(BRP), DRR. This network offers a comprehensive set of tools
for table making, statistical analysis, graphing, curve
fitting, and mathematical and molecular modeling. Stimulated
by discussions of various groups within DRR, the GCRC Branch
and the BRP Branch initiated negotiations about implementing
a trial of the PROPHET System on GCRCs to evaluate further its
usefulness in analyzing data obtained in clinical investiga-
tion. Staff members of both branches are developing a request
for application (RFA) inviting GCRCs to apply for a PROPHET
System. Plans are to consider placing PROPHET terminals in
two GCRCs during the next fiscal year.
4. More innovative technologies should be introduced into core
laboratory facilities. Centers have recently encountered
difficulties in learning about and gaining access to the most
recent advanced technology applicable to clinical research.
Some of the technology is very expensive and requires
technical skills not usually acquired in the training and
experience of physicians. High pressure liquid chromatography
(HPLC) is one well-developed technology that is now becoming
widely applicable to clinical investigations, but which
because of cost and other factors is not readily available to
most investigators. It is appropriate for a core laboratory
resource because of its breadth of applicability to metabolic
studies of proteins, fats, steroids, drugs, hormones, and
metabolic intermediates. It provides advantages of high
specificity and short lag time, relatively low operational
expense, and absence of radioactive waste disposal problems.
5. The GCRC Program evaluated the feasibility of engaging in
several new technologies which could be important for clinical
research. For efficient review of these technologies, a
subcommittee was formed consisting of several members of the
GCRC Advisory Committee, with the collaboration of the Branch
Chiefs of the GCRC Program and the Biotechnology Resources
Program and some of their staff members.
One area which seems to be of great interest to the clinical
investigator is the use of stable isotope labeled compounds
analyzed by mass spectroscopy. The committee agreed to pursue
this area in close cooperation between the GCRC and the BRP.
Another area which may be important to clinical research,
which might need support, is neuropeptide analysis. :
I. There is a need to enhance the management of small scale
clinical trials, which in the forms of experimental
therapeutics may consist of as much as forty percent of the
research activity on GCRCs. Small trials, in contrast to
large ones, often have inadequate staff support, which
interferes with effective data collection and management.
This makes a lack of continuity and consistency in carrying
out tasks. A recently completed survey supported by an
evaluation contract to characterize clinical trials and to
determine the appropriate and needed resources to improve the
clinical trial capabilities of GCRCs is undergoing further
analysis to determine the best ways to improve clinical trial
capabilities of the GCRCs.
7. GCRCs constitute an exceptionally favorable environment for
developing clinical research investigators and sustaining
their continued pursuit of research careers, since they
provide a complete, well-regulated research and care system
for direct studies with patients. GCRCs can play an important
role in helping to meet the national need for well-trained
medical researchers. Bringing additional young investigators
into the research enterprise is part of this role. Retaining
already established and highly skilled researchers is another.
Many difficulties and disincentives are in the path of
medically trained personnel seeking long-term careers in
The GCRC Program staff and its advisors believe that
competitive grant programs which provide reasonable and stable
salaries for those interested in clinical investigation will
make this activity more attractive to talented physicians. In
1974, the Program initiated the CAP Program, which has been
highly successful in attracting capable young investigators
into academic positions in clinical research. It now seems
opportune to provide incentives to induce physicians
established in research careers to continue in
patient-oriented investigations. The target group would be
those who are accomplished, successful, peer-reviewed
scientists. Often these people are forced by the time demands
of teaching and patient care to concentrate their research
efforts on work which can be scheduled flexibly, such as
studies on small mammals or on cell-free systems. A program
is needed which would provide an incentive to capable clinical
scientists to concentrate their efforts on patient-related
Program Directors' Conference
A conference of Clinical Research Center Program Directors is planned
for December 1982. The meeting is to be a joint project of the
Clinical Research Center Program Directors Organization and the GCRC
Branch. The major topics, to be addressed in workshop format, are
Industry-Related Research, Collaborative and Cooperative Efforts Among
Centers, Promotion of Clinical Investigation, New Technologies for
Clinical Research, Organization and Operation of Research Centers, and
Diversification of GCRC Utilization.
The Program Staff believes that In-depth discussions of these issues
will help define the special problems, needs, and goals that apply to
human investigation in U.S. Medical Centers. This should lead to a
more efficient operation of existing Centers and contribute to the
growth and development of the program during the next decade.
Each year the projects on the Centers shed new light on a number of the
perplexing disease problems which are subjected to study. Examples of
these highlights follow:
New evidence indicates that some cancer cells change biochemically as
they develop, and that these changes correlate with increasing
virulence of the cancer and worsening of the prognosis. Initially, the
cells are homogeneous, or at least very similar, becoming more
heterogeneous as the disease progresses. The first practical
application of this finding has come in the counseling of some patients
with an inherited tendency to develop medullary thyroid carcinoma.
