P&S Annual Report
Research Discoveries

Programs in academic medicine are rarely solitary endeavors. The names listed with these summaries represent, in most cases, leaders of the projects. Use these names when contacting the editors with queries about specific projects. 

With Small Steps, Research Advances 

You often hear medical research--especially lab research--described in such grandiose terms as "forging frontiers" or "pushing the envelope." Researchers, however, will admit quite readily that their projects yield more questions than answers and that research successes are built one step at a time, with often frustrating and time-consuming delays along the journey. 

Research discoveries at P&S this past year are evidence that small steps have the potential of generating giant leaps in health care. Individuals with AIDS, cancer, Parkinson's disease, Huntington's disease, and schizophrenia are among the beneficiaries of research discoveries this past year. 

Our most exciting basic research advance in AIDS this past year confirmed our finding, in 1994, identifying Kaposi's sarcoma-associated herpesvirus as the infectious agent responsible for the cancer common in gay and bisexual men with AIDS. Our strength in cancer continues to grow through both research discoveries and clinical advances, aided by the recruitment of Dr. Karen Antman as director of the Herbert Irving Comprehensive Cancer Center. Parkinson's disease research includes population-based studies and a search for familial risk in first-degree relatives. "Death Now, Dying Later: Predictive Testing for Huntington's Disease and Other Late Onset Disorders" is a research project that will develop a protocol for testing and a teaching curriculum to enable people to live with some modicum of freedom and comfort from diagnosis to death from such diseases as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, cancer, and ataxia. 

The Howard Hughes Medical Institute awarded $3.6 million to P&S for development of basic biomedical research. The funds will support young faculty and small pilot studies, maintain and update existing research facilities, enhance scientific communication and information services, and provide for unexpected demands on research budgets. 

The following pages give many examples of research discoveries that promise to prevent illness, improve health, and lengthen lifespans. 

Understanding Nicotine's Grip 

Why is smoking so addictive, and why do relatively tiny amounts of nicotine in a smoker's bloodstream have such a profound effect on mood and mental state? Researchers have found a molecular mechanism in the brain that may explain nicotine's potent physiological effects. The mechanism, triggered by nicotine in concentrations normally found in smokers, could explain nicotine's addictive nature and how it alters mood and improves alertness and cognition. The discovery, by P&S researchers in the Center for Neurobiology and Behavior, may pave the way for development of anti-addiction treatment. 

Dr. Lorna Role, the study's principal investigator, says nicotine acts on a novel nicotinic receptor complex, strategically located at the sites of communication between neurons in the brain. At very low concentrations, nicotine activates the receptor and causes the neuron to release more neurotransmitter, which results in a much stronger signal. Researchers believe nicotine's ability to strengthen signals between neurons may account for the complex behavioral effects of nicotine, such as increased alertness and improved short-term memory. The nicotine-activated brain cells are among those nature designed to reinforce behaviors important to survival. Nicotine acts like the volume knob on a radio, amplifying the signals between nerves in the brain. 

Scientists have known that nicotine can activate nerve cells even though it is not a chemical found naturally in the body. Nicotine is chemically similar to a nerve chemical called acetylcholine and thus it can grab hold and activate the same spots, or receptors, on nerve cells that are activated acetylcholine.

Nicotine apparently can increase the strength of communication between neurons in the brain by increasing the release of glutamate, the key central nervous system excitatory transmitter. These presynaptic receptors are ideal targets for nicotine because of their location, high sensitivity to nicotine, and efficacy in enhancing transmitter release. 

In addition to stimulating parts of the brain tied to alertness and memory, nicotine also affects the part of the brain responsible for "reinforcement," which may explain why smoking is a difficult habit to break.

Answers to Alzheimer's 

Alzheimer's disease has become a high-profile disease, and its familiarity will grow as the American population ages. P&S research dedicated to understanding Alzheimer's disease ranges from basic lab discoveries, to epidemiological research that may predict the disease and offer possible treatments, to ethical insight into uses of tests that might predict susceptibility to the disease. Among the highlights in Alzheimer's disease research this year was development of the Taub Center for Alzheimer's Disease Research, funded by the Henry and Marilyn Taub Foundation, which supplements efforts of the federally funded Alzheimer's Disease Research Center at P&S. The Taub Center funds three full-time scientists, their assistants, and core laboratories for dedicated research into the genetic epidemiology and molecular biology of Alzheimer's disease and related disorders. 

Highlights of Alzheimer's research at P&S this year: 

* Estrogen-Researchers made headlines for a discovery that estrogen may protect women from Alzheimer's disease. Postmenopausal women who used estrogen for a year or more significantly delayed or decreased their risk of developing the disease by as much as 5 percent a year. The study correlated history of estrogen use, medical history, APOE genotype (one of the major risk factors for Alzheimer's), ethnic group, age, and education for 1,124 postmenopausal women. Women who used estrogen for less than one year were protected but to a lesser extent. Estrogen users who developed Alzheimer's did so significantly later in life than non-users. Researcher: Richard Mayeux 

* Depression-Senior citizens who suffer from depressed mood may have an increased risk of developing Alzheimer's disease. It's not clear whether depressed mood is a psychological reaction to memory complaints that occur in the early stages of dementia or whether the depression represents an intermediary factor related to another risk factor yet to be identified. Researchers: Richard Mayeux, D.P. Devanand 

* Genotypes-Sergievsky Center researchers continue their investigation of apolipoprotein E (APOE) genotypes and Alzheimer's disease. Previous findings systematically confirmed the influence of APOE genotypes on the relative risk of Alzheimer's disease in Caucasians and Hispanics. However, the absence of evidence for increased risk among APOE-e4 heterozygote African-Americans suggests that other genetic or environmental factors may modify the effect of APOE-e4 in some populations. Researchers also examined the risks of Alzheimer's disease associated with traumatic head injury and APOE-e4 in 236 elderly residents in Washington Heights. A tenfold increase in the risk of Alzheimer's disease was associated both with APOE-e4 and with a history of traumatic head injury, compared to a twofold increase in risk with APOE-e4 alone. Head injury in the absence of an APOE-e4 allele did not increase risk. These data imply that the biological effects of head injury may increase the risk of Alzheimer's disease but only through a synergistic relationship with APOE-e4. Researcher: Richard Mayeux

