Biomedical subjects
Publications and source records attributed to R Sherwin.
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BACKGROUND: The determinants of differences in blood pressure that emerge in adolescence between black Americans of predominantly African descent and white Americans of predominantly European descent are unknown. One hypothesis is related to intrauterine and early childhood growth. The role of early blood pressure itself is also unclear. We tested whether differences in birth weight and in carefully standardized subsequent measures of weight, height, and blood pressure from 0 to 4 or 5 years were related to black/white differences in blood pressure in adolescence. METHODS AND RESULTS: Two Bogalusa cohorts who had complete follow-up data on birth weights and early childhood and adolescent anthropometric and blood pressure measures were pooled. One hundred eighty-five children (48 black and 47 white boys and 41 black and 49 white girls) were followed up and studied after 15 to 17 years. Birth weights were a mean 443 and 282 g lower in black boys and girls, respectively, than in whites (P<0.001). Blood pressures in adolescence were 3.4/1.9 and 1.7/0.6 mm Hg higher, respectively, and tracked from early childhood. In regression analyses, birth weight accounted for the ethnic difference in adolescent blood pressure, which was also independently predicted, in decreasing impact order, by adolescent height, adolescent body mass index, and systolic blood pressure at 4 to 5 years and inversely by growth from 0 to 4 to 5 years. CONCLUSIONS: If these results can be replicated in larger and independent samples, they suggest that efforts to improve intrauterine growth in black infants as well as lessen weight gain in adolescence might substantially reduce excess high blood pressure/hypertension in this ethnic group.
BACKGROUND AND PURPOSE: The relationship between alcohol consumption and cerebral infarction remains uncertain, and few studies have investigated whether the relationship varies by alcohol type or is present in young adults. We examined the relationship between alcohol consumption, beverage type, and ischemic stroke in the Stroke Prevention in Young Women Study. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. Case patients (n=224) were aged 15 to 44 years with a first cerebral infarction, and control subjects (n=392), identified by random-digit dialing, were frequency matched by age and region of residence. The interview assessed lifetime alcohol consumption and consumption and beverage type in the previous year, week, and day. ORs were obtained from logistic regression models controlling for age, race, education, and smoking status, with never drinkers as the referent. RESULTS: Alcohol consumption, up to 24 g/d, in the past year was associated with fewer ischemic strokes (<12 g/d: OR 0.57, 95% CI 0. 38 to 0.86; 12 to 24 g/d: OR 0.38, 95% CI 0.17 to 0.86; >24 g/d: OR 0.95, 95% CI 0.43 to 2.10) in comparison to never drinking. Analyses of beverage type (beer, wine, liquor) indicated a protective effect for wine consumption in the previous year (<12 g/wk: OR 0.58, 95% CI 0.35 to 0.97; 12 g/wk to <12 g/d: OR 0.55, 95% CI 0.28 to 1.10; >/=12 g/d: OR 0.92, 95% CI 0.23 to 3.64). CONCLUSIONS: Light to moderate alcohol consumption appears to be associated with a reduced risk of ischemic stroke in young women.
MHC class II molecules are critical determinants of genetic susceptibility to human type 1 diabetes. In patients, the most common haplotype contains the DRA1*0101-DRB1*0401 (DR4) and DQA1*0301-DQB1*0302 (DQ8) loci. To assess directly the relative roles of HLA-DQ8 and DR4 for diabetes development in vivo, we generated C57BL/6 transgenic mice that lack endogenous mouse MHC class II molecules but express HLA-DQ8 and/or DR4. Neither HLA-DQ nor HLA-DR transgenic mice developed insulitis or spontaneous diabetes. However, when they were crossed to transgenic mice (C57BL/6) expressing the B7.1 costimulatory molecules on pancreatic beta cells that do not normally develop diabetes, T cells from these double transgenic mice were no longer tolerant to islet autoantigens. The majority of DQ8/RIP-B7 mice developed spontaneous diabetes, whereas only 25% of DR4/RIP-B7 mice did so. Interestingly, when DQ8 and DR4 were coexpressed (DQ8DR4/RIP-B7), only 23% of these mice developed diabetes, an incidence indistinguishable from the DR4/RIP-B7 mice. T cells from both DR4/RIP-B7 and DQ8DR4/RIP-B7 mice, unlike those from DQ8/RIP-B7 mice, exhibited a Th2-like phenotype. Thus, the expression of DR4 appeared to downregulate DQ8-restricted autoreactive T cells in DQ8DR4/RIP-B7 mice. Our data suggest that although both DQ8 and DR4 can promote spontaneous diabetes in mice with a non-autoimmune-prone genetic background, the diabetogenic effect of the DQ8 allele is much greater, whereas DR4 expression downregulates the diabetogenic effect of DQ8, perhaps by enhancing Th2-like immune responses.
