Warfarin vs aspirin for symptomatic intracranial stenosis: subgroup analyses from WASID.

The WASID trial showed no advantage of warfarin over aspirin for preventing the primary endpoint of ischemic stroke, brain hemorrhage, or vascular death. In analyses of selected subgroups, there was no definite benefit from warfarin. Warfarin reduced the risk of the primary endpoint among patients with basilar artery stenosis, but there was no reduction in stroke in the basilar artery territory or benefit for vertebral artery stenosis or posterior circulation disease in general.

Diagnostic chelation challenge with DMSA: a biomarker of long-term mercury exposure?

Chelation challenge testing has been used to assess the body burden of various metals. The best-known example is EDTA challenge in lead-exposed individuals. This study assessed diagnostic chelation challenge with dimercaptosuccinic acid (DMSA) as a measure of mercury body burden among mercury-exposed workers. Former employees at a chloralkali plant, for whom detailed exposure histories were available (n = 119), and unexposed controls (n = 101) completed 24-hr urine collections before and after the administration of two doses of DMSA, 10 mg/kg. The urinary response to DMSA was measured as both the absolute change and the relative change in mercury excretion. The average 24-hr mercury excretion was 4.3 microg/24 hr before chelation, and 7.8 microg/24 hr after chelation. There was no association between past occupational mercury exposure and the urinary excretion of mercury either before or after DMSA administration. There was also no association between urinary mercury excretion and the number of dental amalgam surfaces, in contrast to recent published results. We believe the most likely reason that DMSA chelation challenge failed to reflect past mercury exposure was the elapsed time (several years) since the exposure had ended. These results provide normative values for urinary mercury excretion both before and after DMSA challenge, and suggest that DMSA chelation challenge is not useful as a biomarker of past mercury exposure.

Health effects of long-term mercury exposure among chloralkali plant workers.

BACKGROUND: Inorganic mercury is toxic to the nervous system, kidneys, and reproductive system. We studied the health effects of mercury exposure among former employees of a chloralkali plant that operated from 1955 to 1994 in Georgia. METHODS: Former plant workers and unexposed workers from nearby employers were studied. Exposure was assessed with a job-exposure matrix based on historical measurements and personnel records. Health outcomes were assessed with interviews, physical examinations, neurological and neurobehavioral testing, renal function testing, and urinary porphyrin measurements. Exposure-disease associations were assessed with multivariate modeling. RESULTS: Exposed workers reported more symptoms, and tended toward more physical examination abnormalities, than unexposed workers. Exposed workers performed worse than unexposed subjects on some quantitative tests of vibration sense, motor speed and coordination, and tremor, and on one test of cognitive function. Few findings remained significant when exposure was modeled as a continuous variable. Neither renal function nor porphyrin excretion was associated with mercury exposure. CONCLUSIONS: Mercury-exposed chloralkali plant workers reported more symptoms than unexposed controls, but no strong associations were demonstrated with neurological or renal function or with porphyrin excretion.

Geographic clustering of Pneumocystis carinii pneumonia in patients with HIV infection.

To detect whether there was geographic clustering of Pneumocystis carinii pneumonia cases among patients with human immunodeficiency virus (HIV) infection, we performed a retrospective analysis of a clinical database. The rates of pneumocystosis were analyzed by zip code zones for evidence of geographical clustering. During the study period, 118 patients at our AIDS Treatment Center had a first episode of P. carinii pneumonia. An analysis of the 24 zip code zones for which a P. carinii pneumonia rate was calculated (requiring a denominator of at least 10 known HIV- infected individuals residing in that zone) showed a trend toward geographic clustering (p = 0.07); when all 45 Cincinnati zip code zones were included in the analysis, clustering of cases was observed (p = 0. 02). By contrast, no clustering was observed for 52 HIV-infected control subjects with respiratory disease or for 960 HIV-infected patients treated at our center during the same time period. These data raise intriguing questions about exposure to exogenous sources of P. carinii and suggest the need for prospective studies.

Age at menarche and tanner stage in girls exposed in utero and postnatally to polybrominated biphenyl.

