PDGF-D, a new protease-activated growth factor.

Platelet-derived growth factor (PDGF) has been directly implicated in developmental and physiological processes, as well as in human cancer, fibrotic diseases and arteriosclerosis. The PDGF family currently consists of at least three gene products, PDGF-A, PDGF-B and PDGF-C, which selectively signal through two PDGF receptors (PDGFRs) to regulate diverse cellular functions. After two decades of searching, PDGF-A and B were the only ligands identified for PDGFRs. Recently, however, database mining has resulted in the discovery of a third member of the PDGF family, PDGF-C, a functional analogue of PDGF-A that requires proteolytic activation. PDGF-A and PDGF-C selectively activate PDGFR-alpha, whereas PDGF-B activates both PDGFR-alpha and PDGFR-beta. Here we identify and characterize a new member of the PDGF family, PDGF D, which also requires proteolytic activation. Recombinant, purified PDGF-D induces DNA synthesis and growth in cells expressing PDGFRs. In cells expressing individual PDGFRs, PDGF-D binds to and activates PDGFR-beta but not PDGFR-alpha. However, in cells expressing both PDGFRs, PDGF-D activates both receptors. This indicates that PDGFR-alpha activation may result from PDGFR-alpha/beta heterodimerization.

Gene expression analysis by transcript profiling coupled to a gene database query.

We describe an mRNA profiling technique for determining differential gene expression that utilizes, but does not require, prior knowledge of gene sequences. This method permits high-throughput reproducible detection of most expressed sequences with a sensitivity of greater than 1 part in 100,000. Gene identification by database query of a restriction endonuclease fingerprint, confirmed by competitive PCR using gene-specific oligonucleotides, facilitates gene discovery by minimizing isolation procedures. This process, called GeneCalling, was validated by analysis of the gene expression profiles of normal and hypertrophic rat hearts following in vivo pressure overload.

Concomitant administration of recombinant human interleukin-2 and recombinant interferon alpha-2A in cancer patients: a phase I study.

Twenty-seven patients with metastatic cancer were treated with a daily continuous intravenous (IV) infusion of recombinant human interleukin-2 (rhIL-2) along with daily intramuscular recombinant interferon-alpha-2a (rIFN-alpha-2a) 4 days per week for 4 weeks with repeated treatment after 2 to 4 weeks of rest. The maximum-tolerated dose (MTD) was 3 million U/m2/d of rhIL-2 with 5 to 10 million U/m2/d of rIFN-alpha-2a. The dose-limiting toxicities are moderate hypotension requiring low doses of pressors and chronic fatigue associated with decreased performance status. Other common side effects included fever, chills, fluid retention, nausea/vomiting, erythrodermia, weight loss, elevated liver transminase levels, anemia, thrombocytopenia, and CNS toxic effects. There were seven objective responses among 25 evaluable patients. Four major responses (one complete response and three partial responses) were observed among 10 patients with melanoma treated with the MTD level. These data suggest that for cancer patients, concomitant rhIL-2 and rIFN-alpha-2a therapy is tolerable and has manageable side effects. Further phase II studies will be needed to define the antitumor activity of this combination.

Modularity of the slit protein. Characterization of a conserved carboxy-terminal sequence in secreted proteins and a motif implicated in extracellular protein interactions.

Since our characterization of the slit cDNA sequence, encoding a protein secreted by glial cells and involved in the formation of axonal pathways in Drosophila, we have discovered that the protein contains two additional sequence motifs that are highly conserved in a variety of proteins. A search of the GenPept database with the 73 amino acids at the carboxy terminus of slit revealed that this region contains significant similarity to a carboxy-terminal domain found in six other exported proteins. This observation has allowed us to define a new carboxy-terminal protein motif. In addition, comparisons with a 202 amino acid domain residing between epidermal growth factor (EGF) repeats in slit shows this region to be conserved in laminin, agrin and perlecan and, strikingly, also to lie between EGF repeats in both agrin and perlecan. Our analysis suggests this motif is involved in mediating interactions among extracellular proteins. Consistent with our previous characterization of the slit protein, both new motifs are found only in extracellular proteins. The identification of these two conserved motifs in slit reveals that the entire 1469 amino acids of the protein are made up of modular regions similar to those conserved in other extracellular proteins.

