . 

?ilajor Findings : Only the first generation has been completed. 

Significance : If it can be demonstrated experimentally that all of the 
genetic variation in a quantitative trait such as six-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 

Honors and Awards : None 

Publications : None 



106 



Serial No. DRS-VRB-8 

1. Veterinary Resources Branch 

2 . Veterinary Medicine and 
Surgery Section 

3 . Bethesda 

PHS-NIH 

Individual Project Report 

July 1, 1973 through June 30, 197-4 

Project Title: SODIUM CYMATE NEUROTOXICITY IN MA.CACA NEMISTRINA PRIMATES 

Previous Serial Number: None 

Principal Investigator: David K. Johnson 

Other Investigators: Robert A. Whitney, Jr. 
French Anderson, NHLI 

Cooperating Units: Section on Molecular Hematology, NHLI 

Man Years : 



Total : 


0.6 


Professional 


.3 


Others : 


.3 



Project Description: 

Objectives : Sodi\im cyanate is a potential chemotherapeutic agent for 
treating sickle cell anemia in humans. This study will evaluate alleged 
central neurological lesions caused by sodium cyanate in Macaca nemestrina . 

Methods Employed : Twelve pig-tail monkeys, Macaca nemestrina will be 
given deep intramuscular injections of sodium cyanate, four animals will 
receive sham injections, and four control animals will receive no 
injections. The total duration of the study will be 4- months. Following 
the test period, all animals will be humanely killed and perfused for 
neuropathological examination. During the course of the experiment, 
routine blood samples will be taken for hematological/serum chemistry 
evaluations which will be based on pre-experimentation baseline data. 

Major Findings : Currently unknown. 

Proposed Course : Completion by June 1974. 

Honors and Awards : None 

Publications : None 



107 



Serial No. DRS-VRB-9 

1. Veterinary Resources Branch 

2. Veterinary Medicine and 

Surgery Section 

3 . Bethesda 



PHS-NIH 
Individual Project Report 
July 1,1973 through June 30, 1974 



Project Title: ERYTHROCEBUS PATAS MONKEY AS AN ANIMAL 
MODEL FOR CARDIOVASCULAR RESEARCH 

Previous Serial Number: DRS-VRB-1 

Principal Investigator: David K. Johnson 

Other Investigators: Donald L. Fry, NHLI 

Cooperating Units: Section on Exprimental Atherosclerosis, 
ODIR, NHLI 

Man Years : 

Total: 0.3 
Professional: 0.2 
Other: 0.1 

Project Description: 

Objectives : 1 ) To determine the suitability of the patas monkey for 
atherosclerotic studies as they relate to humans. Positive findings would 
provide an animal model from an African source which could have better 
availability than Asian primates, and 2) To determine whether the patas 
monkey has advantages as an animal model for cardiovascular studies over those 
species presently available. 

Methods Employed : Fifty patas monkeys ( Erythrocebus patas ) were purchased 
and maintained on monkey chow for 4 months while base line data was obtained . 
They were then randomly divided into one group of 10 animals and two groups 
of 20. The group of 10 received monkey chow, one group of 20 received a 
semisynthetic diet with high fat and low cholesterol levels. The other group 
of 20 received a high fat and high cholesterol semisynthetic diet. Monthly 
blood samples are being drawn and a variety of hematological, serum chemical, 
and serum lipid data are being obtained. 

Major Findings : The test group of 20 patas monkeys in the high fat -low 
cholesterol diet had a rapid rise in their serum lipid profile which is 
persisting while being fed the atherogenic diet. The serum lipid profiles 
of the patas monkeys on the high fat-low cholesterol diet patterned the serum 
lipid profiles of the monkeys being fed the monkey chow, which is not varying 

108 



I 



from their baseline data. After 12 months on the test diets, one-half of 
each group was humanely killed and necropsies performed, with emphasis 
placed on the cardiovascular system. Atherosclerotic lesions were evident 
in the high fat-high cholesterol group in contrast to the other two groups. 
Further evaluations are in progress. 

Proposed Course : The balance of the patas monkeys are being maintained on 
the prescribed diets for a total of 2-4 months. Serum lipid fractionations 
are being accomplished to determine if the types and changes in lipid 
components are comparable to human atherosclerosis. Further definition is 
needed relative to lower cholesterol diet levels, exercise, hypertension, 
and other variables. Continued studies employing patas monkeys are 
forecasted as they show definite promise as a useful animal model for 
comparative athero jolerosis. 

Honors and Awards : None 

Publications: None 



109 



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