Accidental contamination of the Michigan food chain with polybrominated biphenyls (PBBs) led to the exposure of more than 4,000 individuals in 1973. Because PBB exposure is suspected to disrupt endocrine function, we assessed pubertal development in females 5-24 years of age (N = 327) who were exposed to PBB in utero and, in many cases, through breastfeeding. We estimated in utero PBB exposure using maternal serum PBB measurements taken after exposure (1976-1979) and extrapolated to time of pregnancy using a model of PBB decay. We found that breastfed girls exposed to high levels of PBB in utero (> or =7 parts per billion) had an earlier age at menarche (mean age = 11.6 years) than breastfed girls exposed to lower levels of PBB in utero (mean age = 12.2-12.6 years) or girls who were not breastfed (mean age = 12.7 years). This association persisted after adjustment for potential confounders (menarche ratio = 3.4, 95% confidence interval = 1.3-9.0). Perinatal PBB exposure was associated with earlier pubic hair stage in breastfed girls, but little association was found with breast development. The associations observed here lend support to the hypothesis that pubertal events may be affected by pre- and postnatal exposure to organohalogens.

Hypothesis testing with the similarity index.

Multilocus DNA fingerprinting methods have been used extensively to address genetic issues in wildlife populations. Hypotheses concerning population subdivision and differing levels of diversity can be addressed through the use of the similarity index (S), a band-sharing coefficient, and many researchers construct hypothesis tests with S based on the work of Lynch. It is shown in the present study, through mathematical analysis and through simulations, that estimates of the variance of a mean S based on Lynch's work are downwardly biased. An unbiased alternative is presented and mathematically justified. It is shown further, however, that even when the bias in Lynch's estimator is corrected, the estimator is highly imprecise compared with estimates based on an alternative approach such as 'parametric bootstrapping' of allele frequencies. Also discussed are permutation tests and their construction given the interdependence of Ss which share individuals. A simulation illustrates how some published misuses of these tests can lead to incorrect conclusions in hypothesis testing.

Maternal age specific risk rate estimates for Down syndrome among live births in whites and other races from Ohio and metropolitan Atlanta, 1970-1989.

Our primary objective was to estimate, by one year and five year intervals, maternal age specific risk rates for Down syndrome among whites and among other races from two different populations, metropolitan Atlanta and south west Ohio, using live birth and prenatally diagnosed cases ascertained during 1970-1989. The five year estimates were also calculated separately for each of the five four year periods during these 20 years. Additionally, we compared two different methods of estimating these risk rates by using a third population of whites, and compared two different statistical methods of smoothing the risk rates. The results indicate good agreement between the metropolitan Atlanta and south west Ohio estimates within races, but show a statistically significant difference between the two race categories. Because 86% of live births in the "other races" category in the combined population are to blacks, these data may be seen as the first estimates of maternal age specific risk rates for Down syndrome among blacks calculated by one year intervals. We found excellent agreement in the risk rate estimates among the five four year time periods, between the estimates obtained by using the two different methods of estimation, and between the estimates obtained using the two different methods of statistical smoothing. Our estimated risk rates for white women in their 20s strongly reinforce those from previous studies currently being used for genetic counselling purposes. While we did find somewhat higher rates for women under 20, and increasingly higher rates for those over 30 years of age, these differences are not substantial. Thus, this study in general supports the risk rates estimated from data collected mostly during the 1960s and 1970s.

Radioiodine-131 therapy for well-differentiated thyroid cancer--a quantitative radiation dosimetric approach: outcome and validation in 85 patients.

For almost five decades, 131I treatment of thyroid cancer has been based empirically on administered activity rather than on actual radiation doses delivered. In 1983, we defined radiation dose thresholds for successful treatment. This report is concerned with the subsequent validation of those thresholds in 85 patients. The successful ablation of thyroid remnants occurred after a single initial 131I administration in 84% of inpatients and in 79% of outpatients when treatment was standardized to a radiation dose of at least 30,000 cGy (rad). Administered activities low enough to permit outpatient therapy could be used in 47% of the patients. Lymph node metastases were treated successfully in 74% of patients with a single administration of 131I calculated to deliver at least 8,500 cGy (rad). For athyrotic patients with nodal metastases only, success was achieved in 86% of patients at tumor doses of at least 14,000 cGy (rad). These success rates are equal to or better than those reported with empiric methods of 131I administration. The individualized treatment planning selectively allocates hospitalization and higher exposures to 131I to those patients who require them.

