Inter-relationships between the severity of metabolic syndrome, insulin and adiponectin and their relationship to future type 2 diabetes and cardiovascular disease.

BACKGROUND: The severity of the metabolic syndrome (MetS) is related to future incidence of type 2 diabetes (T2DM) and cardiovascular disease (CVD). However, the relationship between MetS severity and levels of fasting insulin and adiponectin-markers of insulin resistance-is unclear. METHODS: We used linear and logistic regression to analyze data from 711 participants of the Princeton Lipid Research Cohort with information regarding levels of insulin, adiponectin and MetS severity during 1998-2003 (mean age 39.5 years); 595 participants had MetS severity data from childhood (1973-1976, mean age 12.9 years) and 417 had updated disease status from 2010 to 2014 (mean age 50.9 years). RESULTS: Childhood MetS Z-scores were positively associated with adult insulin levels (P<0.001) and negatively associated with adiponectin levels (P=0.01). In individual analyses, higher insulin levels and MetS Z-score as adults were related to higher odds of incident diabetes and CVD over the next 11.2 years (all P<0.001), whereas lower adiponectin levels were only related to odds of future T2DM (P<0.0001). In a model including insulin, adiponectin and MetS Z-score, adiponectin was not linked to future disease; both insulin (P=0.027) and MetS Z-score (P=0.002) were related to risk of future T2DM, while only MetS Z-score was related to future CVD (P<0.001). CONCLUSIONS: The severity of MetS exhibits long-term links to levels of insulin and adiponectin, suggesting potential genetic and environmental influences on insulin resistance over time. As a long-term predictor of T2DM and CVD, the severity of MetS exhibited consistent independent correlations. This supports clinical utility in evaluating MetS severity as a predictor of risk for future disease.

Receptor Tyrosine Kinase Expression Profiles in Canine Cutaneous and Subcutaneous Mast Cell Tumors.

The receptor tyrosine kinase (RTK) KIT is a major focus of current research into canine mast cell tumors (MCTs). Little is known about the role of other RTKs, such as vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). These RTKs are dysregulated in many human and animal cancers and are key regulators of tumor angiogenesis. The aims of this study were to assess the expression and activation (phosphorylation) status of KIT, VEGFR2, and PDGFR (α and ß) in canine MCTs and to examine associations with various clinical outcomes. c-KITmutational status and KIT cellular localization pattern were also evaluated for these tumors. Twenty-seven MCTs, consisting of 5 subcutaneous and 22 cutaneous tumors, from 25 dogs were evaluated. MCT biopsies, cultured mast cells, and skin from the surgical margin were analyzed through Western blotting. MCT biopsies were also used for KIT immunohistochemical labeling and polymerase chain reaction for c-KITmutational analysis. MCT had heterogeneous expression profiles for all 3 RTKs, which varied in intensity and activation status. Statistical analyses showed phosphorylated KIT, VEGFR2, and KIT cellular localization to be predictive of decreased survival time, disease-free interval, and increased metastatic rate. Expression of VEGFR2 and KIT diffuse cytoplasmic labeling were also significantly associated with increased rate of local recurrence. The results of the study show that phosphorylated KIT, KIT, VEGFR2, and PDGFRß, in addition to KIT localization, may be valuable prognostic determinants in MCTs and should be further studied to improve diagnostic and therapeutic modalities.

Endoscopic assessment of the duodenum in dogs with inflammatory bowel disease.