Addicted and nonaddicted drug users. A comparison of drug usage patterns.

Adetailed analysis of drug usage patterns of 101 multidrug-using soldiers disclosed little differentiation between individuals with a history of heroin addiction (N=68) from demographically similar multidrug-using (but nonaddicted) peers (N=33). Prior to the onset of herion addiction, relatively few differences in drug usage patterns emerged between the two groups, and what differences there were indicated more extensive drug use and a more rapid progression of drug use among the nonaddicted users. A "stepping-stone hypothesis" of heroin addiction is refuted by these data. Differences in drug use emerge after the intiation of heroin. Within a few months after first heroin use, those who did not become addicted returned to their preheroin experimentation levels of drug taking while the addicted group maintained an escalating pattern of opiate use.

Suicide in the U.S. Army: epidemiological and periodic aspects.

An overview of suicide in the U.S. Army is presented in two sections: (1) the epidemiology of U.S. Army suicides, based on biennium reports, and (2) the temporal aspects of those suicides compared with the data for the United States as a whole. A brief historical review documents some of the changes in contemporary military suicide rates compared to those of the past century. The cycles in the number of suicides by day of the week, day of the month, and the month of the year for the U.S. Army are computed and contrasted with those reported for the U.S. resident population.

Witnessed suicides.

Suicides that take place in the presence of others have not been the topic of systematic scientific inquiry. The so-called witnessed suicides account for a small percentage of all suicides but offer a unique view into the dynamics of self-destructive behavior. An epidemiologic and forensic description of 50 witnessed suicides drawn from a 15-year series of over 1,000 cases is presented. A taxonomy is developed based on the role played by the witness and related to previous work on self-destructive behavior and its motivation. Brief vignettes are used to illustrate some of the interpersonal dynamics associated with these deaths.

The Army psychological autopsy: then and now.

The conduct and reporting of an Army psychological autopsy is a complex and relatively infrequent event. The details of these reports may not be completely clear to the behavioral sciences personnel tasked with collecting the data. This paper reviews the current status of the Army psychological autopsy and contrasts it with the development of civilian psychological autopsies. The current thinking of the Department of Defense Health Affairs working group on psychological autopsies is presented. The epidemiological content of the Army psychological autopsy as a scientific resource is presented in the form of an analysis of the psychological autopsies for the 1995 Army suicide data. Suggestions for updating this unique command tool are included.

Parasuicidal behavior on an active duty army training post.

The incidence of suicidal behavior among active duty Army personnel at a training post has not been the subject of analysis since the advent of the all-volunteer military. A review of admissions over 16 consecutive months showed most of the behaviors to be parasuicidal, with low levels of lethality and high rescuability. Compared to previously published studies, the characteristics of these soldiers are little changed over the past 25 years. This report suggests a standard method for handling suicidal behavior which includes an active role for psychiatric consultation to units and commanders.

Compliance with consultations in a military psychiatry clinic.

The study was undertaken to determine the effect of increased information in the referral process on compliance in routine consultations to a military outpatient psychiatry clinic. To evaluate the potential beneficial effects of facilitating factors in a clinic with over 70% baseline compliance, the psychiatrist's name and information about the clinic was provided to one-half of all patients who presented with a routine consult during a 2-month period. There was no increase in compliance rates for patients who were given more than standard information. These results have impact on manpower and staffing issues for the military.

Ambulatory mental health services at a U.S. Army combat support post: the effects of the Persian Gulf War.

A study of ambulatory mental health services on a U.S. Army post where logistic support personnel are stationed compared utilization of psychiatric services before, during, and after the Persian Gulf War. Rates were calculated for service utilization for the at-risk groups from consecutive cases presenting at the post's ambulatory mental health services in the Department of Psychiatry. Our findings include a high rate of dysfunction for soldiers in training during the war; significant age, race, and sex differences between utilizers and non-utilizers throughout the study period; increased routine evaluations for military schools following the war; and significant increases in utilization of services by identified high-stress units during this conflict. Rates of utilization for a combat support post can be used for resource allocation and have implications for mental health manpower planning and stress prevention.

