Induction of immune tolerance in patients with hemophilia A and inhibitors treated with porcine VIIIC by home therapy

Home therapy with porcine factor VIIIC was safe and effective when administered to five hemophilic patients over periods of 8 1/2, 6, 4, 3 1/2, and 2 years. No significant transfusion reactions occurred. Before treatment with porcine factor VIIIC, all five had high-level, high- responding anti-human VIIIC inhibitors initially lacking anti-porcine factor VIIIC activity. Although specific anti-porcine VIIIC inhibitors arose in all patients, these were generally transient, and only one patient became refractory to treatment. We believe that porcine factor VIIIC is the treatment of choice in patients whose inhibitors do not cross-react. All five patients lost their original anti-human VIIIC inhibitors after starting treatment with porcine VIIIC, permitting the reintroduction of human VIIIC in three of them. There has been no recurrence of anti-human VIIIC inhibitor activity during 2 to 3 years of regular treatment with human VIIIC in these patients. This suggests that tolerance to human VIIIC has arisen as a result of treatment with porcine VIIIC. Porcine VIIIC may have a role in the desensitization of some factor VIIIC inhibitor patients.     

Risk factors for childhood respiratory disease. Analysis of pulmonary function

Four thousand elementary-school-age children from a rural area of western Pennsylvania participated in a cross-sectional survey that consisted of a standardized respiratory questionnaire completed by their parents and spirometric testing at school. Spirographic tracings were digitized to obtain the FVC, FEV0.75, FEF25-75, Vmax75, and Vmax90, which were standardized for height, age, and sex for the subsequent analyses. Independent associations of potential risk factors with the standardized pulmonary function measures were evaluated with multiple regression techniques. Asthma, persistent wheeze, and parental smoking habits, especially those of the mothers, were associated with lower flow rates. The effect of parental smoking was primarily due to smoking by the mother and was stronger in girls. In female children of currently smoking mothers, FEF25-75 was 96% of predicted, Vmax75 was 95% of predicted, and Vmax90 was 92% of predicted; each flow measure was 98% of predicted in male children of smoking mothers. Prolonged hospitalization at birth was independently associated with lower FEV0.75 and flow rates. Low socioeconomic status was associated with lower FVC and FEV0.75. Neither current gas stove use nor a history of severe chest illness before 2 yr of age were independently associated with lower levels of pulmonary function.     

Distribution of forced expiratory volume in one second and forced vital capacity in healthy, white, adult never-smokers in six U.S. cities

As part of a longitudinal study of the respiratory health effects of air pollution, we measured the lung function of 2,454 white adults 25 to 74 yr of age who had never smoked and who reported no respiratory symptoms. These measurements were analyzed to develop a simple model for the cross-sectional dependence of pulmonary function on height, sex, and age. Both forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) can be effectively standardized for body size by dividing each pulmonary function measurement by the square of the standing height (HT2). The age-specific distribution of these standardized measurements is approximately Gaussian, with variance that is independent of age. Plots of FEV1/HT2 and FVC/HT2 against age showed a nonlinear relationship consistent with an increase in the rate of pulmonary function loss with age. On the basis of these graphic analyses, both pulmonary function measurements were fitted to a four-parameter normative model including sex and linear and quadratic terms in age as dependent variables. This model gave predictions that were very close to those from more complicated models currently in use. Predicted percentile levels were calculated for each sex and age, and shown to describe the observations well. The estimated annual change in height-standardized lung function based on the cross-sectional model was compared with the observed change between the first and second examinations of these adults 3 yr later. The observed changes were close to predicted values, except for subjects younger than 35 yr of age at their first examination. The observed change was larger for men than for women. Such simple longitudinal comparisons are subject to selection bias. In this study, subjects in the lowest quartile of FEV1/HT2 for their age and sex at the first examination had a lower probability of providing a lung function measurement 3 yr later.     