Although DQA1*0301/DQB1*0302 is the human histocompatibility leukocyte antigen (HLA) class II gene most commonly associated with human type 1 diabetes, direct in vivo experimental evidence for its diabetogenic role is lacking. Therefore, we generated C57BL/6 transgenic mice that bear this molecule and do not express mouse major histocompatibility complex (MHC) class II molecules (DQ8(+)/mII(-)). They did not develop insulitis or spontaneous diabetes. However, when DQ8(+)/mII(-) mice were bred with C57BL/6 mice expressing costimulatory molecule B7-1 on beta cells (which normally do not develop diabetes), 81% of the DQ8(+)/mII(-)/B7-1(+) mice developed spontaneous diabetes. The diabetes was accompanied by severe insulitis composed of both T cells (CD4(+) and CD8(+)) and B cells. T cells from the diabetic mice secreted large amounts of interferon gamma, but not interleukin 4, in response to DQ8(+) islets and the putative islet autoantigens, insulin and glutamic acid decarboxylase (GAD). Diabetes could also be adoptively transferred to irradiated nondiabetic DQ8(+)/mII(-)/B7-1(+) mice. In striking contrast, none of the transgenic mice in which the diabetes protective allele (DQA1*0103/DQB1*0601, DQ6 for short) was substituted for mouse MHC class II molecules but remained for the expression of B7-1 on pancreatic beta cells (DQ6(+)/mII(-)/B7-1(+)) developed diabetes. Only 7% of DQ(-)/mII(-)/B7-1(+) mice developed diabetes at an older age, and none of the DQ(-)/mII(+)/B7-1(+) mice or DQ8(+)/mII(+)/B7-1(+) mice developed diabetes. In conclusion, substitution of HLA-DQA1*0301/DQB1*0302, but not HLA-DQA1*0103/DQB1*0601, for murine MHC class II provokes autoimmune diabetes in non-diabetes-prone rat insulin promoter (RIP).B7-1 C57BL/6 mice. Our data provide direct in vivo evidence for the diabetogenic effect of this human MHC class II molecule and a unique "humanized" animal model of spontaneous diabetes.
BACKGROUND AND PURPOSE: Abnormalities in endogenous fibrinolysis are associated with an increased risk for stroke in men and older adults. We tested the hypothesis that elevated plasma tissue plasminogen activator (tPA) antigen, a marker for impaired endogenous fibrinolysis, is an independent risk factor for stroke in young women. METHODS: Subjects were 59 nondiabetic females ages 15 to 44 years with cerebral infarction from the Baltimore-Washington area and 97 control subjects frequency-matched for age who were recruited by random-digit dialing from the same geographic area. A history of cerebrovascular disease risk factors was obtained by face-to-face interview. Plasma tPA antigen was measured by enzyme-linked immunosorbent assay. RESULTS: Mean plasma tPA antigen levels were significantly higher in stroke patients than control subjects (4. 80+/-4.18 versus 3.23+/-3.67 ng/mL; P=0.015). After adjustment for age, hypertension, cigarette smoking, body mass index, and ischemic heart disease, there was a dose-response association between tPA antigen and stroke with a 3.9-fold odds ratio of stroke (95% CI, 1.2 to 12.4; P=0.03) for the upper quartile (>4.9 ng/mL) of tPA antigen compared with the lowest quartile. The dose-response relationship between tPA antigen and stroke was equally present in white and nonwhite women, and further adjustment for total and HDL cholesterol levels only modestly attenuated this association. CONCLUSIONS: This population-based case-control study shows that elevated plasma tPA antigen level is independently associated with an increased risk for ischemic stroke in nondiabetic females 15 to 44 years of age. These findings support the hypothesis that impaired endogenous fibrinolysis is an important risk factor for stroke in young women.