* DNA Tests-Sergievsky Center researchers examined the policy implications of the newly developed DNA test of risk for Alzheimer's disease: the APOE genotype. While APOE genotypes may indicate a degree of susceptibility, the gene is neither "necessary nor sufficient" to cause the disease. The association between Alzheimer's and APOE also varies with age, genetic background, and ethnic group. In another study,researchers found that the APOE-e4 genotype was a strong predictor of reduced self-reported functional ability in older adults, independent of cognitive status. The results suggest that the genotype may influence functioning directly as well as through its effects on cognitive status. Researchers: Nicole Schupf, Steven Albert, Richard Mayeux

* Selegiline and Vitamin E-P&S researchers directed a two-year multicenter clinical trial of selegiline and vitamin E for treatment of patients with moderately severe Alzheimer's disease as part of the national Alzheimer's Disease Cooperative Study. The study measures treatment effects on institutionalization, loss of ability to perform activities of daily living, and death. A similar study aimed at maintaining function in community elderly at risk for dementia tests the drug selegiline. Researcher: Mary Sano 

* Time frames-An approach to estimate the length of time before an Alzheimer's patient requires nursing home care or dies has been developed and validated. Researcher: Yaakov Stern 

* PET-Studies have begun using PET (positron emission tomography) to test the cognitive reserve of patients with Alzheimer's. The goal of the study is to identify mechanisms by which patients cope with Alzheimer's. Researcher: Yaakov Stern 

* RAGE-Two studies identified two receptors on cells in the brain that may cause neuronal damage in Alzheimer's disease. One study found that the scavenger receptor on microglial cells binds to fibrillar beta amyloid protein but not to its non-fibrillar form. Microglial cells become immobilized when their scavenger receptors bind to fibrillar beta amyloid. This interaction initiates the secretion by microglia cells of chemicals, such as reactive oxygen species, that damage or kill surrounding neurons. The researchers also identified a peptide that blocks the interaction between microglial scavenger receptors and fibrillar beta amyloid. The other study reported that the cellular receptor for advanced glycation endproducts (RAGE) binds amyloid-beta peptide, the principal component of extracellular deposits of filamentous proteins in Alzheimer's disease whose enhanced presence correlates with neuronal dysfunction and dementia. RAGE is found on endothelial, neuronal, and microglial cells in the brain and to an enhanced degree in affected areas in Alzheimer's disease. Researchers: Shi Du Yan, David Stern, Ann Marie Schmidt  

* Cognitive Development-Sergievsky Center researchers characterized and differentiated the progression of cognitive and functional changes in Alzheimer's disease by using a newly developed growth curve modeling approach. They examined the association between age and use of encoding strategies in the acquisition of new verbal material in non-demented elderly individuals. Although overall level of recall declined with advancing age, the ability to benefit from encoding strategies was maintained, suggesting a possible remediation strategy for age-associated memory decline. Researcher: Yaakov Stern 

* More RAGE-The "senile plaques" found in brain tissue in patients with Alzheimer's disease are aggregates of amyloid-beta peptide. Amyloid-beta is known to be neurotoxic, inducing oxidative stress and activating microglia, the scavenger cells of the immune system that patrol the brain. Although those effects are thought to be mediated by binding to a cell-surface receptor, its identity has so far remained obscure. A study by P&S researchers shows that the receptor for advanced glycation end products, or RAGE, is a strong candidate. Not only is oxidative stress induced when amyloid-beta binds to RAGE, but the receptor is abundant on microglia and induces their activation. A related study from P&S shows that microglia can also adhere to amyloid-beta and become activated by means of their so-called class-A scavenging receptor. Taken together, the research may suggest ways in which agents that block those receptors could be used in the treatment of Alzheimer's disease. Researchers: Shi Du Yan, Joseph El Khoury  

* Genetics-Through the Taub Center for Alzheimer's Disease Research, researchers use a structured family history interview to identify Alzheimer's disease and related disorders among first-degree relatives of Alzheimer's patients and control patients identified in earlier research. A DNA bank will also be established from lymphocytes in study group patients to help researchers find an Alzheimer's disease susceptibility gene. Researcher: Richard Mayeux  

Something Good From Snakes

Using a toxin from the venom of a snake, P&S researchers have designed a targeted toxin with the potential to act on HIV, herpes, and other enveloped viruses. Scientists have long tried to harness targeted toxins for therapeutic use against pathological cells, but most toxins are not well-targeted or, if they reach their targets, cannot make it past cell membranes to be effective. 

The new strategy, developed by Dr. Peter D. Kwong and Dr. Wayne Hendrickson, uses bungarotoxin (the venom of the snake Bungarus multicinctus), a presynaptic neurotoxin with targeting and enzymatic action in separate units. The Kunitz subunit guides the toxin to the site of the neuromuscular junction. Once properly located, the phospholipase subunit degrades the presynaptic membrane and blocks nerve transmission. The snake toxin is highly specific, causing complete paralysis without any significant side effects, making it suitable for therapeutic adaptation. 

Dr. Kwong and colleagues propose switching the targeting unit of the toxin to aim it against enveloped viruses instead of presynaptic membranes. Dr. Kwong believes such targeting is ideal because phospholipases degrade extracellular membranes and the virions of enveloped viruses do not have cellular biosynthetic mechanisms to repair the degradation. Therefore, enveloped viruses, including HIV, herpes, influenza, and leukoviruses, are particularly susceptible. 

Researchers believe this therapy might be able to change AIDS from a fatal disease to one that is merely chronic and manageable. Dr. Kwong has prepared a conjugate of the separated bungarotoxin phospholipase linked to the recombinant soluble form of CD4, the primary receptor of HIV. When CD4 binds to its receptor on HIV, the phospholipase would attack the membrane of the virus and kill it. Tests have shown that this conjugate works at least 10 times better than dextran sulfate, a common benchmark of HIV inhibition. The researchers are now focusing on preparing more potent conjugates. 

Using targeted toxins is not new, but this new method allows the toxin to target virions, which are resistant to conventional drugs. "We're taking an old technology and putting a new wrinkle in it by using a natural 'machine' that kills animals and adapting it to kill viruses." 