Use of inpatient psychiatric services on a U.S. Army combat support post during Operations Desert Shield and Desert Storm: the stress of non-deployment.

We studied the utilization of inpatient psychiatric services during Operations Desert Shield and Desert Storm (the Persian Gulf War of 1990-1991) on a U.S. Army combat support post. Inpatient psychiatric admissions and dispositions for the post's catchment area were tallied before, during, and after Operations Desert Shield and Desert Storm. Subjects included active duty soldiers (deployed soldiers were not studied while they were away from the post), their families, and retirees. Overall, there was no increase in psychiatric hospitalizations for active duty soldiers, their family members, or retirees. However, coincident with the return of soldiers from Operations Desert Shield and Desert Storm, the psychiatric proportion of all hospitalizations increased in the subpopulation of soldiers not deployed who had served less than 1 year. These soldiers in training may be more susceptible to increased stress levels associated with the return of soldiers from war because of their inadequate group bonding.

Suicide in United States Army personnel, 1985-1986.

A sixth biennium of epidemiological data on suicide in the U.S. Army was compiled. The annual crude suicide rate per 100,000 soldiers-at-risk for 1985-1986 was found to be 13.8, an increase of 3.8 points from 1983-1984. Sex-specific, race-specific, age-specific, grade-specific, and marital-status-specific rates were studied, and can be compared with the same indices in the previous six biennia. The standardized mortality ratio was calculated for 1986 and was found to be 69, significantly lower than the 100 expected from a civilian population of the same size and age-sex-race composition as the U.S. Army. Demographic data and information on circumstances surrounding the suicidal act were also made available for comparison with previous data. Analysis of the suicidal person's psychosocial situation (as reflected in the kinds of personal problems recorded in the reports and investigations of the incident and as reflected in assessment made of the victims presuicidal "motivational state") showed remarkable constancy in the five time periods studied, and indicates a powerful, consistent association between a dyadic love-object relationship in total collapse and the completed suicide.

Desert Shield deployment and social problems on a U.S. Army combat support post.

We undertook a study of selected mental health-related services at a combat support post to determine if stress levels surrounding Operations Desert Shield/Desert Storm had an effect on the utilization of these services. Our measure was the problem rate formed by adding the visits to the alcohol and drug service and the social work service. The findings (not all of which reached statistical significance in our small study) were that the problem rates were higher in those units which deployed, both before and after deployment. The pre-deployment differences in age, rank, and race between those soldiers deployed and not deployed is a finding which may help to account for the difference between units. There was a transient, but not sustained, problem rate increase immediately following return home for those units which deployed. Implications for mental health-related services staffing and directions for further research are discussed.

Mobilization and rejection of Individual Ready Reserve personnel in Operations Desert Shield/Storm at a U.S. Army Quartermaster post.

The individual Ready Reserve (IRR) is an important component of the U.S. Army's total combat force. After Operations Desert Shield/Storm, we investigated the mobilization of soldiers with combat service support specialties from the IRR to a quartermaster training post. In the initial 2 weeks of activation prior to assignment and deployment, the soldiers went through medical and administrative screening, and general and specialized military training. During this period, a sizable portion (one-quarter) of IRR troops who reported to duty were rejected for a variety of reasons (overweight, inadequate dependent arrangements, etc.) and did not remain on active duty. Potential changes to the policies that led to these rejections are discussed.

Dealing with the stress of an HIV-positive diagnosis at an Army medical center.

Following mandatory military-wide testing for the human immunodeficiency virus (HIV), Army medical facilities have gained extensive experience with HIV-positive persons who undergo special stresses as a result of their affiliation with the military. The consequences of evacuation to medical centers for evaluation of HIV status are presented and the impact of this process on the medical center staff are considered. This paper is a description of one system designed to evaluate, treat, and support HIV-positive soldiers and their families.