BACKGROUND AND PURPOSE: Genetic enzyme variation and vitamin intake are important determinants of blood homocyst(e)ine levels. The prevalence of common genetic polymorphisms influencing homocyst(e)ine levels varies by race, and vitamin intake varies by socioeconomic status. Therefore, we examined the effect of vitamin intake, race, and socioeconomic status on the association of homocyst(e)ine with stroke risk. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. One hundred sixty-seven cases of first ischemic stroke among women aged 15 to 44 years were compared with 328 controls identified by random-digit dialing from the same region. Risk factor data were collected by standardized interview and nonfasting phlebotomy. Plasma homocyst(e)ine was measured by high-performance liquid chromatography and electrochemical detection. RESULTS: Blacks and whites did not differ in median homocyst(e)ine levels, nor did race modify the association between homocyst(e)ine and stroke. After adjustment for cigarettes per day, poverty status, and regular vitamin use, a plasma homocyst(e)ine level of >/=7.3 micromol/L was associated with an odds ratio for stroke of 1.6 (95% CI, 1.1 to 2.5). CONCLUSIONS: The association between elevated homocyst(e)ine and stroke was independent not only of traditional vascular risk factors but also of vitamin use and poverty status. The degree of homocyst(e)ine elevation associated with an increased stroke risk in young women is lower than that previously reported for middle-aged men and the elderly and was highly prevalent, being present in one third of the control group.
BACKGROUND: Postmenopausal hormone therapy has been reported to decrease levels of lipoprotein (Lp)(a) in cross-sectional studies and small or short-term longitudinal studies. We report findings from a large, prospective, placebo-controlled clinical trial that allows a broad characterization of these effects for four regimens of hormone therapy. METHODS AND RESULT: The Postmenopausal Estrogen/Progestin Interventions study was a 3-year, placebo-controlled, randomized clinical trial to assess the effect of hormone regimens on cardiovascular disease risk factors in postmenopausal women 45 to 65 years of age. The active regimens were conjugated equine estrogens therapy at 0.625 mg daily, alone or in combination with each of three regimens of progestational agents: medroxyprogesterone acetate (MPA) at 2.5 mg daily (ie, continuous MPA), MPA at 10 mg days 1 to 12 (ie, cyclical MPA), and micronized progesterone at 200 mg days 1 to 12. Plasma levels of Lp(a) were measured at baseline (n = 366), 12 months (n = 354), and 36 months (n = 342). Assignment to hormone therapy resulted in a 17% to 23% average drop in Lp(a) concentrations relative to placebo (P<.0001), which was maintained across 3 years of follow-up. No significant differences were observed among the four active arms. Changes in Lp(a) associated with hormone therapy were positively correlated with changes in LDL cholesterol, total cholesterol, apolipoprotein B, and fibrinogen levels and were similar across subgroups defined by age, weight, ethnicity, and prior hormone use. CONCLUSIONS: Postmenopausal estrogen therapy, with or without concomitant progestin regimens, produces consistent and sustained reductions in plasma Lp(a) concentrations.
The objectives of this study were to test the hypothesis that alcohol can cause reactive hypoglycemia by attenuating the release of counterregulatory hormones. The subjects were eight healthy volunteers (five men and three women, aged 20-40 yr). Each subject drank, using a randomized, double blind design 1) three large gin with regular tonics (0.5 g/kg alcohol and 60 g carbohydrate, mainly sucrose (G+T); 2) the same amount of alcohol with Slim-line tonic (0.5 g carbohydrate; G alone); and 3) regular tonic without alcohol (T alone). Glucose, insulin, and counterregulatory hormone levels and middle cerebral artery velocity (MCAV), an index of cerebral blood flow, were measured. Alcohol levels averaged 60-70 mg/dL. Peak insulin levels were similar in both studies in which regular tonic was consumed (95% confidence interval for difference, -6 to 22 microU/mL). After the ingestion of G+T, the blood glucose nadir was lower compared to that with T alone (3.35 vs. 3.87 mmol/L; P < 0.02) or G alone (3.35 vs. 3.95 mmol/L; P < 0.01). After drinking gin, subjects reported typical hypoglycemic warning symptoms unrelated to the prevailing glucose level. In both alcohol studies, there was marked blunting of GH release (P < 0.01). Despite a blood glucose nadir of 3.35 mmol/L, plasma epinephrine levels rose only slightly from 267 to 455 pmol/L (P = NS) after G+T. Ingestion of alcohol also caused a transient rise in right MCAV (P < 0.05) followed by a late drop in velocity in both cerebral hemispheres in the G+T study (P < 0.05). In otherwise healthy individuals a combination of gin and regular tonic can induce reactive hypoglycemia. Acute ingestion of alcohol impairs the epinephrine response and markedly suppresses the release of GH in response to a fall in blood glucose levels.