AIDS 

Microbiology and medicine researchers collaborated in a study that offers fresh insights into how vpr, a gene of HIV, stops cell growth. The researchers discovered that vpr stops cells from replicating by blocking cell division at a specific stage just after the cell has copied its DNA but before it has divided. The gene appears to stop cell growth by blocking a cascade of reactions that signal a cell to begin mitosis. Researcher: Jeremy Luban 

A naturally occurring defense system within cells, based on methylation of cytosines in DNA, is being used to inactivate deleterious genes, which may allow scientists to develop treatments for AIDS and cancer. Researchers cloned and sequenced mammalian DNA methyltransferase and used gene disruption techniques to show that DNA methyltransferase protein is required for mammalian development. If the technology can be further developed and harnessed, it holds great promise for reducing the severity and incidence of a number of diseases--such as AIDS, hepatitis B, and human papilloma virus infection--by shutting off the genes that are involved in specific diseases. Researcher: Timothy Bestor 

Columbia researchers in 1994 identified Kaposi's sarcoma-associated herpesvirus, a unique DNA sequence that pointed to a possible end of a 22-year search for an infectious agent responsible for the cancer common in gay and bisexual men with AIDS. Two 1996 studies at P&S and the School of Public Health ended arguments for and against the link by confirming that Kaposi's sarcoma is caused by a new human herpesvirus. The researchers used a newly developed assay to search for KSHV antibodies. Researchers: Shou-Jiang Gao, Patrick Moore, Yuan Chang 

A longitudinal analysis of gender differences in HIV-infected drug users reveals that the odds of neurological impairment increase over time in men, but not women, after adjustments are made for age, education, drug use, history of head injury, and baseline CD4. Researchers: Xiuhua Liu, Karen Marder 

Research in the Sergievsky Center has examined the impact of HIV infection on cognition in gay men and intravenous drug users. Results suggest that the virus that causes AIDS can affect cognition early, even when the patient is medically asymptomatic. Cognitive difficulties worsen as the severity of HIV infection increases, and the advent of clinically significant neurologic signs is associated with progression to more severe cognitive deficits. Researcher: Yaakov Stern 

Cancer

Researchers in microbiology and biochemistry have solved the crystal structure of an antibody fragment that mimics the anti-cancer drug taxol. Reseachers: Bernard Erlanger, Wayne Hendrickson 

CPMC is recognized as a leader in prostate cancer research and treatment. A few years ago, urologists developed a blood test to identify prostate cancer cells in the peripheral circulation. Proving that leadership, basic science studies conducted this year identified a new oncogene associated with prostate cancer, a discovery that could lead to better diagnostic tests for earlier detection and more reliable staging of the cancer. Another gene identified may help control the process of tumor growth and metastasis in prostate cancer. The gene, prostate carcinoma tumor antigen-1 (PCTA-1), is expressed in prostatic intraepithelial neoplasia and metastatic disease, not in benign prostatic hypertrophy or normal prostate tissue. The techniques the researchers used to identify the gene also have potential diagnostic and therapeutic applications: surface epitope masking--a patent-pending immunological subtraction procedure that identifies molecules on the surface of genetically engineered cells even if those molecules are not known in advance. The researchers are now using the technique to search for similar genes in cancers of the breast, central nervous system, colon, and lung. Researcher: Paul Fisher 

Researchers in the Columbia-Presbyterian Cancer Center have cloned and characterized the int-3 oncogene, which is associated with mammary tumors, and identified a novel oncogene associated with multiple myeloma--the MUM-1 gene, which encodes a novel member of the interferon response factor family. Researcher: Jan Kitajewski 

Columbia-Presbyterian Cancer Center researchers have demonstrated the importance of the Bcl-2 gene in enhancing the growth of prostate cancer cells. Researcher: Ralph Buttyan 

Studies that seek to define the association between exposure to electromagnetic fields and the incidence of breast cancer in men who work as electricians, telephone linemen, and electric power workers tend to be inconclusive because they assume the exposure to electromagnetic fields is a constant, time-weighted average, but people constantly enter and re-enter electromagnetic fields of varying strengths for varying periods of time. P&S research is developing a more realistic basis for the design of epidemiological studies that will try to prove the link between breast cancer and electromagnetic fields. Researcher: Reba N. Goodman 

A third category of cellular genes--cyclins and cyclin-related genes--may also be critical targets during multistage carcinogenesis because of the central role they play in controlling cell cycle progression. Research has concentrated on the gene cycline D1, and studies have provided evidence that increased expression of cyclin D1 can play a critical role in the carcinogenic process. The finding may provide a useful biomarker in molecular epidemiology studies on the roles of environmental and dietary factors in causing cancer. The finding also may have identified a useful cellular target for cancer chemoprevention and cancer treatment. Researcher: I. Bernard Weinstein 

Molecular epidemiologists have validated biologic markers and demonstrated the role environment-gene interactions play in procarcinogenic genetic damage. Clear associations between environmental exposures and biomarker levels have been seen in active and passive smokers, workers and populations exposed to ambient pollution, and carcinogens in diet. Research continues on several fronts. Researcher: Frederica Perera 

Alternative Medicine

The Richard and Hinda Rosenthal Center for Alternative/Complementary Medicine exists to study alternative and complementary medicine practices and to provide a resource for the medical community and individuals who want to separate the bogus from the beneficial. As inquiries to the center increase, a grant from the van Ameringen Foundation will help facilitate ongoing activities and create a computer system and database to manage requests for information. Director: Fredi Kronenberg 

The K.J. Lee Family Fellowship Fund in the Center for Alternative/Complementary Medicine encourages researchers to explore the role of religion in healing and to investigate and define the influence of religious beliefs in scientific terms the academic community can accept. The first recipient of a Lee grant is studying the impact of religious beliefs on end-of-life care decisions. Researchers: Maria Sullivan, Philip Muskin, Karen Antman, Mary Arnold 

The goal of the Center for Alternative Medicine in Women's Health is to identify and examine alternative medicine therapies intended to improve women's health. Women use alternative medicine in substantially greater numbers than men. Many studies in women's health have focused on the use of drugs as therapy but little attention has been paid to alternative approaches used daily by large numbers of women. Some of the alternative approaches to be studied are diets, herbal remedies, vitamin therapy, behavioral treatments, acupuncture, and exercise. Fredi Kronenberg 

The Complementary Care Center evaluates alternative medical treatments in an acute care setting. The center recognizes that alternative therapies seem to offer relief and health to many people, although most evidence of their success is non-scientific. Alternative, or complementary, modalities, such as hypnosis to control pain and therapeutic touch to activate innate healing potentials, will be studied. Complementary Care Center researchers will try to determine whether such therapies, combined with current medical practices, can complement a patient's overall care. The researchers hope to find scientific evidence to either substantiate or refute the effectiveness of these practices. Jery Whitworth 

Genetics and Human Reproduction 

In the 1960s, the first amniocentesis procedure conducted in the United States was performed at CPMC. Now, a team of researchers from P&S and Columbia's engineering school is developing bioengineering methods to provide safer and more cost-effective prenatal diagnosis for pregnant women. The research team is working across traditional disciplinary boundaries to learn how to recover fetal cells from the blood of expectant mothers as a way to eliminate the need for amniocentesis and chorionic villus sampling, two costly and somewhat risky procedures used to determine the health and gender of developing fetuses. Researchers: Dorothy Warburton, Daniel Lasser, Edward Leonard, Rene Chevray, Ruby Grewal 