BACKGROUND: Endoscopy is performed for direct inspection of the mucosa and acquisition of biopsies in dogs with inflammatory bowel disease (IBD). AIM: To evaluate the interobserver agreement in the endoscopic assessment of duodenal mucosa in dogs with IBD. METHODS: Thirty-five archived endoscopic images of grossly normal (n = 6) and inflamed (n = 29) duodenal mucosa were displayed to 3 expert and 5 trainee endoscopists. Each image was assessed independently by endoscopists for mucosal abnormalities using established indices (of hyperemia, granularity, friability, lymphatic dilatation, and erosions) or interpreted as normal mucosa (trial 1). A repeated trial (trial 2) was performed with the same images presented in random order 1 month later, and accompanied by a visual template. RESULTS: There was slight interobserver agreement in initial mucosal assessment for expert and trainee endoscopists in trial 1 (kappa ≤ 0.02, P > .05). Interobserver agreement improved in trial 2 for both expert and trainee endoscopists (kappa = 0.2, P > .05) for experts and (P < .05) for trainees. There was a significant (P < .01) improvement in trainee endoscopy scores of lesions from trial 1 to trial 2. Regression analysis showed a significant (P < .01) difference between expert versus trainee endoscopy scores in trial 1. Repeat lesion assessment aided by use of a visual template (trial 2) improved the overall scores of trainee endoscopists to near that of expert endoscopists (P = .06). CONCLUSIONS AND CLINICAL IMPORTANCE: Interobserver agreement of IBD mucosal appearance from endoscopic findings benefitted from operator experience.

Healthy lifestyle factors associated with reduced cardiometabolic risk.

Minimal data are available regarding the cumulative effects of healthy lifestyle behaviours on cardiometabolic risk. The objective of the present study was to examine a combination of healthy lifestyle behaviours associated with cardiometabolic risk reduction. The analysis was based on a cross-sectional study of 1454 participants from the population-based Lipid Research Clinic's Princeton Follow-up Study. The healthy lifestyle factors included fruit and vegetable intake ≥ 5 servings/d, meat intake ≤ 2 servings/d, never smoking, consuming 2-6 alcoholic drinks/week, television (TV) viewing time ≤ 2 h/d and moderate to vigorous physical activity ≥ 4 h/week. The combination of healthy lifestyle behaviours was strongly and negatively associated with the presence of cardiometabolic risk, as well as with a composite cardiometabolic risk score after adjustment for race, age, generation and sex. With each additional healthy lifestyle factor, cardiometabolic risk decreased by 31 % (OR 0·69; 95 % CI 0·61, 0·78). A higher healthy lifestyle score was associated with a lower prevalence of cardiometabolic risk (P for trend < 0·001). Compared with individuals having 0-1 healthy lifestyle behaviours, those with 5 or 6 healthy lifestyle behaviours had a 70 % lower prevalence of cardiometabolic risk (OR 0·30; 95 % CI 0·13, 0·67). Healthy lifestyle behaviours including sufficient fruit and vegetable intake, less meat intake, less TV viewing time, abstinence from smoking, modest alcohol intake and regular exercise are associated with reduced cardiometabolic risk.

Comparison of oral prednisone and prednisone combined with metronidazole for induction therapy of canine inflammatory bowel disease: a randomized-controlled trial.

BACKGROUND: Although prednisone and metronidazole are commonly used to treat canine inflammatory bowel disease (IBD), no randomized-controlled trials have been performed. HYPOTHESIS: Combination drug therapy with prednisone and metronidazole will be more effective than prednisone alone for treatment of canine IBD. Reduction in disease severity will be accompanied by decreased canine IBD activity index (CIBDAI) scores and serum C-reactive protein (CRP) concentrations. ANIMALS: Fifty-four pet dogs diagnosed with IBD of varying severity. METHODS: Dogs were randomized to receive oral prednisone (1 mg/kg; n = 25) or prednisone and metronidazole (10 mg/kg; n = 29) twice daily for 21 days. Clinical (CIBDAI) scores and serum CRP were determined at diagnosis and after 21 days of drug therapy. The primary efficacy measure was remission at 21 days, defined as a 75% or greater reduction in baseline CIBDAI score. RESULTS: Differences between treatments in the rate of remission (both exceeding 80%) or the magnitude of its change over time were not observed. CRP concentrations in prednisone-treated dogs were increased because of many dogs having active disease. Both treatments reduced CRP in comparison with pretreatment concentrations. An interaction between CIBDAI and CRP was identified in 42 of 54 dogs (78%), whereas 8 of 54 dogs (15%) showed disagreement between these indices. CONCLUSIONS AND CLINICAL IMPORTANCE: Prednisone is as effective as combined treatment with prednisone and metronidazole for induction therapy of canine IBD. CRP may be normal or increased in dogs with IBD and may be useful in assessing the response of individual dogs to treatment along with changes in the CIBDAI.

