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deposits of plaque in coronary arteries in the
treatment of coronary heart disease. First the Sec-
tion intends to connect a coherent-bundle fiber-
optic angioscope to a video system to allow
monitoring and recording of conditions in the
artery before and after laser treatment. This will
facilitate evaluations of the ability of various laser
sources to selectively ablate plaque with minimal
arterial damage. Carbon dioxide and argon ion
lasers have been used for laser surgery; they func-
tion by vaporizing matter. Another possibility,
which the Section will explore, is photochemical
decomposition of the deposits by ultraviolet radia-
tion from an excimer laser. NASA Goddard and
the NRL will provide laser sources not available at
NIH. The success of the laser ablation will be
evaluated by studying the thermal profile in
animal and cadaver arteries, following the laser
pulse, as well as by histopathological studies.
BEIB will use miniature thermistors and an infra-
red video system to measure the requisite thermal
profiles. The Section will then develop the system
for delivering laser energy to the desired sites in
coronary arteries, utilizing either waveguides or
fiber-optic light guides, depending upon the type
of laser selected.

In another electro-optic project, the Section
supported a study of cell fusion and aggregation
undertaken by researchers in NINCDS. BEIB
designed custom optics for a stop-flow apparatus,
as well as an interface for a PDP 11/34 computer
used in data acquisition and processing.

With the effort on the Neuro-PET (Neuro Posi-
tron Emission Tomography) scanner tapering off
sharply, as usage becomes routine, the Section
has redeployed those resources to another major
project: magnetoencephalography (MEG). In col-
laboration with the Medical Neurology Branch,
NINCDS, and the Naval Research Laboratory, the
Section has begun efforts to develop a system for



localizing epileptic foci in three dimensions. Long
experience has demonstrated that surface EEG
measurements are insufficient for this, largely
because of the insulating properties of the skull
and the difficulties of producing adequate
mathematical models. MEG, although a difficult
technique, is free of this problem and is capable
of localizing the site of auditory-evoked
responses.

EEG-based analyses of evoked potentials rely
heavily on time averaging, which is of little or no
use with epileptic discharges. To compensate for
this difficulty, the Section hopes to use concur-
rent EEG and MEG data, and it is exploring signal
processing techniques that can extract desirable
information from considerable background noise.
In addition, procurement of a seven channel array
is in progress; this device will further reduce the
need for time averaging.

Two new projects in collaboration with the
Laboratory of Technical Development, NHLBI, are
of particular interest. The first is a study of
fluoroimmunoassay techniques as an alternative
to radioactive and enzyme immunoassays.
Fluorescence techniques are simple, safe, and
convenient, but their sensitivity has been low
because of interference from the normal
background fluorescence of almost all organic
materials. Recently, rare-earth-chelate fluorescent
probes have been developed with decay-time con-
stants an order of magnitude greater than back-
ground time constants, affording in principle an
opportunity to increase greatly the sensitivity of
the method. Overload recovery of the detector is a
problem, however, and the solutions developed for
high speed, high fluorescence work do not ap-
perar to be satisfactory for the low speed,
ultralow-level requirements of this application.
EEES is conducting a broadly based study to
develop the detector and overload circuitry. The
Center for Disease Control, which is interested in-
the method as a tool for research into Acquired
Immunological Defficiency Syndrome (AIDS), is
providing support and collaborating on biochemi-
cal problems that appear at extremely low
chemical concentrations.

The other project, in which Corning Glass
Works is collaborating, is intended to incorporate
a miniature preamplifier into an otherwise or-
dinary specific-ion electrode. It is intended that
the resulting device can be used directly with
computerized digital data acquisition systems,
rather than with electrometers, allowing the com-
puter to handle calibration, temperature compen-
sation, and the like. This approach provides some
of the benefits that were generally expected five
years ago from a different technology— ion selec-
tive field-effect transistor (ISFET) electrodes— but
do not appear realizable in that way.



This past year, the ever increasing role of conn-
puters in biomedical research was reflected in the
incorporation of a microcomputer into the large
bus-oriented instrumentation system that BEIB
originally developed for a fermentation system in
NIADDK. The Section also interconnected a
custom flow cytometry cell (developed by BEIB's
ACES) to a computer, and developed requisite
software. Similarly, BEIB incorporated a computer
into an elaborate environmental monitoring and
control system for animal facilities of the DRS
Veterinary Resources Branch (Building 14) to meet
the specific needs of an NIAID research program.

