Faculty Bibliography

BACKGROUND: Taurine (2-aminoethanesulfonic acid), a conditionally essential sulfur-containing amino acid, is mainly obtained from diet in humans. Experimental studies have shown that taurine's main biological actions include bile salt conjugation, blood pressure regulation, anti-oxidation, and anti-inflammation. METHODS: We conducted a prospective case-control study nested in the New York University Women's Health Study, a cohort study involving 14,274 women enrolled since 1985. Taurine was measured in pre-diagnostic serum samples of 241 stroke cases and 479 matched controls. RESULTS: There was no statistically significant association between serum taurine and stroke risk in the overall study population. The adjusted ORs for stroke were 1.0 (reference), 0.87 (95% CI, 0.59-1.28), and 1.03 (95% CI, 0.69-1.54) in increasing tertiles of taurine (64.3-126.6, 126.7-152.9, and 153.0-308.5 nmol/mL, respectively). A significant inverse association between serum taurine and stroke risk was observed among never smokers, with an adjusted OR of 0.66 (95% CI, 0.37-1.18) and 0.50 (95% CI, 0.26-0.94) for the second and third tertile, respectively (p for trend = 0.01), but not among past or current smokers (p for interaction < 0.01). CONCLUSIONS: We observed no overall association between serum taurine and stroke risk, although a protective effect was observed in never smokers, which requires further investigation. Taurine, Stroke, Epidemiology, Prospective, Case-control study, NYUWHS.

Purpose: The purpose of this paper is to investigate the relationship between occupational degree requirement and mortality between ethnic groups in a cohort of urban workers. Design/methodology/approach: The study included 118,606 health-insured full-time workers from the New York City Health and Hospitals Corporation (HHC). Mortality rates (MR) and mortality rate ratios (MRR) were calculated for major ethnic categories. Estimates were adjusted for age, sex, and occupational degree requirement. Findings: Prior to adjustment for degree requirement, mortality rates (MRs) by ethnic groups in the Health and Hospitals Corporation were in line with national estimates: highest for blacks, followed by whites, Hispanics, and Asian/Pacific Islander (APIs). After adjustment, the MR for blacks became comparable to whites (mortality rate ratio (MRR) = 1.02). The low-Hispanic MR did not change; the Hispanic advantage persisted (MRR = 0.66), as did the API advantage (MRR = 0.50). Research limitations/implications: Higher education may not substantially change the MR for Hispanics, and it may only account for a portion of the survival advantage among APIs. The findings also suggest that without reducing the disparity in higher education attainment between blacks and whites, equality in other socioeconomic factors may not abolish the disparity in mortality between these groups. Originality/value: This study bypassed common limitations of ethnic mortality studies, with intrinsic parity for certain socio-economic status factors (full-time employment and health care access) across cohort members and consistent ethnic classification across time-points. This includes a cohort of API workers with complete self-identification of ethnicity, which has not been accomplished by previous investigations.

Inhaled nitric oxide (iNO) has been shown to reduce ischemia/reperfusion (I/R) injury in several different organ systems including the brain. We investigated whether iNO was neuroprotective in a mouse model of transient focal ischemia. Male Swiss Webster mice underwent middle cerebral artery occlusion for 1h followed by reperfusion for 47h. Mice were divided into 5 concentration groups and administered nitric oxide (NO) at either 10, 20, 40, 60 or 80ppm. Each of the 5 concentration groups was subdivided into 4 duration groups which were treated with iNO for 5, 8, 16 or 24h beginning immediately after artery occlusion. Results showed both concentration and duration determined efficacy. At 10ppm only the 24hr duration group exhibited reduced infarct volume while at 20, 40 and 60ppm only 8 and 16h of exposure led to smaller infarctions. At these concentrations the dose response curves were strongly U shaped indicating a loss of benefit at long durations. At 80ppm, reduction in infarct volume was not observed at any duration. Additional experiments showed that 60ppm iNO could be transported from lung to brain and that iNO administered for 8h improved recovery from subarachnoid hemorrhage and reduced the inflammatory response accompanying ischemic stroke. Enhanced blood flow during reperfusion may be an important mediator of these effects.

