Faculty Bibliography

Our laboratory, in collaboration with Oxigene Inc, has been involved in identifying commercially feasible clinical applications of measurement or modulation of ADP-ribosylation as a core technology. For this purpose a pivotal regulatory role for ADP-ribosylation in the repair of DNA lesions leading to cytotoxic as well as mutagenic events has been hypothesized. A new class of DNA repair inhibitors, the N-substituted benzamides, has been identified which can react with radiation to produce reactive intermediates that oxidize thiol amino acids. Their proposed mechanisms of action are two-fold: ie they can interact with radiation: i) to directly enhance DNA damage; and ii) to react with thiols in the zinc finger DNA binding domain of poly ADP-ribosyl transferase to inhibit DNA repair and thereby increase DNA damage. Sensamide, a clinically relevant formulation of metoclopramide which is an N-substituted benzamide, has indicated enhancement of tumor response and survival in patients with inoperable squamous cell carcinoma of the lung when it was administered as a radiosensitizer in a phase I/II trial and compared to historical controls. A mechanism of endogenous regulation of human mononuclear leucocyte ADP-ribosylation has been identified to be HOCl/N-chloramine production via the oxidative burst of phagocytes. HOCl/N-chloramines are potent oxidants of thiol-containing proteins. Quantitative estimation of N-chloramine sensitive plasma thiols has been identified as an effective surrogate measure of leucocyte poly ADPRT.(ABSTRACT TRUNCATED AT 250 WORDS)

A pair-matched, case-control design was used to study exposure to Histoplasma capsulatum and other environmental factors, and to determine various host characteristics including human leukocyte antigen (HLA) typings in 94 young patients with macular choroidal neovascularization (CNV) and in 94 controls with other eye diseases. Patients with two types of retinal patterns were studied: Type I, or those with CNV with one or no chorioretinal atrophic spots in the posterior pole or periphery (n = 51), and Type II, or those with CNV and 2 or more chorioretinal atrophic spots (n = 43). Our purpose was to explore whether these two variants of idiopathic CNV have different and distinguishable epidemiologies which may or may not be related to prior exposure to Histoplasma. We found that histoplasmin skin tests were negative in all but two Type I cases. The combination of the HLA-B7 and HLA-DR2 markers (but not either marker alone) was significantly increased in Type I cases. Among Type II cases, HLA-B7, HLA-DR2, HLA-DQ1, a positive histoplasmin skin test, myopic refractive error, prior residence in a histoplasmosis endemic area, occupations involving exposure to animals, and hypertension were all significantly increased. Histoplasmin skin test responses were positive in 18 Type II cases (45%). In the multivariate analysis, only DR2 and the combined presence of DQ1 and a positive histoplasmin skin test remained predictive of Type II disease. Our findings suggest that histoplasmin sensitivity is associated with some, but not all, cases of Type II disease. However, histoplasmin sensitivity appears to have no relationship to Type I disease. HLA factors may play a role in both disease types, possibly by producing a modified immune response to Histoplasma and/or other unidentified agents

We propose a method to estimate the usually unknown time since infection for individuals infected with human immunodeficiency virus type 1 (HIV-1). If we assume the time since infection has an exponential prior distribution, then under the model the conditional distribution of time since infection, given the CD4 level at the time of the first positive HIV-1 antibody test, is a truncated normal density. We applied the method to prevalent cohort data both from intravenous drug users and from homosexual/bisexual men. For the intravenous drug users the estimated mean time since infection was 15.0 months from infection at a presumed mean CD4 level of 1060 cells/ml to first positive antibody test at a CD4 level of 597 cells/ml, which was the average CD4 at enrollment for infected subjects. For the homosexual/bisexual men the estimated mean time since infection was 16.7 months from infection at a presumed mean CD4 level of 699 cells/ml to first positive antibody test at an average CD4 level of 577 cells/ml. We performed a validation study using initially seronegative subjects in these cohorts who seroconverted to HIV-1-positive antibody status during the follow-up period. For the intravenous drug users, data were too few to provide definitive verification of the method. In the cohort of homosexual/bisexual men, however, there was a total of 70 seroconverters with relevant data. Among them, the median absolute difference between the midpoint of the known seroconversion interval and the estimated mean infection date was 4.6 months, conditional on CD4-lymphocyte measurements taken approximately 18 months subsequent to infection. Conditional on CD4 approximately 30 months after infection, this median difference increased modestly to 8.2 months. Our analysis suggested that the underlying mathematical model tends to overestimate short times since infection and underestimate long times since infection. We consider potential corrective modifications to the model