Homogeneous tumors are much less likely to spread widely and
aggressively than those with a mixture of cells with extreme
Reye' s Syndrome
Six children in four unrelated families developed during fasting a
severe illness characterized by hypoglycemia, coma, and other features
reminiscent of Reye's syndrome. The condition was due to a defect in
the children's ability to oxidize fatty acids, and was associated with
very low levels of carnitine, a co-factor for this process. The
discovery of this disorder raises the possibility that in some patients
Reye's syndrome is due to an inherited disorder of fatty acid
A similar disorder mimicking Reye's syndrome is caused by a defect in
the biosynthesis of carnitine itself. A dramatic improvement in this
condition has been obtained in a single patient treated with carnitine
therapy coupled to a low fat diet.
It has been suspected that mercury exposure represents a health hazard
of dental practice, but no analysis of the effects of chronic exposure
has been made. In a recent study it was found that dentists with high
mercury levels have a 30% incidence of polyneuropathies, while dentists
without detectable mercury levels have a zero incidence. Other health
complaints are also greater. Apparently the use of mercury as a
restorative material can result in a long-term health risk to
Normal parents of diabetic children sometimes have blood vessel changes
like those commonly found in adults with diabetes. When these changes
are present, the gene for human leukocyte antigen DR4 usually can be
found as well. This does not mean that any one gene causes diabetes,
but it suggests that a gene involved in diabetes is on the short arm of
the sixth chromosome, linked to the DR locus.
A rare defect in the metabolism of steroid hormones, preventing the
conversion of testosterone to androsterone , causes certain genetically
male children to be born with apparently female genitalia. Normal male
genitalia develop at puberty. Though raised as girls, these
individuals mostly develop normal male attitudes and normal sexual
orientation after puberty. Social adjustment can be difficult, but it
is often successful, refuting the widely-held idea that sexual identity
is established at a very early age and can never be changed.
The biochemical substances involved in producing sunburn in response to
ultraviolet light have been poorly understood. The sunburn reaction is
important because it may bear on skin cancer and premature aging, two
conditions associated with ultraviolet light exposure. Recent evidence
that histamine, which dilates blood vessels, increases four-fold in the
blood in response to sunburn, suggest that this substance may be the
initial mediator of the sunburn reaction. Later elevations in
prostaglandin E2 , a hormone released by most tissues of the body in
response to injury, suggest that prostaglandins may mediate later
phases of sunburn.
Functional Renal Failure
One of the most mysterious of the many causes of kidney failure is
"functional renal failure", in which it appears that blood flow is
shunted away from the kidney. Its most common and severe form occurs
in patients with liver disease. Studies in animals suggested that the
production by the kidney of thromboxane A-2 , a very potent
vasoconstrictor substance, may be involved in this disease. Studies in
humans had to await the development of specific radioimmunoassays,
worked out by GCRC investigators over a three-year period and validated
by a very specific mass spectrometer method at the GCRC-supported
'CLINSPEC facility. Studies utilizing these assays have produced the
exciting finding that urinary thromboxane is dramatically increased in
patients with this disorder, providing a clue to its etiology and a
lead to its possible therapy with inhibitors of thromboxane action.
It has been discovered that many asthmatics who believe they are
allergic to certain foods may actually be sensitive to a type of
chemical preservative. This preservative, called potassium
raetabisulf ite, is used to preserve a wide variety of foods and
beverages, from restaurant salads to wines. It has no effect on most
people, but in others it may precipitate an asthma attack so severe
that emergency treatment is required to restore breathing.
The way fat is distributed on the human frame appears to indicate the
degree of risk that people have of developing diabetes. Individuals
whose fat is distributed mostly above the waist are more likely to
develop diabetes than those who carry most of their excess weight in
the hips and thighs. The bigger the waist compared to the hips and
thighs, the higher the risk of developing diabetes. This pattern of
upper-body obesity is a clear marker of increased diabetes risk which
is easy to recognize and could be widely used to identify those
patients who should be carefully watched for early signs of this
It is generally believed that glucose intolerance, a decrease in the
body's ability to handle glucose, is an inevitable result of aging.
During the past year, however, it has been demonstrated that this
intolerance is markedly alleviated in non-obese, physically fit, active
older subjects. Thus, it may actually result from environmental
factors such as obesity and decreased activity, rather than from normal
aging. Since glucose intolerance may increase the risk of
atherosclerotic heart disease, the prevention of age-related glucose
intolerance by proper nutrition and exercise may provide an effective
way to reduce the frequency of heart attacks.
A very high incidence of severe infections, especially recurrent
pneumonias, occurs in Navajo infants. It has been found that these
infections result from a high incidence of severe combined
immunodeficiency in these children. Definition of this problem in the
Navajo population has allowed for the early recognition of the children
with this disorder, so that appropriate therapy can be initiated early,
preventing possibly fatal infections.