BACKGROUND: Few reports on stroke in young adults have included cases from all community and referral hospitals in a defined geographic region. METHODS: At 46 hospitals in Baltimore City, 5 central Maryland counties, and Washington, DC, the chart of every patient 15 to 44 years of age with a primary or secondary diagnosis of possible cerebral arterial infarction during 1988 and 1991 was abstracted. Probable and possible etiologies were assigned following written guidelines. RESULTS: Of 428 first strokes, 212 (49.5%) were assigned at least one probable cause, 80 (18.7%) had no probable cause but at least one possible cause, and 136 (31.8%) had no identified probable or possible cause. Of the 212 with at least one probable cause, the distribution of etiologies was cardiac embolism (31.1%), hematologic and other (19.8%), small vessel (lacunar) disease (19.8%), nonatherosclerotic vasculopathy (11.3%), illicit drug use (9.4%), oral contraceptive use (5.2%), large artery atherosclerotic disease (3.8%), and migraine (1.4%). There were an additional 69 recurrent stroke patients. CONCLUSIONS: In this hospital-based registry within a region characterized by racial/ethnic diversity, cardiac embolism, hematologic and other causes, and lacunar stroke were the most common etiologies of cerebral infarction in young adults. Nearly a third of both first and recurrent strokes had no identified cause.
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OBJECTIVE: To determine the association of hypertension, diabetes, and cigarette smoking with incidence of ischemic stroke in young adults. DESIGN: Case-control study. SETTING: Population-based sample of cases and controls. SUBJECTS: The study included 296 cases of incident ischemic stroke among black and white adults aged 18 to 44 years in central Maryland counties from the Baltimore-Washington Cooperative Young Stroke Study and 1220 black and white adults aged 18 to 44 years from the Maryland Behavioral Risk Factor Survey, a telephone survey of a random sample of the same region, to serve as controls. MAIN OUTCOME MEASURES: Logistic regression models were developed to determine the age-adjusted odds ratios for each risk factor. Population-attributable risk percent were computed based on the odds ratios and prevalence of each risk factor. RESULTS: The age-adjusted odds ratios (95% confidence intervals) for white men (WM), white women (WW), black men (BM), and black women (BW) were as follows: current cigarette smoking: WM, 2.0 (1.1-3.8), WW, 2.1 (1.1-4.3), BM, 3.3 (1.6-6.6), and BW, 2.2 (1.3-3.9); history of diabetes mellitus: WM, 22.9 (5.8-89.6), WW, 6.2 (1.9-20.2), BM, 4.2 (0.8-21.9), and BW, 3.3 (1.4-7.7); and history of hypertension: WM, 1.6 (0.7-3.2), WW, 2.5 (1.1-5.9), BM, 3.8 (1.8-7.9), and BW, 4.2 (2.4-7.5). The population-attributable risk percent (95% confidence intervals) were as follows: current cigarette smoking: WM, 22.6 (3.1-38.2), WW, 17.2 (4.0-34.0), BM, 40.5 (23.1-54.0), and BW, 29.1 (13.5-41.9); history of diabetes mellitus: WM, 19.0 (8.2-28.5), WW, 15.8 (3.8-26.3), BM, 13.2 (5.3-20.4), and BW, 22.1 (12.5-30.7); and history of hypertension: WM, 21.7 (6.2-34.6), WW, 21.3 (5.4-34.5), BM, 53.5 (39.0-64.4), and BW, 50.5 (37.1-61.1). CONCLUSIONS: Hypertension, diabetes mellitus, and current cigarette smoking are important risk factors in a biracial young adult population. Cigarette smoking and hypertension, the 2 most modifiable risk factors, were particularly important risk factors in young blacks.
THE AUTHORS PRESENT DATA FROM 361, 662 MEN ages 35 to 57, screened from 1973 to 1976 for possible participation in the Multiple Risk Factor Intervention Trial (MRFIT). Volunteers identified themselves as "white," "black," "Oriental," "Spanish American," "American Indian," or "other." They also noted if they were taking medication for diabetes. A trained technician measured blood pressure after participants had rested for 5 minutes, using the fifth Korotkoff sound to define diastolic pressure and averaging the second and third of three readings. Differences among the groups included the following: blacks had consistently higher systolic and diastolic blood pressure (SBP and DBP) than other groups; Orientals had slightly lower pressure than other nonblack groups; American Indians had somewhat higher pressure than other nonblack groups at ages 35 to 44 but lower at ages 45 to 54; Hispanics in Miami and Davis, California, had significantly higher SBP and DBP than whites in the same area; Orientals in California had significantly higher DBP (but not SBP) than whites in California.