Endometrial carcinoma is associated with antecedent simple and complex hyperplasia, and the endometrium is a target tissue for the action of cytokines and growth factors. Transforming growth factor (TGF)-beta s are potent cellular growth and differentiation regulatory factors. Therefore, we investigated the potential role for TGF-beta s in the normal proliferative endometrium and its possible involvement in the transition to complex hyperplasia and progression to endometrial carcinoma. The angiogenic and mitogenic growth factor, basic fibroblast growth factor, was used for comparison. Differential TGF-beta isoform-specific immunoreactivity was observed in the normal endometrium, which is composed of glandular and stromal cells. There was an increase in TGF-beta 3 but not TGF-beta 1 or TGF-beta 2 in the glandular epithelium from the proliferative to the secretory phase of the menstrual cycle. Immunostaining for TGF-beta 2 was more intense in the stroma than the glands. In contrast, TGF-beta 1 and TGF-beta 3 were near equal intensity in these two endometrial compartments, TGF-beta 3 being the most intense. The glandular epithelium demonstrated a statistically significant stepwise increase in the expression of all three TGF-beta s progressing from the normal proliferative endometrium to simple hyperplasia and on to complex hyperplasia. However, the stromal cells maintained approximately the same level of immunoreactivity for TGF-beta in all these samples. In comparing proliferative endometrium with complex hyperplasia, there was a 5.1-, 3.4-, and 2.6-fold increase in immunostaining in the glands for TGF-beta 1, TGF-beta 2, and TGF-beta 3, respectively (P < or = 0.001). There was no further increase in immunoreactivity with progression from preneoplastic complex hyperplasia to carcinoma. Immunoreactive basic fibroblast growth factor was slight in normal endometrium and simple hyperplasia. There was a 4.6- and 4.2-fold increase in immunostaining observed in complex hyperplasia compared with proliferative endometrium in the glandular (P < or = 0.0054) and stromal (P < or = 0.0053) cells, respectively, with no further increase in carcinoma. By in situ hybridization, an increase in mRNA for all TGF-beta isoforms paralleled TGF-beta immunoreactivity. However, in contrast to the increased immunostaining in the glands in complex hyperplasia, there was remarkably more mRNA in the stromal cell compartment. The discordant expression of mRNA and protein was only observed in the pathological endometrium since both were more highly expressed in the stromal cells in normal proliferative endometrium.(ABSTRACT TRUNCATED AT 400 WORDS)

An historical cohort study of twins, aged 6 to 15 years, found reduced cognitive performance related to subclinical exposure to lead (Pb) much earlier in life. Pairs of twins discordant for blood Pb (low-Pb twins ranged from 30-50 micrograms/dl and high-Pb twins ranged from 43-80 micrograms/dl) exhibited reduced learning of a computer-administered visual discrimination and reversal by the twin having the higher exposure. There was no evidence that sensory or motor impairment contributed to the cognitive deficit. Performance of a reference group indicated that test's validity for age-related cognitive development and the method's suitability for children of varying socio-economic or racial status. Because the reversal learning approach required only one 20-min test session and was powerful enough to document Pb-related deficits in a small sample (n = 8), it may indicate a practical method for obtaining early evidence of environmentally induced developmental delays. An advantage of the test is that it can be used with both humans and animals. Tests capable of direct comparison of behavioral data from humans and animals can guide the search for behavioral and biological mechanisms in experiments that can be done only with animals. They also can augment the clinical procedures currently used