The Columbia Genome Center (CGC) is a Universitywide enterprise to map the genomes of human and selected model organisms in the next phase of the genome program initiated in 1988 as part of the NIH Human Genome Project. CGC has expanded the genome program from three technological areas to five; molecular genetics and DNA sequencing sections have been added to the existing sections of physical mapping, recombinant DNA, and informatics. The CGC is mapping and sequencing the BRCA2 region on chromosome 13, the second of three genes that predict a susceptibility to breast cancer. Director: Isidore S. Edelman 

Sergievsky Center researchers were the first to demonstrate an association between stressful life events near the time of conception and spontaneous abortion of a chromosomally normal fetus. Researchers reported that adverse maternal life events in the period immediately before or immediately after conception were associated with a 2.5-fold increase in odds of a spontaneous abortion. Researcher: Richard Neugebauer 

Sergievsky Center researchers found that, contrary to earlier observations, smoking 14 or more cigarettes a day was only slightly associated with genetic mutations. Researchers: Jennie Kline, Bruce Levin, Zena Stein, Mervyn Susser, Dorothy Warburton, Ann Kinney 

Sergievsky Center researchers identified a relatively non-invasive technique--transvaginal sonography--that can detect a two-fold difference in the numbers of antral ovarian follicles, follicles that are mature and ready for ovulation, between ages 20 and 40. The technique could be used to assess fertility or study women about to enter menopause. Researchers: Jennie Kline, Lynne Reuss, Bruce Levin, Ilan Timor-Tritsch, Rosa Santos 

An Institute of Human Nutrition researcher reported a novel approach to identifying new genes in humans. By using a gene key to cholesterol metabolism in humans, the research identified a similar gene in yeast and, using that gene, found a second similar gene in yeast. Searching the human genome bank for a sequence similar to the second yeast gene, the researcher found a previously unidentified human gene, likely to be a major contributor to human cholesterol metabolism. Researcher: Stephen Sturley  

Epidural anesthesia to ease the labor pains of pregnant women also helps fathers who attend deliveries, research at St. Luke's-Roosevelt Hospital Center found. Fathers, for several years, have been active in the birthing process but often are psychologically unprepared to deal with their partners' long, difficult, and painful labor. Because a father's fear and anxiety may negatively affect labor, epidural anesthesia can rescue the situation and permit more enjoyable deliveries for both parents. Researcher: David J. Birnbach 

The Social Science Research Unit in the Center for Population and Family Health is involved in two studies on birth control decision-making. An NIH-funded study analyzes why women choose Norplant and how they decide to continue or discontinue it, and a similar study looks at decision-making in the use and continuation of Depo-Provera. 

The International Operations Research Program in the Center for Population and Family Health conducts studies on reproductive health (HIV and other sexually transmitted diseases, pregnancy outcomes, and family planning) in Rakai District Uganda, a collaboration between Columbia, the Ugandan Ministry of Health, Johns Hopkins University, and researchers at Uganda's Makerere University. One study is a community-based, randomized, controlled trial of the effects of intensive STD control--via mass treatment--on sexually transmitted diseases, pregnancy outcomes, and HIV transmission. The study has enrolled more than 12,000 adults in 56 rural villages and determined very high baseline rates of STDs and genital tract infections in these underserved communities. 

Findings from 10 multidisciplinary teams in Ghana, Nigeria, and Sierra Leone, working through the Center for Population and Family Health's Prevention of Maternal Mortality Program, have revolutionized ideas about preventing maternal mortality. Most obstetric complications cannot be predicted or prevented, the research teams discovered, so attention must be focused on the availability of treatment for complications. Emphasis has changed from prenatal care and training of birth attendants to improving services in hospitals serving the study areas and peripheral facilities. Project participants identified extensive but under-utilized health systems, worked with local truck driver unions to organize emergency transportation, conducted education campaigns about the need for prompt treatment of complications, and helped communities develop emergency loan funds. Case fatality rates showed maternal mortality was reduced by these efforts. 

Improving Health Care

* Parkinson's disease-In a population-based study, Parkinson's disease patients were found to have an increased intake of fat and calories from animal sources. The association of increased intake of calories and animal fats with Parkinson's disease is biologically consistent with the hypothesis that oxidative stress plays a central role in the pathogenesis of this disease. Researchers: Giancarlo Logroscino, Richard Mayeux  

Bad timing, rather than nerves, may explain the irregular motions of patients with Parkinson's disease. Researchers have discovered that Parkinson's patients have difficulty estimating and remembering timed intervals, leading researchers to hypothesize that the jerky motions of Parkinson's may result from a patient's inability to time smooth, fluid movement, creating instead a series of separate, stop-and-go motions. Treatment with levodopa, which when metabolized by the body increases the level of dopamine, is effective in treating motor problems in patients with Parkinson's but less so in treating cognitive problems and is less effective as the disease progresses. L-DOPA therapy for the treatment of Parkinson's disease was developed at CPMC in the 1960s. Researcher: John Gibbon 

Research continues into familial risk for Parkinson's disease in first-degree relatives. Researchers study 233 Parkinson's patients and 1,172 non-affected community residents. The research so far has identified a 2.3-fold increase in the risk to first-degree relatives of Parkinson's patients. Caucasians are 2.4 times as likely as African-Americans or Hispanics to develop the disease. Men are at twice the risk. Researcher: Karen Marder 

* Stroke-The Stroke and Aging Research Project, in the Department of Neurology, has a pilot study to determine whether nimodipine, a medication, delays the progression of memory and functional impairment brought on by cerebrovascular dementia. Researcher: J.P. Mohr 

* Other Stroke Study Findings-Physical activity dramatically reduces the risk of stroke. Exercise is a strong protective factor: The risk of stroke is 2.5 times greater among people who do not exercise. Other analysis from the Northern Manhattan Stroke Study reveals that African-Americans and Hispanics have a higher frequency than whites of strokes due to atherosclerotic disease of large arteries within the brain. Those stroke subtype differences may help explain increased mortality from stroke in minority groups and suggest strategies for stroke prevention. Researcher: Ralph Sacco 

* Gut reaction-Researchers identified a molecule in the digestive system that inactivates secreted serotonin (5-HT, 5-hydroxytryptamine). The discovery is the latest in a series of crucial pieces of evidence supporting the role of a serotonergic system in controlling peristalsis in the digestive tract and has implications for the control of gastrointestinal side effects of drugs aimed at serotonin receptors in the brain and for the development of new drugs to treat ailments of both gut and brain. The research suggests that many drugs aimed at the brain may also affect the GI tract. Researchers: Michael D. Gershon, Paul R. Wade 