Rhenium-186 hydroxyethylidene diphosphonate for the treatment of painful osseous metastases.

Rhenium-186 (tin)hydroxyethylidene diphosphonate (HEDP) is a new radiopharmaceutical that localizes in skeletal metastases in patients with advanced cancer. A single intravenous administration of approximately 34 mCi (1,258 MBq) resulted in significant improvement in pain in 33 of 43 evaluable patients (77%) following the initial injection, and in 7 of 14 evaluable patients (50%) following a second treatment. Patients responding to treatment experienced an average decrease in pain of about 60%, with one in five treatments resulting in a complete resolution of pain. The only adverse clinical reaction was the occurrence after about 10% of the administered doses of a mild, transient increase in pain within a few days following injection. Statistically significant but clinically unimportant decreases in total white blood cell counts and total platelet counts were observed within the first 8 weeks following the injection; no other toxicity was apparent. Rhenium-186(Sn)HEDP is a useful new compound for the palliation of painful skeletal metastases.

Rhenium-186(Sn)HEDP for treatment of painful osseous metastases: results of a double-blind crossover comparison with placebo.

Rhenium-186 (tin) hydroxyethylidene diphosphonate (HEDP) is a new radiopharmaceutical that simultaneously localizes in multiple skeletal metastases in patients with advanced cancer. A single intravenous administration of 30-35 mCi (1110-1295 MBq) is associated with a prompt, significant relief of osseous pain in about 80% of such patients. The efficacy of this new compound was evaluated further by utilizing a double-blind crossover comparison with 99mTc-methylene diphosphonate (MDP) as a radioactive placebo. The new rhenium compound resulted in a significantly (p less than 0.05) greater decrease in pain than did treatment with the radioactive placebo. Rhenium-186(Sn)HEDP appears to be a useful new compound for the palliation of painful skeletal metastases.

Low-grade vesicoureteral reflux. Variability in grade on sequential radiographic and nuclear cystograms.

Paired voiding cystourethrogram (VCU) and nuclear cystogram (NC) studies in 68 children with vesicoureteral reflux (VUR) were analyzed to determine the variability of VUR on sequential studies. Sequential paired examinations included 82 studies where a VCU was followed by a repeat VCU study and 128 studies where a VCU was followed by a NC study. Grade I VUR on the initial VCU was difficult to duplicate on repeat cystography, regardless of the follow-up modality. When the initial VCU showed no VUR, 20% of follow-up studies demonstrated VUR. Follow-up VCU and NC studies showed similar results in detecting increases and decreases in the grade of VUR. Low-grade VUR may be intermittent, and clinical therapeutic decisions should take this variability into account.

Statistical issues in risk assessment of reproductive outcomes with chemical mixtures.

Establishing the relationship between a given chemical exposure and human reproductive health risk is complicated by exposures or other concomitant factors that may vary from pregnancy to pregnancy. Moreover, when exposures are to complex mixtures of chemicals, varying with time in number of components, doses of individual components, and constancy of exposure, the picture becomes even more complicated. A pilot study of risk of adverse reproductive outcomes among male wastewater treatment workers and their wives is described here. The wives of 231 workers were interviewed to evaluate retrospectively the outcomes of spontaneous early fetal loss and infertility. In addition, 87 workers participated in a cross-sectional evaluation of sperm/semen parameters. Due to the ever-changing nature of the exposure and the lack of quantification of specific exposures, six dichotomous variables were used for each specific job description to give a surrogate measure of exposure. Hence, no quantitative exposure-response relationships could be modeled. These six variables were independently assigned by two environmental hygienists, and their interrater reliability was assessed. Results are presented and further innovations in statistical methodology are proposed for further applications.