Fasting has been the most useful general test for the diagnosis of
hypoglycemia (low blood sugar), but may require 36-48 hours.
Administration of 2-deoxyglucose , a competitive inhibitor of glucose
transport which rapidly stimulates the hypothalamic response to
hypoglycemia, has been found to be as reliable as fasting in
distinguishing hypoglycemic children, and it has the advantage of not
producing symptoms associated with fasting.
Pheochroraocytomas are tumors of adrenergic tissues which secrete
hormones that cause severe symptoms, including hypertension. They are
fatal if not excised. These tumors are not rare - at least 100,000
Americans suffer their effects - but they are often difficult to
detect, even by sophisticated methods. A new radiopharmaceutical,
metaiodobenzylguanidine , concentrates in pheochromocytomas, allowing
their detection by a method called scintigraphy (mapping of the source
of gamma rays emitted by a radioisotope).
A number of patients with juvenile diabetes have been found to have
limited joint mobility because of an abnormality of connective tissue.
Subjects with this disability have more than three times the risk of
microvascular complications from their diabetes than do those without
it. Limitation of joint mobility thus identifies a population
excessively at risk for the development of these complications.
The use of heat guns by homeowners for do-it-yourself removal of old
paint can result in volatilization of lead in the paint and excessive
lead exposure. Physicians should be aware that lead poisoning can
occur from avocational pursuits as well as vocational ones, and should
maintain a high index of suspicion of the disease in patients
presenting with nonspecific complaints referable to the central nervous
and gastrointestinal systems.
A new radioimmunoassay for parathyroid hormone in plasma has been
developed by GCRC investigators. It is sensitive enough for
measurements in normal human beings and specific for the
biologically-active araino-terminal portion of the parathyroid hormone
molecule. This new assay represents a technical advance which will be
a major tool in studies of parathyroid function.
A method has been developed to desensitize persons who have asthma
induced by aspirin. This method is important because aspirin is
included in many drug preparations and cannot be easily avoided. Also,
many aspirin-sensitive persons are also sensitive to other
anti-inflammatory drugs, and some even to yellow food dye number 5;
recent studies suggest that desensitization to aspirin may also
desensitize patients to these other compounds.
A technique has been developed for inserting a shunt into the brain of
a fetus with incipient hydrocephalus, relieving excessive fluid
pressure which could damage the brain. Ordinarily, hydrocephalic
infants are treated by a shunt procedure performed after birth. In
many instances, however, such severe brain damage has already occurred
by the time of birth that the procedure only serves to facilitate
custodial care. The new technique could allow many of these infants to
develop more normally.
Between 1970 and 1978 the number of Cesarean sections nearly tripled,
rising from 5 to 15% of all deliveries. A new analysis and recent
research indicate that criteria for Cesarean section need not be as
rigid as they have been, and that the number of sections can be
reduced, especially when they are perfonned for dystocia (difficult
labor) or because of a previous section. On one GCRC, a newly
developed computer program allows diagnosis of the specific abnormality
causing dystocia; this abnormality can then be treated specifically,
often avoiding the requirement for a Cesarean section.
Ventricular fibrillation, a lethal complication of myocardial
infarction, is characterized by rapid, irregular heartbeats that
completely stop the pumping action of the heart. An automatic
defibrillator that can be implanted in patients who are at high risk of
developing ventricular fibrillation was successfully tested last year.
Now a way to implant the defibrillator without major chest surgery has
been devised, allowing the patient to leave the hospital in one week
rather than two or three. The cost of the implantation method is half
that of conventional surgery, and it frees the patients from the risk
of complications of major chest surgery, such as severe pain or partial
Researchers at a General Clinical Research Center have rehabilitated 12
of 14 victims of kwashiorkor, a severe illness caused by protein
malnutrition, which typically has a 50 percent mortality. Kwashiorkor
occurs most commonly among poverty-stricken children in underdeveloped
countries. Success of the therapy is attributed to prompt diagnosis
and treatment of complications that frequently develop during
Traditional therapy for patients with hormone-secreting pituitary
tumors has been surgery or radiation therapy. In most cases the
therapy has been empiric, based upon the preference of the physician.
In an effort to predict patients' subsequent response to therapy, a
large number of tests of pituitary function were conducted on a large
number of patients with hyperfunctioning pituitary tumors. The results
indicate that tumors secreting ACTH or growth hormone are best treated
by surgery, while those secreting prolactin are not. This means that
the choice between surgical and radiation therapies can be made by
determining the secretory properties of the tumor.