* ALS-Sergievsky Center and neurology researchers have launched a project to follow a cohort of patients with amyotrophic lateral sclerosis from diagnosis to death to examine determinants of palliative care decision-making. The project was funded by the Project on Death in America. Researcher: Steven Albert 

* Orthopaedics-The Orthopaedic Research Laboratory is one of the largest and most active orthopaedic research programs in the nation. The strength of the lab is its interdisciplinary approach to orthopaedic research by orthopaedic faculty, medical students, bioengineering and biochemistry faculty, postdocs, and graduate students. Studies range from large-scale supercomputer simulations of musculoskeletal kinematics and dynamics to measurement of monoclonal antibody 3B3(-) epitopes in synovial fluids for early detection of osteoarthritis. Among recent research discoveries and accomplishments: the novel application of quantitative polymerase chain reaction to assay changes in cartilage cell gene expression in response to mechanical loading; discovery of a novel lubrication mechanism in human joints that has eluded investigators for more than 50 years; the development of large-scale computational models to calculate stresses and strains within normal and diseased cartilage during joint function; and development of a method to obtain precise anatomic maps of joint surfaces and joint contact areas (for knees) using new MRI and segmentation methods. Researcher: Van C. Mow 

* Asthma-Federal funding will help researchers confront the high incidence of asthma 
morbidity and mortality in central Harlem, where the hospitalization rate for asthma is three times higher than in all of New York City for individuals under age 34. An Asthma Research Center established as part of the Asthma Clinical Research Network will design and conduct clinical trials for asthma in the central Harlem population. Using the Harlem Asthma Research Team, the center also will mobilize clinical investigators from Harlem Hospital Center, P&S, and the School of Public Health. Researcher: Jean G. Ford 

* Sickle Cell Disease-Research at the Comprehensive Sickle Cell Center, one of 10 NIH-supported sickle cell centers in the country, focuses on molecular genetics of sickle cell diseases and stroke prevention and treatment. Genetic engineering seeks to replace the abnormal gene for Hgb S in the red cell precursors with the normal gene for the Hgb A. These modified red cell precursors, when reinjected into the patient, should proliferate and replace the defective red cells, completely correcting the disease. An animal model for sickle cell diseases has been developed. The sickle gene is introduced at the earliest stage of development; so far, the research has produced animals with a large quantity of Hgb S but still retaining a small percentage of their own normal hemoglobin. By repeated inbreeding, researchers hope to produce an animal with 100 percent sickle hemoglobin like its human sickle cell patient counterpart. Other research studies the cause of stroke, a common and devastating complication of sickle cell diseases. Magnetic resonance imaging has revealed brain infarction even in clinically asymptomatic patients. Researcher: Sergio Piomelli 

* Obesity-Investigators at the Obesity Research Center at St. Luke's-Roosevelt Hospital Center study the causes and consequences of obesity. Studies range from the psychological and social factors that affect eating habits to the morphology and biochemistry of the adipocyte. Researcher: F. Xavier Pi-Sunyer 

Improving Health Care 

* Clowning around-For nearly a decade, the Big Apple Circus Clown Care Unit has brightened the days of hundreds of pediatric inpatients. The effectiveness of the unit is now being studied through research funded by the Center for Alternative/ Complementary Medicine. Studies will examine clown therapy and pediatric surgery, the impact of clowns during invasive procedures in pediatric oncology day clinics, and the effect of clowns on decreasing physiological and psychological indicators of distress in children and adolescents undergoing cardiac catheterization. Researchers: Arthur J. Smerling, Eric Skolnick, Kenneth S. Gorfinkle, Jonathan A. Slater 

* TB in children-Although the number of adult cases of tuberculosis has decreased, the number of cases in children increased by 40 percent from 1987 to 1992. "Tuberculosis in Children: Epidemiology, Diagnostic Methods and Nosocomial Transmission" is a two-year study that could have impact on New York City children and adults at risk. Researcher: Lisa Saiman 

* Sudden infant death-Pediatrics and developmental psychobiology researchers are working together to understand the genesis of sudden infant death in hopes of predicting infants at risk. The researchers study infants of the Oglala Sioux Indian tribe on the Pine Ridge Reservation in South Dakota and infants born at CPMC. Researchers: Raymond Stark, William Fifer 

* Retinal degeneration-When microbiology researchers knocked out the cyclic GMP 
phosphodiesterase gamma gene in mice, retinal degeneration resulted shortly after birth. Researcher: Stephen Goff 

* TB treatment-Microbiology and physiology and cellular biophysics researchers 
identified a novel antibiotic to treat tuberculosis. Researchers: Howard Shuman, Samuel Silverstein 

* Cancer-A microbiologist identified a new gene required for DNA repair and recombination in a family of genes that have been shown to play a role in the development of certain cancers. Researcher: Lorraine Symington 

* Outer space-NASA funds a research project, "Development of the Fish Medaka In Microgravity," on the specific stages of embryonic development in Medaka fish under space flight conditions, including microgravity. The ultimate goal is to understand the potential effects of space flight on human development. Researcher: Debra J. Wolgemuth 

* Hypoxia-The goal of the multidisciplinary Perinatal Emphasis Research Center is to understand the response to hypoxia of the developing fetus and infant. Renewal of the center's grants will support research into the 21st century. Raymond Stark 

* Brain tumors-Brain tumors in children are particularly resistant to therapy, but pediatric oncologists are gratified by successes seen in autologous bone marrow transplants for brain tumors in infants. The program offers new hope for childhood brain tumors. James Garvin 

* Eyesight-A $2.2 million Department of Energy grant funds a long-term epidemiological study of radiation cataract development in clean-up workers at the Chernobyl nuclear plant in Ukraine to establish risk estimates per unit dose for cataract development following radiation exposure, to assess the potential role of incidental radiation exposure in the development of senescent cataracts, and to test whether a dose threshold for cataract development exists. Researcher: Basil V. Worgul 

* Anesthesiology-Research reflects interests ranging from chronic fetal hypoxia, perinatal drug abuse, adrenergic reception alterations during pregnancy, and regulation of beta-adrenergic function in the immature heart to the brain protection during cardiac and carotid surgery, manipulation of cerebrovascular resistance to treat cerebral ischemica, and psychosocial antecedents of post-herpetic neuralgia. 