We employed a nested case-control study design to evaluate the efficacy of bleach-cleaning of needles and syringes among injecting drug users (IDUs) as a means of preventing human immunodeficiency virus (HIV) infection. Sixteen HIV-seroconverters who responded to bleach use questions and who reported injecting with shared or used equipment in the 6 months prior to their first positive visit were compared with 89 controls. Controls had remained HIV-seronegative at two or more visits, reported injecting with shared or used equipment, responded to bleach-cleaning questions, and were seen at recall visits +/- 6 months from the date of seroconversion of the index case. Risk factors associated with HIV seroconversion in univariate analyses were a history of sexual intercourse with an HIV-infected partner and the frequency of speedball (mixed heroin and cocaine) injections. After adjusting for confounders, we found no evidence that bleach use protected against HIV infection

OBJECTIVES--To examine trends in acquired immunodeficiency syndrome (AIDS) risk behavior and human immunodeficiency virus (HIV) seroprevalence among injecting drug users (IDUs) in New York City from 1984 through 1992. DESIGN AND SETTING--Comparisons were made between two surveys of IDUs at the same hospital-based New York City drug abuse detoxification program: 141 IDUs in 1984 and 974 IDUs in 1990 through 1992. National Death Registry, New York City Health Department, and drug treatment program records were also used. PARTICIPANTS--Persons attending detoxification program randomly selected for participation. Eligibility was based on injection within previous 2 months; 99% acceptance rates were obtained. Participants in the 1984 and 1990 through 1992 surveys were 66% and 79% men, 21% and 19% white, 33% and 34% African American, and 45% and 46% Latin American, respectively. INTERVENTIONS--Community-based AIDS prevention programs, including underground syringe exchanges. MAIN OUTCOME MEASURES--Acquired immunodeficiency syndrome risk behaviors; HIV serostatus; CD4+ cell counts; death rates among 1984 subjects; and injection and intranasal routes of drug administration. RESULTS--The HIV seroprevalence remained stable at slightly more than 50%. Mean CD4+ cell counts declined from 0.716 x 10(9)/L (716/microL) to 0.575 x 10(9)/L (P < .009). Annual death rate among 1984 subjects was 3%, with a significantly higher rate among HIV-seropositive subjects (relative risk, 2.57; 95% exact binomial confidence interval, 1.12 to 6.61). Large-scale declines were observed in AIDS risk behaviors, eg, use of potentially contaminated syringes declined from 51% to 7% of injections (P < .001). Recent additional risk reduction was associated with use of the underground syringe exchanges. Intranasal heroin use was the primary route of drug administration for 46% of heroin admissions to New York City drug treatment programs. CONCLUSIONS--The HIV seroprevalence has remained stable among this population of New York City IDUs for almost a decade. Continuation of current trends should lead to further reduction in HIV transmission, although reversal of the trend to intranasal use could lead to substantially increased transmission

The objectives of this study were to investigate HIV-1 seroprevalence and risk factors, disease progression, and awareness of HIV-1 serostatus in a population of inner city, substance using, psychiatric inpatients. To pursue these goals, we tested 118 (103 M, 15 F) dually diagnosed, acute care inpatients for HIV-1 antibodies and administered structured interviews. Twenty-seven (23%, including 24 M and 3 F) of the subjects were HIV-1 seropositive. Seropositivity was twice as great among intravenous drug users and men who had sex with other men as among patients not belonging to either of these two groups. Logistic regression analysis among male subjects revealed a significantly elevated HIV-1 risk associated with a primary diagnosis of depression (odds ratio adjusted for age, race, and presence of an AIDS risk behavior = 4.2, 95% confidence interval = 1.1, 16.5; p = 0.04). Less than half of the seropositives knew their HIV-1 status prior to this study, one had AIDS and four had two or more constitutional symptoms of AIDS. The high rate of seropositivity in this indigent, dually diagnosed population presents challenges to the health-care community. That few individuals had HIV-1 related symptoms may have implications for other treatment settings