As always, the Section continued substantial
effort on older projects, a variety of consultations,
and smaller new projects in such areas as video
systems, microprocessor-based instruments, data
acquisition systems, and controllers.

Several new developments promise to enhance
the capabilities of the Section. The EEES is begin-
ning to exploit the capabilities of a new digital
oscilloscope. This instrument has many desirable
features, such as storage, pre-trigger record, and
hard copy output, as well as many digital proces-
sing functions, such as spectral analysis, auto-
and cross-correlation, averaging, multiplication of
traces, convolution, and integration — all available
at the touch of a button. Because the instrument
is portable, engineers in the Section can easily
take it to labs where they can use it to experiment
easily with a variety of signal processing ap-
proaches; this is expected to be most helpful
during the definition phase of a project. EEES is
also acquiring a computer-based digital data ac-
quisition system, and in the coming year will in-
stall a work station for computer-aided design and
engineering. Initial capabilities of the system will
include electronic drafting, two-dimensional me-
chanical drafting, logic simulation, and automated
generation of wiring and parts lists.

Mechanical Engineering System (IVIES)

The Mechanical Engineering Section conducted
a wide diversity of collaborative efforts with
members of NIH's intramural research program,
involving analytical and experimental studies and
the development of specialized instrumentation. A
multi-year effort in collaboration with the Radia-
tion Oncology Branch, NCI, is making substantial
progress in the development of equipment and
protocols for regional microwave hyperthermia,
used as an adjunctive treatment for cancer. The
goal is to gain better understanding of elec-
tromagnetic and thermal processes in tissue and
to improve the efficacy of systems under develop-
ment. In order to determine patterns of energy
deposition in tissue, the group has used a large-
scale computerized "block model" of man, as well
as various types of electric field and temperature



probes in conjunction with various microwave
applicators.

The Section has shown that some hyperthermia
protocols, developed elsewhere, can cause unde-
sirable heating outside of an intended region in a
patient's body. In addition, the Section has
developed new types of phantom materials to
simulate the microwave properties of tissue, and
it is developing a new biomass and heat transfer
model that accurately incorporates the effects of
blood flow. The MES anticipates that the integra-
tion of these experimental and analytical efforts
will culminate in the development of a clinical
system, using computer-controlled protocols,
within the next two years.

The Section continues its innovations in bio-
mechanics. It has coupled a theory of the pro-
pagation of pressure pulses in arteries with a
mathematical model of the left ventrical, allowing
studies of the interaction between the two
systems. In work with the Hypertension-Endocrine
Branch, NHLBI, analysis of clinical data on the
pulse wave in the brachial artery has resulted in
improved understanding of the mechanics of
vasoactive responses in both normal and hyper-
tensive patients. A mathematical model of
arteriolar contraction was developed to study the
mechanism of reduction in lumenal area, taking
into account certain properties of endothelial
cells. Moreover, a new study aimed at assessing
the role of vascular tortuosity in vascular
resistance was undertaken, using both theoretical
and physical models. In the area of cochlear pro-
cessing, the Section collaborated with the Mathe-
matical Research Branch, NIADDK, to complete a
theoretical model for the ear incorporating basilar
membrane motion, couplings between fluid and
cilia, and hair cell transduction.

Last year the Section developed an improved
version of the toposcopic catheter— a device that
moves through blood vessels with minimal fric-
tion. The new implementation is easier to use and
can deliver high flow rates, such as those re-
quired in a clinical protocol under way with the
Diagnostic Radiology Department, CC. In a col-
laboration with the Department of Gastroen-
terology, Naval Medical Command, Bethesda,
Maryland, the Section has adapted the catheter
so that it can fit through a duodenoscope used
for endoscopic retrograde cholangiopancreatog-
raphy (ERCP) and other clinical procedures of the
gastrointestinal tract. The catheter was honored
with a 1984 l-R 100 Award, presented by Research
& Development magazine. The Section is also
developing the capability of extruding miniature
tubing with various cross sections.



Collaboration with the Laboratory of
Biophysics, NINCDS, to develop a miniature
microtonne that fits inside a scanning electron
microscope continues to make progress. It cur-
rently produces slices .5 microns thick; a version
under development is expected to produce slices
only .1 micron thick.

Other work on instrumentation involves an
ultrasonic system for assessing ventricular
contractility, automated measurements of turbidi-
ty in bacterial cultures in situ, a suction probe for
surgical transection of the liver, and improved
means of monitoring cerebral blood flow during
and after surgery.