* Oral health-P&S and School of Dental and Oral Surgery researchers collaborated to study the pathogenesis of temporomandibular joint (TMJ) disorders. Researchers analyze TMJ synovial fluid for biochemical mediators of cartilage degradation--specifically, keratan sulphate--in patients with severe TMJ disorders who undergo arthroscopy. The research is at the frontier of identifying the major role of cartilage breakdown in TMJ. Another study with orthopedic surgery researchers studies a healing joint's mobility and the biomechanical effects of stress and compression on TMJ cartilage. Researchers: Howard Israel, Anthony Ratcliffe 

* Infectious diseases in children-The pediatric infectious diseases division has hosted, for five years, a national referral center to study potential antibiotic combinations, antibiotics under development, and resistance mechanisms from multiresistant organisms in patients with cystic fibrosis. Lisa Saiman 

Cardiology 

A P&S study provides new evidence that Syndrome X has a physiological basis. In the study, 30 patients with the classic findings of Syndrome X (chest pain, abnormal stress tests, and normal angiograms) were examined using intravascular ultrasound, which is more sensitive than angiography. The research showed that patients who have chest pain and abnormal exercise tests should have intravascular ultrasound, which can be done at the same time as the angiogram, adding 30 minutes and a tiny additional risk. The findings should offer some comfort to the tens of thousands of people who have been diagnosed with Syndrome X and should help design appropriate treatment plans. Researcher: Mark Apfelbaum 

Pivotal findings on how estrogen replacement therapy (ERT) helps protect postmenopausal women from heart disease resulted from the first crossover study to evaluate the effects of short-term ERT on cardiovascular hemodynamics. Short-term ERT appears to decrease the workload of the heart, which may contribute to its heart-protective effects above and beyond its known benefits in improving the cholesterol profile. The findings may help explain the 50 percent lower risk of heart disease seen in postmenopausal women who take hormone replacement. Researcher: Elsa-Grace Giardina 

Although triglycerides have received considerably less research attention than high- and low-density lipoproteins, a high triglyceride level is also a risk factor for coronary heart disease. But some believe the test to measure triglyceride levels may be partly inaccurate. Researchers are seeking new ways to measure triglyceride levels and looking at genetic variations affecting triglyceride clearance. In a study performed in conjunction with Harlem Hospital Center, the researchers tested whether postprandial triglyceride levels were associated with coronary artery disease independent of other traditional risk factors. The researchers recommend developing strategies for testing lipoproteins in states other than the fasting states. Researcher: Henry Ginsberg 

Scientists have long recognized the role of neutrophils in damaging heart tissue and impairing heart function after a heart attack, but the contribution of neutrophils to arrhythmias, particularly those associated with reperfusion (the restoration of coronary artery flow following ischemia), have been largely neglected. Pharmacology researchers have developed a technique to study the interactions between canine neutrophils and single heart muscle cells, or cardiac myocytes, while recording the electrical activity of the myocytes. Activation of neutrophils bound to a myocyte liberates platelet-activating factor. This factor, in turn, modifies the cardiac sodium channel to cause consistent arrhythmogenic changes in electrical activity. However, this action can be prevented by blocking the receptor for platelet-activation factor. The researchers plan to extend these studies to the in situ canine heart. Researcher: Brian Hoffman 

Pharmacology research projects focus on genetically determined patterns of electrical activity in the mammalian heart. One project investigates the molecular pharmacology of the Long-QT Syndrome, an inherited cardiac arrhythmia. Using recombinant ion channels expressed in cultured cells, the research has identified unique therapeutic strategies that can target the mutant gene defect in patients. Studies in patients are under way. Other research is studying the way ion channel expression is regulated in the developing mammalian heart. Researcher: Robert S. Kass 

Sergievsky Center and pediatric cardiology researchers evaluated children who underwent the Norwood procedure for hypoplastic left heart to assess developmental outcome. While the children had fine-motor deficits and in general performed more poorly than controls and children who underwent a less invasive cardiac procedure, the children were not as impaired as previous reports suggested. Most of the children in the sample were in the low average range of intelligence; only one met criteria for mental retardation. The research will give parents and clinicians a clearer idea of potential outcome as they consider the Norwood procedure as a surgical option. Researcher: Veronica Hinton 

Researchers have found that the relationship between HDL and atherosclerosis is much more complex than initially thought. Recent analysis of Japanese-American men in the Honolulu Heart Program, begun in 1976, has demonstrated that those with cholesteryl-ester transfer protein (CETP) deficiency in their plasma actually had an increased incidence of coronary heart disease. CETP catalyzes the transfer of cholesteryl esters from high-density lipoproteins (HDL) to other lipoproteins, which is important because individuals with natural CETP deficiency (due to a gene mutation) have high levels of HDL. CETP deficiency appears to be an independent risk factor for cardiovascular disease in Japanese men. That suggests that rather than inhibiting CETP, it may be beneficial to increase CETP. Asians of Japanese nationality have the CETP gene mutation more commonly than any other group. The new information reveals a more complex relationship between high HDL and low incidence of atherogenesis. The finding has highlighted the need to develop a better understanding of the genes that regulate HDL levels and reveals a more complex relationship between high HDL and low incidence of atherogenesis. Researcher: Alan Tall 

Exploring the Mind and the Brain 

Schizophrenia 

Columbia researchers have found that approximately 30 percent of patients with schizophrenia have serum antibodies to human hsp60 protein (heat shock protein). Investigators used a patented method for detecting antibodies to hsp60 in cerebrospinal fluid. About 67 percent of patients with schizophrenia have anti-hsp60 antibodies, compared with 6 percent of controls with inflammatory neurological diseases. Antibodies were not detected in normal subjects. Detection of these antibodies may serve as a marker for autoimmune forms of schizophrenia and open avenues of treatment. Researcher: Saud A. Sadiq 

The Diagnostic Center for Linkage Studies in Schizophrenia at the New York State Psychiatric Institute studies the genetics of schizophrenia by studying families who have had two or more members who have suffered from schizophrenia. It is one of three centers in the United States. Researcher: J. Harkavy Friedman 

A mother's nutritional status during pregnancy may be connected with her offspring's risk of developing schizophrenia. Researchers used food rationing and health outcomes records kept by the Dutch during and after the Hunger Winter, the severe famine from October 1944 to early May 1945 that resulted from a Nazi blockade established in 
retaliation for the Dutch underground's support of an Allied invasion. Using the dates of birth to estimate the dates of conception, researchers found that individuals who were conceived during the peak of the famine had twice the risk of developing schizophrenia as individuals conceived either in the early months of the famine or after it ended. Researchers suspect a nutritional deficiency is involved. Researcher: Ezra Susser 