Re-186(Sn) HEDP for treatment of painful osseous metastases: initial clinical experience in 20 patients with hormone-resistant prostate cancer.

Rhenium-186(tin) hydroxyethylidene diphosphonate (HEDP) is a new radiopharmaceutical that localizes in areas of osseous metastases in a manner similar to that of standard bone-scanning agents. It also emits beta particles with sufficient energy to be therapeutically useful. A single intravenous injection of about 33 mCi (1,221 MBq) was given to each of 20 elderly patients with advanced skeletal metastases from hormonally resistant prostate cancer. Prompt, significant relief of pain occurred 80% of the time with no significant side effects and only minimal, transient marrow toxicity. Re-186(Sn) HEDP appears to be a useful new agent for the palliation of painful osseous metastases in prostate cancer.

Prediction of cardiac and pulmonary complications related to elective abdominal and noncardiac thoracic surgery in geriatric patients.

PURPOSE: Major cardiac and pulmonary complications associated with abdominal and noncardiac thoracic surgery are a common cause of mortality and serious morbidity in elderly patients. We postulated that a simple, inexpensive bicycle exercise test could provide objective documentation of cardiopulmonary reserve and, therefore, predict perioperative pulmonary as well as cardiac complications. PATIENTS AND METHODS: Prior to elective surgery, 177 patients aged 65 years or older had assessment of the clinical history, results of physical examination, electrocardiogram, chest radiograph, blood chemistries, pulmonary function test findings, supine exercise test results, Dripps classification, and Goldman cardiac risk factors. Observations in patients with and without major perioperative cardiac and/or pulmonary complications were compared using univariate analysis followed by a multivariate logistic regression procedure. RESULTS: Major perioperative complications were pulmonary in 24 patients, cardiac in 25 patients, and either cardiac or pulmonary in 39 patients. By multivariate analysis, inability to perform two minutes of supine bicycle exercise raising the heart rate above 99 beats/minute was the best predictor of perioperative pulmonary, cardiac, and combined cardiopulmonary complication (p less than 0.0005). Among 108 patients who were able to achieve these exercise criteria, cardiac or pulmonary complications occurred in 10 patients (9.3%), with one death (0.9%). Among 69 patients unable to exercise satisfactorily, cardiac or pulmonary complications occurred in 29 patients (42%), with five total deaths (7.2%). CONCLUSION: Objective measurement of exercise capacity by supine bicycle ergometry appears to be of clinical value for preoperative risk stratification for both pulmonary and cardiac complications prior to major elective abdominal or noncardiac thoracic surgery in elderly patients.

Parathyroid hormone and calcitriol changes in normal and insulin-dependent diabetic pregnancies.

In pregnancy, an increase in serum calcitriol and parathyroid hormone concentrations has been reported in several studies, though the increase in parathyroid hormone remains controversial. In magnesium deficiency states, parathyroid hormone and calcitriol secretion may be decreased. Because magnesium deficiency may occur in insulin-dependent diabetic patients, mainly because of urinary magnesium losses, we hypothesized that serum parathyroid hormone and calcitriol do not increase in the diabetic pregnancy. We studied, in a prospective longitudinal manner, 35 nondiabetic and 199 insulin-dependent diabetic pregnancies. In diabetic women, the goals of glycemic control were fasting blood glucose below 100 mg/dL and postprandial blood glucose less than 140 mg/dL. Serum magnesium, calcium, parathyroid hormone (whole molecule; ie, 1-84 fragment), and calcitriol were measured three times: 1) 8-12 weeks, 2) 22-28 weeks, and 3) 32-38 weeks' gestation. In normal women, serum parathyroid hormone did not change significantly over pregnancy, and a wide scatter of values was observed. Serum calcitriol increased significantly with advancing gestation. In diabetic women, serum parathyroid hormone had a narrow scatter, but values were within the low-normal range. During the third trimester there was no increase, and even a decrease, in serum calcitriol concentrations. Diabetics had, throughout pregnancy, significantly reduced serum magnesium concentrations when compared with controls. Their serum calcium and ionized calcium concentrations were similar to those of controls, except in the third trimester, when diabetic women had significantly lower serum calcium and ionized calcium concentrations than controls. We speculate that mineral metabolism abnormalities in diabetic pregnancies might be due to relative magnesium and/or insulin deficiency.