THE AUTHORS OF THIS PAPER SUMMARIZED the major themes that emerged from a 2-day workshop entitled Epidemiology of Hypertension in Hispanic Americans, Native Americans, and Asian/Pacific Islander Americans, sponsored by the National Heart, Lung, and Blood Institute (NHLBI) in Washington, DC. Data from the papers were synthesized using seven points: similarities, variability within and between groups, lost prevention opportunities, emergence of explanatory variables, differences in types of data collected, missing or inconsistently reported data, and socioeconomic characteristics. Virtually all of the population groups demonstrated rises in blood pressure with age. These rises appear to be largely attributable to potentially modifiable risk factors, for example, high body mass index (BMI). Despite high levels of awareness, the levels of control of high blood pressure were poor in each population studied. Based on the themes that emerged from the data, we presented several recommendations to the workshop. One was that data be collected on these population groups repeatedly and in a standardized fashion. Another called for increased efforts aimed at control of high blood pressure in these groups. A third recommended major nationwide programmatic efforts aimed at the prevention and control of high blood pressure.
OBJECTIVE: To determine the validity of a self-reported physician diagnosis of rheumatoid arthritis (RA) in elderly women. METHODS: Women with self-reported RA were contacted and permission requested to contact their physician. Physicians were mailed a questionnaire requesting information on the subject's arthritic condition. Hand radiographs obtained at study entry were read for changes of RA. RESULTS: The self-reported diagnosis of RA could be confirmed in 26 (21%) individuals. CONCLUSION: The positive predictive value of self-reported RA was low in this cohort. Caution needs to be exercised in the use and interpretation of self-report data concerning arthritic conditions in epidemiologic studies.
OBJECTIVE: This study was undertaken to assess human fetal behavior and fetal blood flow after insulin-induced symptomatic maternal hypoglycemia of sufficient magnitude to elicit counterregulatory hormones and a symptomatic response. STUDY DESIGN: Plasma glucose was lowered from approximately 95 mg/dl to 45 mg/dl in decrements of 10 mg/dl every 40 minutes with the insulin clamp technique. In 10 insulin-dependent diabetic women in the third trimester, the fetus was studied by monitoring fetal heart rate and recording fetal body and breathing movements and by performing Doppler waveform analysis with real-time ultrasonography. Maternal levels of glucagon, cortisol, epinephrine, and growth hormone were measured at each plasma glucose level. RESULTS: The mean number of fetal limb and body movements at the start of the study was 25 +/- 16 per 15 minutes, which increased to a mean of 38 +/- 28 at a glucose level of 60 mg/dl and then declined to a mean of 23 +/- 10 at a glucose level of approximately 45 mg/dl. These changes, however, did not achieve statistical significance. In addition, no significant reductions in fetal breathing movements or heart rate were observed, although maternal epinephrine and growth hormone levels were significantly (p < 0.001) increased. No consistent changes in Doppler velocity waveforms were observed. CONCLUSION: These data suggest that fetal well-being remains unaltered in spite of moderate maternal hypoglycemia in diabetic women.
There is growing and consistent evidence that estrogen use in postmenopausal women is associated with a substantial reduction in the occurrence of cardiovascular disease. However, remarkably little is known about the biological mechanisms by which estrogen therapy may influence risk. Even less information is available on the cardiovascular effects of combined estrogen-progestin use. PEPI was not designed to test whether estrogen and estrogen-progestin therapy is efficacious in the prevention of cardiovascular disease, as a much larger trial with clinical disease outcomes is needed to answer that question. However, PEPI will provide critical evidence regarding the potential effectiveness of the various estrogen and estrogen/progestin regimens ni altering risk factors for cardiovascular disease in women. Detailed information on factors such as adherence, side effects, and general patient acceptability will also be ascertained. The main results from PEPI will provide the scientific community with information on the basic actions of estrogen and estrogen/progestin therapy on four biological systems believed to be causally associated with cardiovascular disease occurrence. Further, since the trial is designed to continue for 3 years, PEPI will be able to provide information on longer term as well as short-term effects on these systems. Finally, the results from PEPI should enable women and their physicians to select an optimal hormonal regimen, i.e., one that is acceptable, safe, and provides the most beneficial and least deleterious changes in cardiovascular and other risk factors.