The Theodore and Vada Stanley Foundation gave its 1995 research award to NYSPI researchers conducting a feasibility study designed to examine the possibilities of combining and immortalizing the data collected in 13 high-risk for schizophrenic studies done here and abroad 20 to 30 years ago. The researchers aim to establish an integrated data bank of those studies, whose common goal was to identify the precursors of schizophrenia to address neurobiological and neurodevelopmental issues of current interest in schizophrenia research. The researchers will look at the old samples to perform new diagnostic examinations on adults now in their 20s, 30s, and 40s. Researchers: L. Erlenmeyer-Kimling, Jean Endicott, Donald Rock 

A pilot study is examining the relationship between prenatal levels of folate and schizophrenia. The study examines frozen blood samples taken from women during various stages of their pregnancies to correlate levels of micronutrients in the mothers with any later development of schizophrenia in their offspring. The researchers also will search for a connection between schizophrenia and prenatal exposure to the flu: previous studies suggest a connection between exposure in mid-gestation to an influenza epidemic and an increased risk of schizophrenia. Researcher: Ezra Susser 

Other Mind/Brain Discoveries 

A group of researchers at the Howard Hughes Medical Institute and Center for Neurobiology and Behavior identified a protein that blocks the formation of long-term memories. The protein, ApCREB2, was identified in the marine snail Aplysia californica but is similar to the protein CREB2 in humans. In previous work, researchers found that the conversion of short-term memories into long-term ones involves the activation of certain genes. So far, they have found three proteins that activate this long-term memory gene "switch." CREB2, however, is the first protein that represses the switch. With CREB2 present, it takes repeated signals to activator proteins to switch on long-term memory. Without CREB2, just one signal is sufficient to produce long-term memory on the cellular level. Researcher: Eric Kandel 

Neonatal cranial ultrasound abnormalities indicative of white matter injury are highly predictive of mental retardation in low birth-weight infants, Sergievsky Center research shows. Researcher: Agnes Whitaker 

Infants with transient severe hypothyroxinemia of prematurity have 10 times the risk for disabling cerebral palsy and a 15-point reduction in mental development scores compared with infants with normal thyroxine levels, according to research by the Sergievsky Center. Researchers: M. Lynne Reuss, Mervyn Susser, Nigel Paneth 

Girls who suffer from anxiety disorders in childhood are more likely to be one to two inches shorter than non-anxious girls as adults. Researchers examined the relationship between anxiety disorders and stature in early adulthood in more than 700 children (half girls, half boys) for nine years. They found an association between childhood anxiety disorders and short adult stature, but only in girls. Researcher: Daniel S. Pine 

Significant data now support the observation that depression dramatically increases the risk of dying after a heart attack. Psychiatry researchers gathered data from studies on the use of antidepressants in patients with heart disease and studies on smoking. Researchers have begun studies on the safety and efficacy of use of antidepressant drugs immediately following a heart attack. Researchers: Alexander H. Glassman, Peter A. Shapiro, Lidia Lidagoster, Elsa-Grace Giardina 

For the first time, researchers have shown in animal models that the trait of separation anxiety in infants can be inherited. The experiment serves as a model for the development and inheritance of affective disorders. Researchers: Susan A. Brunelli, Myron A. Hofer 

Depressed patients who respond well to the antidepressant fluoxetine (Prozac) favor the left brain over the right in various cognitive tests, according to a collaborative study with Harvard. Results held true in four studies, each of which used different treatments for depression, including cognitive therapy. Researcher: Gerard Bruder 

A cross-national study of major depression and bipolar disorder has revealed striking similarities across countries in patterns of major depression and bipolar disorder. The study suggests that cultural differences or different risk factors may affect the expression of depression when differences in rates are seen. For example, the lifetime rates for major depression vary widely across countries, ranging from 1.5 cases per 100 adults in the sample in Taiwan to 19 cases per 100 adults in Beirut. Lifetime rates of bipolar disorder are more consistent across countries (0.3 per 100 in Taiwan to 1.5 per 100 in New Zealand); the sex ratios are nearly equal; and the age at first onset is earlier (average=6 years) than the onset of major depression. Individuals separated or divorced had significantly higher rates of major depression than married people in most countries, and the risk was somewhat greater for divorced or separated men than women in most countries. Researcher: Myrna M. Weissman 

Unpredictability in early rearing conditions in non-human primates can cause biochemical changes analogous to human mood and anxiety disorders in later life. Researchers have explored the neurobiology of early trauma, stress, and subsequent anxiety patterns using an animal that experimentally excludes genetic influences on development, a strategy not normally feasible in humans. The study looked at cerebrospinal fluid concentrations of corticotropin-releasing factor (CRF), a pivotal regulator of the body's hormonal immunological, physiological, and behavioral response to stress, in primates reared by mothers confronting various foraging conditions. Mothers were assigned to one of three groups. The study found that although CRF levels were normal for both groups raised by mothers with high and low foraging demand, monkeys raised under variable foraging conditions showed an increase in CRF levels. The study also found that variably reared primates had low cortisol levels. Generally, CRF stimulates the pituitary gland to release ACTH, which in turn stimulates the release of cortisol, the major peripheral stress hormone. Researcher: Jeremy D. Coplan 

Approximately 10 percent of all pregnant women suffer depression before delivery--a significant risk factor for postpartum depression. Federal funding will pay for "Antepartum Depression, Interpersonal Therapy, and Sleep EEGs," which includes clinical trials. The goal of the research is to develop successful treatment for depression during and after pregnancy to improve maternal mood, improve role transition to parenthood, and decrease family morbidity. Researcher: Margaret G. Spinelli 

When a researcher went looking for children diagnosed a decade ago with major depressive disorders, 5 percent of those found had committed suicide and another 30 percent of the children--now adults--had attempted suicide in the same 10-year period. The researcher was able to locate 159 of 204 people studied 10 years ago when they were diagnosed between ages 10 and 13. The 5 percent figure is higher than the national rate for teen suicides (0.1 percent). Experts predict 3 million to 6 million children may suffer from depression, most never diagnosed or treated. Researcher: Myrna Weissman 

The incidence of non-febrile, acute symptomatic seizures is 40 per 100,000 person years, a rate almost equal to that of epilepsy, Sergievsky Center studies show. As with epilepsy, the incidence for this class of convulsive disorders is highest in the very young and in the elderly. Other Sergievsky Center research has shown that the number of cases of epilepsy in children has declined by almost 50 percent over the past 50 years, while epilepsy in people over 65 has doubled. The increase in the elderly may reflect improved long-term survival of people with cerebrovascular disease, a group at high-risk for epilepsy. Researcher: W. Allen Hauser 