Fluorescence in situ hybridization confirms clearance of visible Helicobacter spp. associated with gastritis in dogs and cats.

BACKGROUND: The results of studies examining the role of Helicobacter spp. in the pathogenesis of canine and feline gastritis are inconclusive. Furthermore, data evaluating the effectiveness of medical therapy for eradication of Helicobacter infection are limited. AIM: To detect Helicobacter spp. in mucosal biopsies of dogs and cats diagnosed with gastritis, with fluorescence in situ hybridization (FISH). ANIMALS: Three dogs and 2 cats with signs of chronic gastrointestinal disease. METHODS: Dogs and cats infected with Helicobacter spp. were treated with triple antimicrobial therapy and fed an elimination diet for 21 days. Helicobacter spp. status in endoscopic (3 dogs, 1 cat) or surgical biopsies (1 cat) of gastric mucosa was compared pre- and posttreatment in each animal by histology, FISH analysis, and polymerase chain reaction (PCR). RESULTS: Gastritis of varying severity with intraglandular spiral bacteria was observed in all animals. Pretreatment diagnostic tests confirmed the presence of mucosal Helicobacter spp. in all animals by FISH and histopathology and in 4/5 animals by PCR. Rapid resolution of vomiting episodes was observed in all animals. Gastric biopsies performed after triple therapy revealed clearance of visible Helicobacter spp. by histopathology and negative FISH analysis, as well as PCR in all animals. CONCLUSIONS AND CLINICAL IMPORTANCE: Application of FISH to routine biopsy specimens enabled rapid and specific identification of Helicobacter spp. within the gastric mucosa of dogs and cats. Although medical therapy was useful in resolution of clinical signs and clearance of visible Helicobacter spp. in gastric biopsies, gastric inflammation persisted.

The pediatric metabolic syndrome.

The metabolic syndrome is a frequent subject of attention, discussion, and debate in medical research, because of its linkages to the growing problem of obesity on the one hand and both diabetes mellitus and cardiovascular disease on the other. It is also the grounds for contention, as respected researchers disagree on its definition and even on its validity as a construct. This clustering of obesity, dyslipidemia, elevated blood pressure, impaired glucose metabolism, and acute phase reactants can be seen in children as well as in adults. There are at least five definitions of adult metabolic syndrome promulgated by different societies and organizations, and as many as 40 different definitions of the syndrome have been used in pediatric studies. In 2007, the International Diabetes Federation published a definition of pediatric metabolic syndrome; whether it unifies the field remains to be seen. In addition, long term cohort studies have furnished data showing that clusters of the factors used to identify metabolic syndrome do predict the presence of type 2 diabetes and cardiovascular disease defined as myocardial infarction, stroke, coronary artery bypass graft, and/or positive angiogram. In addition, longitudinal studies have demonstrated compromised vascular function in young adults with metabolic syndrome, variously defined, as children and adolescents. This review discusses the background and development of the concept of a metabolic syndrome, the inter-relationships among its constitutive elements, the debates surrounding the uses of the concept and possible treatment avenues.

Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS.

Pancreatic exocrine and bone marrow dysfunctions are considered to be universal features of Shwachman-Diamond syndrome (SDS) whereas the associated skeletal dysplasia is variable and not consistently observed. The genetic defect in SDS has recently been identified; causative mutations have been shown in the SBDS gene. The aims of this study were to characterize the nature, frequency, and age-related changes of radiographic skeletal abnormalities in patients with SBDS mutations and to assess genotype-phenotype correlation. Fifteen patients (mean age 9.7 years) with a clinical diagnosis of SDS and documented SBDS gene mutations were included. Review of their skeletal radiographs showed abnormalities in all patients. The skeletal changes were variable, even in patients with identical genotypes. The typical features were (1) delayed appearance of secondary ossification centers, (2) variable widening and irregularity of the metaphyses in early childhood, followed by progressive thickening and irregularity of the growth plates, and (3) generalized osteopenia. There was a tendency towards normalization of the epiphyseal maturation defect and progression of the metaphyseal changes with age. The results suggest that the characteristic skeletal changes are present in all patients with SDS and SBDS mutations, but their severity and localization varies with age. No phenotype-genotype correlation was observed.