Serum unconjugated estriols in insulin-dependent diabetic pregnancies: normative data and clinical relevance.

The purpose of this study was to establish normative reference values for serum unconjugated estriol (E3) concentrations in insulin-dependent diabetic pregnancy. There were 1973 samples analyzed in 63 diabetic pregnancies not complicated by fetal distress and/or neonatal asphyxia. These samples were compared with 867 samples collected in 25 pregnancies complicated by fetal distress and/or neonatal asphyxia and 103 samples collected in seven nondiabetic, uncomplicated pregnancies. E3 values were found to be significantly higher in diabetic compared with nondiabetic healthy gravid women, correlating with infant birthweight. The percent change of daily E3 values from the highest previous 3 days mean (maximum mean) was 1 +/- 27% (mean +/- SD). The 95% confidence limit for this percent change indicates that a decrease of 52% or more is theoretically seen in 2.5% of the observations. Using the traditional decrease of 40% currently used in the literature, there were false-negative and false-positive predictions of fetal distress and/or neonatal asphyxia at rates unacceptable for patient management. The use of E3 determinations in combination with nonstress test-contraction stress test did not improve the predictability of this latter test. Serum E3 determinations are of little clinical value in the management of insulin-dependent diabetic pregnant women.

Prediction of coronary artery disease in a population of insulin-requiring diabetic patients: results of an 8-year follow-up study.

To identify predictors of clinical coronary artery disease, 110 insulin-requiring diabetic patients with no symptoms suggestive of cardiac disease and with a normal resting ECG underwent metabolic and noninvasive cardiovascular screening including a history and physical examination, exercise ECG, M-mode echocardiography, and chemical laboratory testing. During a median follow-up interval of 100 months, 14 of these patients had clinical evidence of coronary artery disease consisting of acute myocardial infarction, sudden cardiac death, or anginal chest pain with angiographic documentation of occlusive coronary artery disease. Baseline variables that were univariately predictive of subsequent clinical coronary disease included age, peak treadmill heart rate, and retinal neovascularization. According to multivariate analysis the peak treadmill heart rate was the single most important predictor of subsequent development of clinical coronary disease. A treadmill ECG result that was either abnormal or inconclusive because of failure to achieve 90% of predicted maximal heart rate identified each patient in whom clinical coronary artery disease developed within 50 months after entry testing. Thus the entry treadmill ECG provided prognostic information not available from the history and physical examination results, but little further prognostic information was provided after the first 50 months of follow-up, suggesting the need for serial testing.

Social and biological factors in relation to survival among black vs. white women with breast cancer.

Longer survival for white women than black women with breast cancer has been observed even when relative survival rates are used and stage at diagnosis is controlled. This study compared prognostic factors in relation to survival for 144 white women and 67 black women with breast cancer diagnosed 1969 to 1979 and identified through the tumor registry. Data were obtained from medical records, the registry, death certificates, and pathology files. Median survival was 7.5 years for whites, vs. 5.6 years for blacks. Significant differences between races were also observed for histological type and grade of tumor, presenting symptoms, and health status at diagnosis. Although Cox multiple regression analyses showed pathological stage at diagnosis and number of positive nodes to be the best predictors of survival in both whites and blacks, the differences in histological type observed in this sample merits further research; blacks have fewer well-differentiated tumors, the type associated with positive estrogen receptors and with better survival.

A model for variability in arteriographic reading.

We propose a class of models for the joint cumulative distribution function (c.d.f.) of the values of two independent readings of percentage stenosis from a coronary arteriography. We show that these models are identifiable and that a certain subclass has unique consistent estimators for the parameters in question. We obtain these estimates for a data set from a substudy of the Coronary Artery Surgery Study (CASS).