Analytical Methods Group

Members of the Analytical Methods Group con-
tinue to develop advanced physico-chemical
methods for identifying, characterizing, and quan-
titating a large variety of constituents making up
complex biochemical and biological systems. Re-
cent work has included the development of tech-
niques to fractionate complex chemical species
of biologically important elements, using
chromatographic methods, and then to quantify
these species using electrothermal atomization
and atomic absorption spectrophotometry. The
Group can also apply the techniques of neutron
activation analysis when it is necessary.

This work has emphasized quantitation of com-
plex chemical species of metallic elements pre-
sent in trace concentrations. Moreover, the
biological samples themselves are often less than
one gram. Most of the projects are conducted in
collaboration with investigators in the National
Institute of Dental Research (NIDR), National
Institute of Mental Health (NIMH), National In-
stitute on Alcohol Abuse and Alcoholism (NIAAA).
NCI, and NHLBI,

The Group has been studying the quantitative
distribution of chemical species of cis-platin, a
drug used in cancer treatment. Transformations
among various species occur slowly; physicians
may be able to use this behavior to obtain re-
duced toxicity with the drug.

Collaboration with NIMH and NIAAA is continu-
ing on the determination of very low levels (10 g/g)
of vanadium in the blood and cerebrospinal fluid
of normal volunteers and patients with manic-
depressive behavior.

Further, in collaboration with researchers at the
Oscar Lambret Cancer Treatment Center in nor-
thern France, the Group is characterizing the
kinetics and uptake of trace levels of platinum
complexes in cultures of human respiratory tract
tumors. In some cases, where local concentra-
tions are sufficiently high, use of a microprobe
has permitted analysis of elements localized in
subcellular structures. This work has been con-



ducted in collaboration with investigators in NCI,
NHLBI, NIMH, and NIAAA.

In collaboration with the NHLBI and NIMH, the
Group has established a Secondary Emission
Mass Spectrometer (SEMS) system used to study
particle-induced ionization of biological com-
pounds. The Group has also studied the energe-
tics of various organic compounds in relation to
the different experimental conditions that occur in
organic Secondary Ion Mass Spectrometry
(organic SIMS). The data reported on the energy
distribution of secondary organic ions are an im-
portant contribution to the understanding of the
mechanisms by which bombarding particles
ionize labile compounds. In collaboration with
NIMH, the Group has used SEMS to study metab-
olites in brain tissues that play an important role
in drug-induced parkinsonism. These studies used
the techniques of SIMS/MS to confirm proposed
conversion of the drug MPTP into MPP in the
brains of monkeys.

The Group proposes to modify the SEMS
system to enable it to obtain spatial distributions
of organic materials in biological specimens. This
so-called "molecular microscope" will employ an
ion microprobe as a primary beam and an MS/MS
system for mass analysis. The computer system
for controlling the microprobe and data acquisi-
tion is under development. The Group believes
that imaging of organic compounds in biological
specimens by this method has the potential to
become a major analytical tool.

In a collaborative study with NINCDS, the
Group has completed a study using analytical
ultracentrifugation in an investigation of the
thermodynamics of the association of the A and
B chains of ricin, and extremely toxic plant pro-
tein used in the chemotherapy of leukemia. The
correlation of the thermodynamics of the chemi-
cal association and toxic activity of the protein
has also been studied. In addition the Group is
also involved in collaborative studies with NIDR
on the interactions of proteins involved in blood
clotting and fibrinolysis.

Electron Beam Imaging and Microspectroscopy
Group

In the past year the Group has been applying the
computer-controlled analytical electron micro-
scope and microprobe to a number of collabora-
tive projects, as well as continuing to improve ex-
perimental and computational methods. In par-
ticular, a new cryotransfer sample stage for the
analytical electron microscope (AEM) has allowed
examination of frozen dehydrated and hydrated
cryosections at -160 (degrees) C. This technique is
important in helping to preserve elemental
distributions during preparation of tissue sections.



10



Moreover, numerous software developments
have taken place in the processing of elemental
images: Electron energy-loss mapping (EELS) is
now quantitative; the Group has established con-
ditions for optimizing detection limits; and a
detailed analysis has been made of the system-
atic and statistical errors in background fitting for
the energy loss spectrum at each pixel in an
image.