Epstein-Barr virus latent membrane protein 2A activates beta-catenin signaling in epithelial cells.

The Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) functions to maintain latency in EBV-infected B lymphocytes. Although LMP2A is nonessential for the immortalization of B lymphocytes by EBV, its expression in B lymphocytes prevents viral reactivation by blocking B-cell receptor activation and signaling. LMP2A also provides an antiapoptotic signal in transgenic mice that express LMP2A in B lymphocytes. LMP2A activates phosphatidylinositol 3-kinase (PI3K) and the serine/threonine kinase Akt in lymphocytes and epithelial cells. Here we show that EBV LMP2A activates the PI3K and beta-catenin signaling pathways in telomerase-immortalized human foreskin keratinocytes (HFK). LMP2A activated Akt in a PI3K-dependent manner, and the downstream Akt targets glycogen synthase kinase 3beta (GSK3beta) and the Forkhead transcription factor FKHR were phosphorylated and inactivated in LMP2A-expressing HFK cells. GSK3beta is a negative regulator of the Wnt signaling pathway, and inactivation of GSK3beta by LMP2A signaling led to stabilization of beta-catenin, the central oncoprotein of Wnt signaling. In LMP2A-expressing cells, beta-catenin accumulated in the cytoplasm and translocated into the nucleus via a two-step mechanism. The cytoplasmic accumulation of beta-catenin downstream of LMP2A was independent of PI3K signaling, whereas its nuclear translocation was dependent on PI3K signaling. In the nucleus, beta-catenin activated a reporter responsive to T-cell factor, and this activation was augmented by LMP2A coexpression. The Wnt pathway is inappropriately activated in 90% of colon cancers and is dysregulated in several other cancers, and these data suggest that activation of this pathway by LMP2A may contribute to the generation of EBV-associated cancers.

Assessing the body composition of 6-17-year-old Black and White girls in field studies.

The purpose of the study was to develop ethnic-specific equations for fat-free mass (FFM) from selected anthropometric dimensions and bioelectrical impedance measures of resistance (R) and reactance (Xc) for use in the NHLBI Growth and Heath Study. Using dual-energy X-ray absorptiometry measures of body composition as the dependent variable and field measures of body composition by anthropometry and bioelectrical impedance as the explanatory variables, ethnic-specific prediction equations were developed on a sample of girls representing a wide range of ages and BMI. The equations were cross-validated using (1) the Prediction of Sum of Squares (PRESS) statistic and (2) an independent sample of 20 girls of each race from a study conducted at the National Institute of Child Health and Human Development (NICHD). Subjects were 65 White and 61 Black girls 6-17 years of age. The best race-specific equations for FFM each explained 99% and 97% of the variance in the White and Black girls, respectively. Root mean square errors (RMSE) ranged from 1.14 to 1.95 kg. The equation for Black girls used Stature2/Resistance (R), weight, and reactance (Xc) as predictor variables; the equation for White girls used Stature2/R, weight, and triceps skinfold thickness. The results indicate that (1) equations to predict FFM in girls should be ethnic-specific and that (2) accurate values for TBF and %BF can be calculated from the predicted FFM.

Impact of timing of pubertal maturation on growth in black and white female adolescents: The National Heart, Lung, and Blood Institute Growth and Health Study.