A population-based case-control study of mesothelioma deaths among U.S. railroad workers

We have completed a case-control analysis of mesothelioma deaths among current and retired U.S. railroad employees. Cause-specific death certificates were obtained for 87% of 15,059 deaths reported by the railroad retirement board, and 20 mesotheliomas were identified according to death certificate diagnosis. A 10:1 matched analysis with railroad workers dying of nonmalignant, nonaccidental causes yielded a very strong association with prior railroad work in jobs with potential asbestos exposure (odds ratio = 7.2, 95% lower confidence limit = 3.3). Consideration of railroad occupations with regular asbestos exposures (e.g., skilled trades, steam locomotive repair) yielded an odds ratio of 21.4 (95% lower confidence limit = 8.7), but the occupations with potential intermittent exposure (e.g., engineers, firemen, carmen) yielded a nonsignificant odds ratio of 2.3 (95% lower confidence limit = 0.5). Applying mesothelioma mortality rates from this study to the population of U.S. railroad workers at risk yields an estimate of 416 cases of mesothelioma occurring among U.S. railroad workers between 1981 and 2000.     

A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease

BACKGROUND: Most primary prevention studies have found that long-term users of postmenopausal hormone therapy are at lower risk for coronary events, but numerous questions remain. An adverse influence of hormone therapy on cardiovascular risk has been suggested during the initial year of use; however, few data are available on short-term hormone therapy. In addition, the cardiovascular effects of daily doses of oral conjugated estrogen lower than 0.625 mg are unknown, and few studies have examined estrogen plus progestin in this regard. OBJECTIVE: To investigate duration, dose, and type of postmenopausal hormone therapy and primary prevention of cardiovascular disease. DESIGN: Prospective, observational cohort study. SETTING: Nurses' Health Study, with follow-up from 1976 to 1996. PATIENTS: 70 533 postmenopausal women, in whom 1258 major coronary events (nonfatal myocardial infarction or fatal coronary disease) and 767 strokes were identified. MEASUREMENTS: Details of postmenopausal hormone use were ascertained by using biennial questionnaires. Cardiovascular disease was established by using a questionnaire and was confirmed by medical record review. Logistic regression models were used to calculate relative risks and 95% CIs, adjusted for confounders. RESULTS: When all cardiovascular risk factors were considered, the risk for major coronary events was lower among current users of hormone therapy, including short-term users, compared with never-users (relative risk, 0.61 [95% CI, 0.52 to 0.71]). Among women taking oral conjugated estrogen, the risk for coronary events was similarly reduced in those currently taking 0.625 mg daily (relative risk, 0.54 [CI, 0.44 to 0.67]) and those taking 0.3 mg daily (relative risk, 0.58 [CI, 0. 37 to 0.92]) compared with never-users. However, the risk for stroke was statistically significantly increased among women taking 0.625 mg or more of oral conjugated estrogen daily (relative risk, 1.35 [CI, 1.08 to 1.68] for 0.625 mg/d and 1.63 [CI, 1.18 to 2.26] for >/=1.25 mg/d) and those taking estrogen plus progestin (relative risk, 1.45 [CI, 1.10 to 1.92]). Overall, little relation was observed between combination hormone therapy and risk for cardiovascular disease (major coronary heart disease plus stroke) (relative risk, 0.91 [CI, 0.75 to 1.11]). CONCLUSIONS: Postmenopausal hormone use appears to decrease risk for major coronary events in women without previous heart disease. Furthermore, 0.3 mg of oral conjugated estrogen daily is associated with a reduction similar to that seen with the standard dose of 0.625 mg. However, estrogen at daily doses of 0.625 mg or greater and in combination with progestin may increase risk for stroke.     

Locus assignment of two alpha-globin structural mutants from the Caribbean basin: alpha Fort de France (alpha 45 Arg) and alpha Spanish Town (alpha 27 Val)

Two alpha-globin structural mutants were mapped to their encoding loci by in vitro translation of hybrid-selected alpha 1- and alpha 2-globin mRNA. The more highly expressed mutant, alpha Spanish Town (alpha 27Val), is encoded at the alpha 2 locus and the less expressed mutant, alpha Fort de France (alpha 45Arg), is encoded at the alpha 1 locus. These results further define the distribution of alpha-globin structural mutations within the alpha-globin gene cluster and substantiate the dominant role of the alpha 2-globin locus in alpha- globin expression.