Luteinizing hormone (LH), one of the gonadotropic hormones which
control the functions of the gonads, is secreted from the pituitary
gland in pulses which have an optimum frequency. If attempts are made
to exceed this frequency by too-frequent injections of LH-releasing
hormone, the pituitary becomes refractory and eventually completely
unresponsive. This unexpected discovery has been exploited to develop
remarkably effective new treatments for precocious sexual development
in children and for infertility in men and women with subtle
Phenytoin, a drug widely used in the treatment of epilepsy, markedly
reduces the lesions of a severe and often fatal disease of the skin and
mucous membranes. Seventeen children with recessive dystrophic
epidermolysis bullosa, a genetic disorder characterized by severe
generalized blistering after minor wounds or even brief frictional
trauma, were found to respond to oral phenytoin with a 52 percent
decrease in blistering. No serious adverse effects of phenytoin were
observed. Phenytoin thus represents a therapeutic option of relatively
low risk in a disease for which there has been no rational therapy.
A new anti-arrhythmic drug, encainide, has proved much more effective
than previous treatments in suppressing a type of heart irregularity
called ventricular ectopic depolarization. The drug has largely been
ignored in clinical investigation because its half-life is short (3
hours) , but investigators have now found that the therapeutic index of
the drug is so high (i.e., it is so non-toxic) that it can be safely
given in large doses every 8-12 hours.
Instruments have been developed which allow bursts of laser energy to
be applied through fiberoptic endoscopes used for examining the
esophagus, stomach, duodenum, and colon. These bursts can be used to
produce coagulation of bleeding vessels in an ulcer or small vascular
tumors, or to destroy polyps (small nodules of the colon with the
potential of becoming malignant). The laser treatment can replace
abdominal surgery previously required for these conditions.
A method of intravenous injection of reserpine has been used to treat a
type of severe hand or foot ischemia (lack of blood flow) caused by
blood vessel spasm. The method allows prolonged contact of the drug
with sympathetic nerve endings, blocking their action for up to five
days. The procedure, which can be performed in an office or outpatient
clinic, produces relief of symptoms for one to two weeks.
Congenital Heart Disease
Propanolol is a drug commonly used to alleviate symptoms in children
with cyanotic congenital heart disease ("blue babies") until corrective
surgery can be performed on them. With the low doses of drug
recommended for children, however, therapeutic failures are common. It
has now been found that larger doses, similar to those recommended for
adults, can safely and effectively be used in children, producing a
better response rate.
The yeast Cryptococcus neoformans is the most common cause of fungal
meningitis. The disease is increasing in frequency because it tends to
occur in patients whose immune mechanisms are compromised, such as
transplant recipients and patients receiving cancer chemotherapy. Even
though the untreated meningitis is fatal, a modification of treatment
of its chronic forms has been developed that allows for patients to be
treated as outpatients after the first two weeks of therapy. This
results in a lowering of the average hospital cost to them from $12,000
Many children who have cholestasis (abnormal bile flow) since infancy
develop chronic vitamin E deficiency. This is manifest as a slowly
progressive central nervous system disease with poor coordination,
rapid eye movements, and decreased sensation. Since vitamin E is not
absorbed from the intestinal tract by these children, they must receive
it by injection; this results in improvement in their neurologic
disease, without obvious adverse effects.
Rapid progress has been made in recent years in the treatment of
diabetes, using programmable pumps which automatically inject insulin
subcutaneously . One new development in this field is the invention of
a miniaturized, implantable pump about the size of a cardiac pacemaker;
this can replace the bulkier, externally worn pumps now in common use.
Another development is the technique of intraperitoneal infusion, which
avoids the problems of intravenous lines and the uncertainties of
The hormone prostacyclin has been found to be a safe alternative to
heparin in preventing blood clotting in patients being dialyzed on an
artificial kidney. Moreover, prostacyclin may also increase the
efficiency of the dialysis.
During the past year, the GCRC Program has continued to receive
recognition as a vital component of the NIH clinical research effort.
Centers throughout the Nation have continued to celebrate their 20th
anniversaries with special events. These events have celebrated the
scientific advances made possible with program support and have
featured visits from distinguished scientists and Congressional
leaders. The following institutions have held ceremonies celebrating
their ZOth year with the Program: Johns Hopkins University, Baltimore,
Maryland; University of Southern California, Los Angeles, California;
Yale University, New Haven, Connecticut; Washington University, St.
Louis, Missouri; New York University, New York, New York; Duke
University, Durhman, North Carolina; University of Rochester,
Rochester, New York; Ohio State University, Columbus, Ohio; and
Vanderbilt University, Nashville, Tennessee.
The number of research societies and public boards supporting the
Program has increased. The National Diabetes Advisory Board has
continued its support and strong endorsement of the Program and the
National Digestive Disease Board has added its statement of support.
The American Federation for Clinical Research, the Endocrine Society,
the Society for Pediatric Research, the American Pediatric Society and
the Association of Medical School Pediatrics Department Chairmen have