In collaboration with the Laboratory of Neuro-
biology, NINCDS, the Group is studying the distri-
butions of potassium and calcium in rapidly
frozen rat cerebella, with the aim of determining
how they change following trauma. These are the
first direct confirmations of movements of sub-
cellular potassium and calcium in traumatized
tissue. The collaborators are producing elemental
maps of synaptosomes derived from cholinergic
endings of squid optic lobe. A bimodal distribu-
tion of potassium is found in this case, indicating
that only a fraction of synaptosomes are physi-
ologically equivalent to the cholinergic endings in
whole cells.

In a collaboration with the Laboratory of Oral
Biology and Physiology, NIDR, the Group has
made a study of mouse mandibular condyle in
order to determine the role of matrix vesicles in
cartilage mineralization. High calcium concentra-
tions were found inside vesicles in the mineral-
ization zone, but vesicles nearer the surface con-
tained little of the element, indicating that the
latter may be involved in processes other than
mineralization.

In collaboration with the Pathology Branch,
NHLBI, the Group has obtained EELS images and
energy dispersive x-ray spectroscopy (EDS) im-
ages of lung macrophages lavaged from patients
exposed to coal dust and silicates. The Group is
quantifying these images to determine statistical
information about the frequency and sizes of
inclusions.

In collaboration with the Department of Phar-
macology and Experimental Therapeutics, Univer-
sity of Maryland, elemental distributions are being
obtained from beta cells of the rat pancreas in
order to understand further the process of insulin
secretion. Nitrogen images show the presence of
nucleotides and proteins, while sulphur maps
reveal the distribution of insulin concentrated in
the secretory granules. Certain granules also con-
tain calcium, believed to be involved in the secre-
tion process.

Collaboration has continued with the
Laboratory of Central Nervous System Studies,
NINCDS, on a study of the role of elements such
as calcium, aluminum, magnesium, and phos-
phorus in the development of amyotrophic lateral
sclerosis (ALS), parkinsonian dementia, and
Alzheimer's premature senile dementia. A pre-
liminary study of the distribution of calcium in



gerbil hippocampus after induced ischemia has
begun with the Laboratory of Neuropathology and
Neuroanatomical Sciences, NINCDS.

In both of these collaborations, quantitative
elemental x-ray maps of the elements of interest
have been produced using the Cameca MBX
microprobe. Two major improvements in the com-
puterization of the microprobe have increased the
efficiency of the data acquisition. Additional hard-
ware has enabled simultaneous acquisition of up
to four fully background-corrected x-ray maps us-
ing an energy dispersive detector under control of
acquisition software written by members of
DCRT's Computer Systems Laboratory. The se-
cond improvement consists of software to focus
dynamically two wave-length-dispersive spec-
trometers during data acquisition. Simultaneous
with the EDS maps, two WDS elemental maps
may now be acquired at low magnification (lOOx).
This permits surveys of areas of up to 1mm by
1mm with no artifacts in the images due to
background or spectrometer defocusing.

In other work related to image processing,
members of the Group have completed work on
the theory of quantitation limitations imposed by
background radiation in positron emission tomog-
raphy. They have now begun work on the sen-
sitivity of fluorodeoxyglucose models to noisy
data.

Nuclear Magnetic Resonance Imaging Group

Advances have taken place on several
fronts— one of the most satisfying being the suc-
cessful installation of commercially produced
imaging equipment in the Diagnostic Radiology
Department CC.

Because of the amount of steel in the floor of
the NMR suite, the magnet's manufacturer could
only attain a field homogeneity of 100 ppm over a
30 cm diameter, even though the specifications
called for 10 ppm. By placing small quantities of
steel inside the bore of the magnet in a manner
calculated by the Group, it was possible to attain
the specification and ensure the optimal function-
ing of the device.

Considerable controversy exists in the NMR im-
aging community over the question of whether
there is an optimal field strength at which to im-
age. By developing bench techniques for measur-
ing signal-to-noise ratios and power absorption at
various frequencies, the group is beginning to pro-
duce much-needed experimental data that will
help to clarify the situation.

A collaboration with investigators at the Johns
Hopkins University has produced a means of ob-
taining a highly selective inversion of nuclear spin
populations of considerable importance in spec-
troscopy. This unusual result, achieved through



11



the use of a complex hyperbolic secant puis, is
only the second know analytical solution of the
nonliner differential equations that govern NMR
phenomenon. Moreover, above a critical threshold,
population inversions appear to be independent of
irradiating power.