Concurrent use of diuretics diminishes the risk of new onset unprovoked seizures in older adults, regardless of whether the diuretics were effective for the reason for which they were prescribed. The finding supports recent lab data that suggests furosemide (Lasix) has anticonvulsant properties. Researcher: Dale Hesdorffer 

Sergievsky Center research has shown that estrogen use after menopause may help women maintain cognitive abilities, especially memory, better than women who never used estrogen. Other research among the elderly shows that overall level of recall may decline with age, but the elderly are still able to benefit from encoding strategies to acquire new verbal material. The findings suggest possible remediation strategies for age-associated memory decline. The results of another study that compared English- and Spanish-speaking older adults on a comprehensive neuropsychological test suggest caution when using non-verbal measures to assess cognition in non-English speaking populations. The two groups scored comparably on most verbally medicated neuropsychological measures, but Spanish speakers scored significantly lower on several measures generally considered to be "non-verbal." Researcher: Diane M. Jacobs 

Epilepsy 

Genetic susceptibility to risk for epilepsy is found only in individuals who develop epilepsy in the absence of postnatal environmental risk factors, such as a head injury, stroke, or brain infection. The risk of epilepsy to relatives of an individual who develops epilepsy with such an insult to the central nervous system does not increase. However, genetic susceptibility may raise the risk for epilepsy associated with neurological deficit presumed to be present at birth. The increased risk is present only up to age 35. Researcher: Ruth Ottman 

Men and women with epilepsy have reduced rates of reproduction. Live birth rates were reduced in persons with epilepsy even within marriage, indicating that the reduced reproductive rates were not entirely attributable to reduced marriage rates. Reproductive rates were reduced only after onset of epilepsy, suggesting that reduced reproduction may be caused by epilepsy or its treatment per se, rather than by genetic factors. Researchers: Ruth Ottman, Nicole Schupf 

Researchers now believe generalized and localization-related epilepsies may not be genetically distinct. The degree of increased risk for epilepsy is greater in families of subjects with generalized epilepsy than in the families of those with localization-related epilepsy, but risks increased for both generalized and localization-related epilepsies in families of subjects with generalized epilepsy. Researcher: Ruth Ottman 

Additional analyses suggest that epilepsy is underreported in relatives born many years before the interview. Reported risk of epilepsy during comparable age periods was higher for relatives born recently (such as offspring) than for those born earlier (such as parents). This underreporting must be taken into account in testing genetic models. Researcher: Ruth Ottman 

Basic Research 

When microbiology researchers knocked out the cyclic GMP phosphodiesterase gamma gene in mice, retinal degeneration resulted shortly after birth. Researcher: Stephen Goff 

Microbiology and physiology and cellular biophysics researchers identified a novel antibiotic to treat tuberculosis. Researchers: Howard Shuman, Samuel Silverstein 

A microbiologist identified a new gene required for DNA repair and recombination in a family of genes that have been shown to play a role in the development of certain cancers. Researcher: Lorraine Symington 

These other basic research discoveries were reported by the Department of Microbiology: 
 -- a new transcriptional regulatory protein (NF-IL6) that's required for replication of HIV-1 in monocytes and macrophages (Kathryn Calame) 
 -- a zinc finger protein Blimp-1, a master regulator of terminal B-cell differentiation, as a repressor of the c-myc oncogene (Kathryn Calame) 
 -- cloning of the A1 adenosine receptors of human and mouse adipose tissue. This receptor regulates the storage and mobilization of fats. (Bernard Erlanger) 
 -- genetic tools to analyze the periodontal pathogen Actinobacillus actinomycetemcomitans. Researchers characterized a tenaciously adherent clinical isolate of this organism and an isogenic non-adherent variant. (David Figurski) 
 -- demonstration that the plasmid RK2, which transfers antibiotic resistance among bacteria, codes for a host-specific accessory function that promotes inheritance of the plasmid by the pathogen Pseudomonas aeruginosa (David Figurski) 
 -- evidence for RNA antisense regulation of a protein repressor encoded by resistance transfer plasmids (David Figurski) 
 -- dissection of a regulatory network in yeast that controls meiosis (Aaron Mitchell) 
 -- demonstration of a repressor Rme1p that works by blocking DNA-binding at distant sites (Aaron Mitchell) 
 -- isolation of thermostable mutants of poliovirus whose mutations are being introduced into vaccine strains, which have the potential of proliferating in tropical areas where the stability of the vaccine has compromised the success of vaccination programs to eradicate Poliomyelitis (Vincent Racaniello) 
 -- demonstration of the interferon-gamma beta subunit as a cell surface molecule that differentiates among the two major classes of CD4+ helper T cells (Paul Rothman) 
 -- identification of the regions of the IL-4 receptor that are important in IL-4 induced signaling (Paul Rothman) 
 -- demonstration of a unique intracrine mechanism of cytokine signaling by the v-able oncogene (Paul Rothman) 
 -- development of a novel expression vector to produce abd select full length proteins (patent pending) (Saul Silverstein) 
 -- demonstration of the presence of Varicella Zoster Virus DNA in both neurons and supporting satellite cells in individuals latently infected with the virus (Saul Silverstein) 
 -- demonstration of the role of an important developmental signaling pathway in T lymphocyte development (Gerald Siu) 
 -- demonstration of the role of discrete regions of DNA, called silencers, in positive selection of T lymphocytes (Gerald Siu) 
 -- demonstration that CD40, a cell surface molecule, is critical for early neonatal B lymphocyte development and that injection of anti-CD40 antibody can modify the development of defined subsets of B lymphocytes (Allan Stall) 
 -- generation of Adenovirus vectors that can express transcription factors in vivo and can create double strand breaks in vivo, important for gene targeting and therapy (Charles Stuart Hamish Young) 

Pediatrics Research 
 
--the cognitive and emotional development of homeless children (Candace Erickson) 
 --brief intensive chemotherapy for Burkitt's lymphoma and psychosocial studies of art therapy and adolescent adaptation (James Garvin) 
 --epidemiology of tuberculosis in children in New York and the risk of nosocomial transmission of TB to pediatric health care workers (Lisa Saiman) 
 --prenatal effects of crack and cocaine on neurobehavioral development (Tove Rosen) 
 --study of a man with a complete absence of estrogen, secondary to a deficiency of the aromatase enzyme, to elucidate mechanisms involved in male osteoporosis and to suggest potential treatments (Akira Morishima)