OBJECTIVES: To evaluate the impact of early, mid-onset, and late maturation, as assessed by timing of menarche, on height, height velocity, weight, body mass index, and sum of skinfolds in a group of white and black girls. STUDY DESIGN: The Growth and Health Study recruited 9- and 10-year-old girls from Richmond, California, Cincinnati, Ohio, and Washington, DC. There were 616 white and 539 black participants recruited at age 9 and 550 white and 674 black participants recruited at age 10. Participants were seen annually for 10 visits. Longitudinal regression models were used to test for differences in each growth measure by timing of menarche across all ages and to determine whether these differences change with age. RESULTS: Mean age at menarche among white participants was 12.7 years, and among black participants, 12.0 years. According to race-specific 20th and 80th percentiles, early maturers were tallest at early ages and shortest after adult stature had been attained. Peak height velocity and post-menarche increment in stature were greatest in early maturers and least in late maturers. Weight was greatest in early and least in late maturers, as was body mass index. Sum of skinfolds was also greatest in early and least in late maturers. There was no impact of timing of maturation on two common measures of regional fat distribution. CONCLUSIONS: Girls who matured early were shorter in early adulthood, despite having greater peak height velocity and post-menarchal increment in height. Throughout puberty, early maturers had greater ponderosity and adiposity, although there was no association with regional distribution of fat.

Racial differences in the sums of skinfolds and percentage of body fat estimated from impedance in black and white girls, 9 to 19 years of age: the National Heart, Lung, and Blood Institute Growth and Health Study.

OBJECTIVES: This National Heart, Lung, and Blood Institute Growth and Health Study report assesses racial differences in fat patterning in black and white girls ages 9 to 19 years, comparing the sum of triceps and subscapular skinfolds (SSFs) and percentage of body fat (%BF) from impedance as two indices of adiposity. It is hypothesized that racial differences in fat patterning manifest during puberty. RESEARCH METHODS AND PROCEDURES: SSF and %BF were measured annually. Racial differences in SSF and %BF were evaluated by age. Associations between %BF and SSF were evaluated using the Pearson's correlations coefficient. Classification agreement was evaluated using the kappa-statistic. Effects of pubertal stage and race on classification agreement were examined using multivariate models. RESULTS: White girls had a greater mean %BF at 9 to 12 years of age; black girls had a greater %BF thereafter. Black girls had a greater mean SSF at every age. The correlation coefficient between SSF and %BF was 0.79, and there was good agreement between %BF and SSF in separating high (>85th percentile) from not high (kappa = 0.60 for whites and 0.66 for blacks). SSF associated more with %BF in prepuberty and early puberty than in late puberty. DISCUSSION: Despite good correlations between %BF and SSF, the two methods indicate different fat patterns in black and white girls.

Racial divergence in adiposity during adolescence: The NHLBI Growth and Health Study.