In another development, the Group has suc-
cessfully tested a novel probe design that in-
creases signal-to-noise ratios by 40 percent, while
reducing transmitter power requirements by a fac-
tor of two. The group also extended the upper fre-
quency limit of head coil design from 84 MHz to
130 MHz with the aid of a phased-array receiving
coil.

Scientific Equipment Services (SES)

SES is continually updating equipment and serv-
ices provided to keep abreast of changing
technology. For example, a second numerically-
controlled milling machine has been purchased
which will permit rapid fabrication of unusually
shaped molds used by BEIB's Plastics Unit.
The Scientific Equipment Rental Program
(SERP) has expanded the variety of instruments it
provides, such as microcomputers that can con-
trol other laboratory instruments. SERP has also
instituted procedures that will permit researchers
to exchange instruments that are no longer need-
ed for credit against future rentals.



12



Publications

Andrews, S.B., Leapman, R.D., Landis, D.M.D., Fiori, C.E., and
Reese, T.S.: Elemental distribution in rapid-frozen cerebellar
cortex. J. Cell Biol, (in press).

Arbeit, J.M., Lees, D.E., Corsey, R., and Brennan, M.F.: Resting
energy expenditure in controls and cancer patients witti
localized and diffuse disease. Ann. Surg. 119:292-298, 1984.

Armand, J. P., Macquet, J. P., and LeRoy, A. P.: Cerebrospinal
fluid-platinum kinetics of cisplatinum kinetics of cisplatin in
man. Cancer Treat. Rep. 67:1035-1037, 1983.

Armand, J. P., Macquet, J. P., and LeRoy, A. P.: Pharma-
cokinetics of cisplatin in CSF of man. In Hacker, M.P.,
Douple, E.B. and Krakoff, I.H. (Eds.): Platinum Coordination
Complexes in Cancer Ciiemotherapy. Boston, Martinus
Nijfioff Publishing, 1984, p. 142.

Boretos, J.W. and Eden, M. (Eds.): Contemporary Biomaterials:
Material and Host Response, Clinical Applications. New
Technology and Legal Aspects. Noyes Publications, Park
Ridge, NJ, 1984, 673 pp.

Bryne, J., and Tozeren, A.: An index for the bladder contrac-
tility. Am. J. Physiol. 243:R673-677, 1983.

Chadwick, R.S.: Mechanics of arteriole contraction.
Preceedings of the 4th International Conference on
Mechanics in Medicine and Biology, Buffalo, (in press).

Chadwick, R.S., and McGuire, D.A.: Contraction of the left
ventricle against an arterial system with propagating pulse
waves. Proceedings of the Vlth International Conference
and Workshop of the Cardiovascular System Dynamics
Society, Philadelphia (in press).

Chen, C-N., Hoult, D.I., and Sank, V.J.: A parallel algorithm for
rotating frame zeugmatography. Magn. Reson. Med.
1:354,1984.

Chen, C-N, Hoult, D.I., and Sank, V.J.: Quadrature detection
coils - a further v'2 improvement in sensitivity. J. Magn.
Reson. 54:32, 1983.

Corsey, R.: Electrical safety of investigational and research
devices. Hospital Electrical Safety: A Reevaluation, AAMI (in
press).

Curt, G.A., Grygiel, B.J., Corden, B.J., Ozols, R.F., Weiss, R.B.,
Tell, D., Myers, C.E., and Collins, J.M.: A phase I and
pharmacokinetic study of carboplatinum (CBDCA) NSC
241240. Cancer Res. 43:4470-4473, 1983.

Dedrick, R.L.: Applications of model systems in pharma-
cokinetics. In Silvers, A., and Newell. G.W. (Eds.): New
Directions for Human Risk Assessment, Vol. 2, Toxicokine-
tics in Risk Assessment. Pala Alto, CA, Electric Power
Research Institute (in press).

Dedrick, R.L.: Applications of model systems in pharmaco-
kinetics. Proceedings of the Banbury Conference: Human
Risk Estimation (in press).

Dedrick, R.L, Flessner, M.F., Collins, J.M., and Schultz, J.S.:
A distributed model of peritoneal transport. Proceedings of
the III Symposium on Peritoneal Dialysis (in press).

Dedrick, R.L, Oldfield, E.H., and Collins, J.M.: Arterial drug


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Online LibraryNational Institutes of Health (U.S.) Division of RAnnual report : National Institutes of Health. Division of Research Services (Volume 1984 pt.A) → online text (page 2 of 5)