Anti-platelet integrin GPIIIa49-66 Ab induces complement-independent platelet oxidative fragmentation and death by generation of platelet peroxide following NADPH oxidase activation. A C-terminal 385 amino acid fragment of ADAMTS-18 (A Disintegrin Metalloproteinase with Thrombospondin motifs produced in endothelial cells) induces oxidative platelet fragmentation in an identical kinetic fashion as anti-GPIIIa49-66 Ab. Endothelial cell ADAMTS-18 secretion is enhanced by thrombin and activated by thrombin cleavage to fragment platelets. Platelet aggregates produced ex vivo with ADP and fibrinogen are destroyed by the C-terminal ADAMTS-18 fragment. Anti-ADAMTS-18 Ab shortens the tail vein bleeding time. The C-terminal fragment protects against FeCl3 induced carotid artery thrombosis as well as cerebral infarction in a post-ischemic stroke model. Thus, a new mechanism is proposed for platelet thrombus clearance, via platelet oxidative fragmentation induced by thrombin cleavage of ADAMTS-18

OBJECTIVES: The purpose of this experiment was to determine if the low molecular weight heparin (LMWH) enoxaparin could extend the treatment window for thrombolysis in a mouse model of embolic stroke. METHODS: To establish the treatment window, mice were treated with tPA 2, 3 or 4 hours after clot insertion. Results showed that only the 2 hour treatment group exhibited infarct volumes significantly smaller than untreated controls. We attempted to widen this window by pre-treating mice with enoxaparin (10 mg/kg, s.c.; n=36) 1 hour before embolization. A control group (n=24) was given a saline injection. The enoxaparin-treated animals were subdivided and treated with tPA either 4 (n=12) or 6 hours (n=12) after clot insertion, while the third group (n=12) was given saline. The saline-pre-treated mice were dived into two groups: one group (n=12) received tPA and the other group (n=12) received saline 4 hours post-stroke. Embolization was confirmed by laser Doppler flowmetry and the effects of the resulting infarcts were evaluated by triphenyltetrazolium chloride staining and by behavioral testing. RESULTS: Results showed large infarcts and impaired sensorimotor coordination in the saline pre-treated animals confirming the narrow treatment window. Enoxaparin pre-treatment produced significantly smaller infarcts and improved motor behavior in groups treated with tPA both 4 and 6 hours after embolization. Neither the 4 nor the 6 hour tPA-treated groups showed evidence of intracerebral hemorrhage or external bleeding. CONCLUSION: These data indicate that the LMWH enoxaparin can significantly increase the therapeutic time window in a mouse model of embolic stroke

Low molecular weight heparins (LMWHs) have significantly reduced infarct size in animal studies but they have not been effective in clinical trials, probably because they were administered after ischemic injury had become irreversible. The present study was designed to explore the temporal characteristics of the LMWH enoxaparin with the objective of determining the duration of the treatment window in a rat model of temporary focal ischemia. Focal cerebral ischemia was induced by the intraluminal suture, middle cerebral artery occlusion (MCAO) method. Enoxaparin (10 mg/kg) was administered subcutaneously twice; the first dose was administered to different groups of animals either 1 h before or 1.5, 3, or 5 h after MCAO, and the second 4, 6, 9, or 25 h after the first dose. At 48 h animals were tested for motor coordination and brains were removed for determination of infarct size. Results showed that infarct size and degree of motor impairment were a function of time of the first and the second treatments. If the first treatment was given 1 h prior to MCAO, significant reductions in infarct size were obtained when the second treatment was given up to 6 h after the first (5 h after MCAO), but not when the second dose was given at longer intervals. If the first treatment was given 1.5 h after stroke onset, reduced infarct size was observed only in the group treated for the second time 4 h after the first injection. If the first treatment was given 3 h after MCAO, infarct size was not reduced in any group. However, if enoxaparin was administered intravenously rather than subcutaneously, significant reductions in infarct size were obtained when the first dose was given as long as 5 h after MCAO. These findings indicate that enoxaparin can reduce infarct size in rats when administered prior to stroke onset and suggest that the drug might be considered for prophylactic treatment in a phase 3 clinical trial