BACKGROUND: Black women are particularly vulnerable to obesity, with a prevalence rate of >50%. The higher mortality and morbidity from cardiovascular disease, stroke, and diabetes have been attributed, in part, to their obesity. In recent years, a particular public health concern is the increasing secular trend in obesity with an even greater racial disparity, especially in girls and women. Between the early 1960s and late 1980s, the prevalence of obesity tripled in young black girls 6 to 11 years of age, while it doubled in white girls. Similarly, both overweight and obesity in adolescent girls 12 to 17 years of age also increased, with a greater increase again seen in adolescent black girls. This secular trend in obesity with a greater increase in black girls signals a potentially grave future chronic disease burden on black women, which is already higher than in white women. The increasing occurrence in children and adolescents of noninsulin-dependent diabetes, traditionally viewed as an adult-onset condition, may be a consequence of the currently high prevalence of obesity in American youth. Not surprisingly, this condition is seen more frequently among black youths. Prepubescent black girls are generally leaner than age-comparable white girls, but by 20 years of age, black women are considerably heavier than are white women. Thus, it is assumed that the racial disparity in adiposity evolves during adolescence. However, the specific age at which this occurs and underlying factors are yet to be identified because of the current paucity of longitudinal cohort data. OBJECTIVES: In 1985, the National Heart, Lung, and Blood Institute (NHLBI) initiated a 10-year longitudinal multicenter study (the NHLBI Growth and Health Study [NGHS]) to investigate the development of obesity in black and white girls during adolescence and its environmental, psychosocial, and cardiovascular disease risk factor correlates. The purpose of this report is to examine the natural history of adiposity and weight accretion during adolescence in a biracial cohort of girls to investigate the evolution of the racial divergence in adiposity and to examine the relationships between increases in adiposity and pubertal maturation, energy intake, and physical activity. PARTICIPANTS AND SETTING: A total of 2379 black (51%) and white (49%) girls, 9 to 10 years of age, were recruited from public and parochial schools in Richmond, California, and Cincinnati, Ohio, and from families enrolled in a large health maintenance organization in the Washington, DC area. Participant eligibility was limited to girls and their parents who declared themselves as being either black or white and who lived in racially concordant households. DESIGN AND STATISTICAL ANALYSIS: The NGHS is a multicenter prospective study of black and white girls with annual visits from 9 to 10 years of age through 18 to 19 years of age. The follow-up rate was 89% at the 10th annual visit. Skinfold measurements were obtained at the triceps, suprailiac, and subscapular sites with Holtain calipers. Sexual maturation was assessed by trained registered nurses. The onset of menarche was ascertained annually by questionnaire. All clinical assessments were conducted using a common protocol by centrally trained staff. Longitudinal regression (generalized estimating equations) models were used to examine the relationship between adiposity and race, age, pubertal maturation, daily energy intake, and physical activity. MAIN OUTCOME MEASURES: The main outcome measure was the sum of skinfolds (SSF) at the triceps, subscapular, and suprailiac sites as an index of adiposity for comparison between the 2 racial groups. Body mass index (BMI; weight in kilograms divided by height in meters, squared) distributions were examined by age and race. RESULTS: Racial differences in SSF, unadjusted for maturation, were evident at 10 years of age. For each chronological age, there was a higher proportion of black girls with more advanced pubertal maturation than white girls. The 15th percentiles for SSF were similar and remained thus throughout the study. The median for SSF for black girls, although similar to the median SSF of white girls at 9 years of age, became greater for black girls at 12 years of age (36 mm vs 32.5 mm) and at age 19 years the difference was 6 mm (49.5 mm vs 43.5 mm). In contrast, the difference in the 85th as well as the 95th percentile values for SSF were substantially higher in black girls at all ages (9 mm and 10 mm, or 18% and 15%, respectively, at age 9 years) and these racial differences widened with age (20 mm and 26 mm, or 25% and 24%, respectively, by age 19 years). The racial difference in the median BMI increased from 0.4 to 2.3 kg/m(2) between ages 9 and 19 years. Unlike SSF at the 15th percentile, the BMI for lean 9-year-old black girls was ~3% higher than whites. (ABSTRACT TRUNCATED)

The prevalence of upper lip hair in black and white girls during puberty: a new standard.

In order to develop standards for upper lip hair in adolescent girls, 4693 observations in 856 black and white subjects were made over 9 years. Up to 2 years after menarche, 90% of girls had no upper lip hair. More than 2 years after menarche, 48.8% of black girls and 9.0% of white girls had small amounts of upper lip hair. This may be more significant in adolescent girls than in older women.

Utility of different measures of body fat distribution in children and adolescents.

The distribution of body fat has been shown to be an important determinant of cardiovascular disease risk. The purpose of this study was to evaluate which method of evaluating body fat distribution compares most favorably with dual-energy x-ray absorptiometry. The study included 201 children and adolescents aged 7-17 years who were recruited from Cincinnati, Ohio, schools in 1992-1993. The strongest correlate of fat distribution was waist circumference (r = 0.80). Age was a more important determinant of fat distribution than was pubertal maturation. There was a greater relative deposition of central body fat with increasing age. Multiple regression analysis demonstrated that waist circumference was the best simple measure of fat distribution, since it was least affected by gender, race, and overall adiposity. Waist circumference is easy to determine and is a useful measure of fat distribution for children and adolescents.

Estradiol and testosterone effects on lipids in black and white boys aged 10 to 15 years.

Previous studies of lipids in adolescent males have shown greater increases in triglycerides and decreases in high-density lipoprotein cholesterol (HDL-C) in white boys compared with black boys, significant correlations between sex hormones and lipids, and complex body mass index (BMI) hormone-lipid associations. Within this frame of reference, we assessed race, BMI, and sex hormones as predictors of lipid parameters in 536 black and white boys recruited from area schools. Black boys were more advanced in puberty than white boys. After adjusting for pubertal stage, estradiol (E2) levels were higher in black boys but free testosterone (T) levels did not differ. Age, pubertal stage, race, BMI, free T, and E2 were entered as explanatory variables for lipids in backward stepwise regression analyses. The BMI and race were retained in every model. Black boys had lower triglycerides and apolipoprotein B (apo B) and higher HDL-C. E2 was inversely associated with total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), apo B, and the LDL-C/HDL-C ratio. Free T was inversely associated with HDL-C and positively associated with apo B. Given the increases in free T and E2 during adolescence and the association of these hormones with both atherogenic and protective lipid parameters, racial differences in E2 could contribute to the more atherogenic lipid profile found in white boys after puberty.

Exposure assessment for a large epidemiological study of aircraft manufacturing workers.

Methods were developed to assess exposure to a wide variety of chemicals for nearly 80,000 workers involved in manufacturing aircraft since 1928. The facilities, now closed, consisted of four major plants, over 200 buildings, and a changing workforce during 60 years of operation. To access chemical exposures by specific jobs and calendar years, we reviewed complete work histories, examined detailed job descriptions available going back to 1940, interviewed long-term employees, conducted walk-through visits of aircraft manufacturing plants, reviewed comprehensive environmental assessment reports and industrial hygiene surveys on the facilities, and built on experience gained in previous studies of the aircraft industry. Using computer-based imaging systems, we examined and evaluated the complete work histories found on service record cards for the cohort and abstracted detailed information on all jobs held among the factory workers who had been employed for at least one year. Jobs were classified into one of three exposure categories related to the use of specific chemicals: routine, intermittent, and none, and these classifications were subsequently used in the epidemiological analyses. The approach to exposure assessment began with the most general categorization of employees (i.e., all workers) and then became progressively more specific, that is, factor workers, job families (similar activities), job titles, and jobs with chemical usage (exposure potential). Because exposure surveys were limited or absent during the early years of plant operations, we did not assign quantitative measures of exposure to individual job activities. Instead, we used as our exposure metric, the length of time spent in jobs with potential exposure to the chemical. Important occupational exposures included chromate-containing compounds such as used in paint primers, trichloroethylene and perchloroethylene used as vapor-state degreasing solvents, and a broad range of other solvents.

Surreptitious superwarfarin ingestion with brodifacoum.

Physicians must have a high index of suspicion when patients have unexplained prolongation of the prothrombin time and bleeding in the absence of detectable warfarin. Several common rodenticides contain modified versions of warfarin that are not detectable in standard warfarin assays. We present a case of surreptitious brodifacoum ingestion in a patient who had years of unexplained bleeding and negative warfarin levels.

Serum glutathione in adolescent males predicts parental coronary heart disease.

BACKGROUND: Traditional risk factors account for only half of the morbidity and mortality from coronary heart disease (CHD). There is substantial evidence that oxidative injury plays a major role in the atherosclerotic process. Thus, antioxidants may protect against development of atherosclerosis. Glutathione, an intracellular tripeptide with antioxidant properties, may be protective. METHODS AND RESULTS: This case-control study compared total serum glutathione (tGSH) in 81 adolescent male offspring of parents with premature CHD (ie, before 56 years of age) and 78 control male offspring of parents without known or suspected CHD. Case offspring had significantly lower tGSH than control offspring. In multiple logistic regression with parental CHD status as the dependent variable, age entered as a covariate, and other CHD risk factors competing to enter the model as significant independent predictor variables, LDL cholesterol (odds ratio [OR], 2.15 [units=1.5 SD]; 95% CI, 1.21 to 3.82), tGSH (OR, 0.40; 95% CI, 0.22 to 0.71), HDL cholesterol (OR, 0.42; 95% CI, 0.22 to 0.78), and total serum homocysteine (OR, 2.6; 95% CI, 1.35 to 5.02) entered the model as significant predictors of parental CHD status. CONCLUSIONS: Low tGSH in adolescent boys is a significant independent predictor of parental CHD, in addition to elevated LDL cholesterol, low HDL cholesterol, and elevated total serum homocysteine concentrations.