Development and Evaluation of New Accelerometer Cut Points for Adolescent Girls

Current negative trends in adolescent disease risk factors (e.g., overweight) may be related to physical activity. To study these relationships using accelerometers, how to estimate physical activity from accelerometer counts must be better understood. PURPOSES: (1) To develop new accelerometer cut points for estimating physical activity using disease risk factors as criteria. (2) To evaluate how estimates of physical activity using these newly developed cut points agree with comparison measures (i.e., a previously suggested cut point and self-report physical activity recall questionnaires). METHODS: National Health and Nutrition Examination Survey (NHANES) and Trial of Activity for Adolescent Girls (TAAG) data were examined. New cut points were developed using iterative correlations and signal detection and receiver operating characteristic (ROC) curves. To identify new cut points, potential cut points were identified in a development sample and validated in an evaluation sample. Agreement between new cut points and comparison measures was examined using concordance correlation coefficients, Bland-Altman plots, McNemar's tests, and proportions of agreement. RESULTS: Using the correlation method, two new combinations of light, moderate, and vigorous intensity cut points were identified in NHANES (1900, 4300, and 10000 counts/min and 1900, 4000, and 5000 counts/min) and two in TAAG (1450, 1950, and 2450 counts/30 sec and 1050, 1550, and 2050 counts/30 sec). Using the signal detection/ROC curve method, eleven new cut points were identified in NHANES (ranging from 100 to 2300 counts/min) and three in TAAG (ranging from 100 to 200 counts/min). Concordance correlation coefficients for minutes of activity with a previously suggested cut point tended to be stronger (≥ 0.60) with higher cut points (≥ 2300 count/min), while those with questionnaires were less than 0.10 or the 95% confidence intervals included zero. One new cut point (1800 counts/min) was similar (p = 0.6) to a comparison measure for classifying meeting recommendations. CONCLUSIONS: Some cut points may be more strongly associated with disease risk factors than previously suggested cut points developed using oxygen consumption, but associations are not strong. The new cut points and comparison measures may be measuring different aspects of physical activity, as they were in poor agreement

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Identifying Adolescent Metabolic Syndrome Using Body Mass Index and Waist Circumference

IntroductionMetabolic syndrome is increasing among adolescents. We examined the utility of body mass index (BMI) and waist circumference to identify metabolic syndrome in adolescent girls.MethodsWe conducted a cross-sectional analysis of 185 predominantly African American girls who were a median age of 14 years. Participants were designated as having metabolic syndrome if they met criteria for 3 of 5 variables: 1) high blood pressure, 2) low high-density lipoprotein cholesterol level, 3) high fasting blood glucose level, 4) high waist circumference, and 5) high triglyceride level. We predicted the likelihood of the presence of metabolic syndrome by using previously established cutpoints of BMI and waist circumference. We used stepwise regression analysis to determine whether anthropometric measurements significantly predicted metabolic syndrome.ResultsOf total participants, 18% met the criteria for metabolic syndrome. BMI for 118 (64%) participants was above the cutpoint. Of these participants, 25% met the criteria for metabolic syndrome, whereas only 4% of participants with a BMI below the cutpoint met the criteria for metabolic syndrome (P <.001). Girls with a BMI above the cutpoint were more likely than girls with a BMI below the cutpoint to have metabolic syndrome (P = .002). The waist circumference for 104 (56%) participants was above the cutpoint. Of these participants, 28% met the criteria for metabolic syndrome, whereas only 1% of participants with a waist circumference below the cutpoint met the criteria for metabolic syndrome (P <.001). Girls with a waist circumference above the cutpoint were more likely than girls with a waist circumference below the cutpoint to have metabolic syndrome (P = .002). Stepwise regression showed that only waist circumference significantly predicted metabolic syndrome.ConclusionBoth anthropometric measures were useful screening tools to identify metabolic syndrome. Waist circumference was a better predictor of metabolic syndrome than was BMI in our study sample of predominantly African American female adolescents living in an urban area

Associations Between Family Support, Family Intimacy, and Neighborhood Violence and Physical Activity in Urban Adolescent Girls

We examined the association between various dimensions of the family environment, including family intimacy and involvement in activities, family support for physical activity, and neighborhood violence (perceived and objective) and physical activity among urban, predominantly African American, ninth-grade girls in Baltimore, Md. Greater family intimacy (P=.05) and support (P=.01), but not neighborhood violence, was associated with physical activity. Family factors, including family intimacy and support, are potential targets in physical activity interventions for urban high-school girls

Rotavirus is associated with decompensated diarrhea among young rhesus macaques (Macaca mulatta)

Diarrhea with secondary decompensation is the main cause of morbidity and mortality in captive young rhesus macaque (Macaca mulatta) colonies. Approximately 25% of diarrhea cases with secondary decompensation are considered to be idiopathic chronic diarrhea. The purpose of this study was to investigate the suspected but not systematically examined association between rotavirus infection and diarrhea with secondary decompensation among young rhesus macaques at the California National Primate Research Center (CNPRC). Blood and stool samples were collected from 89 randomly selected young animals (age range: 6 months to 1.5 years) and were tested for the presence of rotavirus antibody, and rotavirus antigen, respectively, using enzyme-linked immunosorbent assays (ELISA's). Test and clinical data were analyzed using Fisher's exact tests and multivariate logistic regression model. Our analysis indicates that rotavirus is endemic among young outdoor-housed rhesus macaques at the CNPRC. Although the relationship between detectable rotavirus antigen in stool and symptomatic diarrhea with secondary decompensation was not significant, there was a significant association between rotavirus seropositivity and a history of diarrhea with secondary decompensation within the past 6 months. While our cross-sectional and case-control study suggests an association between rotavirus infection and diarrhea with secondary decompensation among captive rhesus macaques, more extensive longitudinal studies on larger cohorts and with more intensive sample collection are needed to confirm these findings

Novel Inhibitors of InhA Efficiently Kill Mycobacterium tuberculosis under Aerobic and Anaerobic Conditions▿

Drug resistance in Mycobacterium tuberculosis has become a serious global health threat, which is now complicated by the emergence of extensively drug-resistant strains. New drugs that are active against drug-resistant tuberculosis (TB) are needed. We chose to search for new inhibitors of the enoyl-acyl carrier protein (ACP) reductase InhA, the target of the first-line TB drug isoniazid (also known as isonicotinoic acid hydrazide [INH]). A subset of a chemical library, composed of 300 compounds inhibiting Plasmodium falciparum enoyl reductase, was tested against M. tuberculosis. Four compounds were found to inhibit M. tuberculosis growth with MICs ranging from 1 μM to 10 μM. Testing of these compounds against M. tuberculosis in vitro revealed that only two compounds (CD39 and CD117) were bactericidal against drug-susceptible and drug-resistant M. tuberculosis. These two compounds were also bactericidal against M. tuberculosis incubated under anaerobic conditions. Furthermore, CD39 and CD117 exhibited increased bactericidal activity when used in combination with INH or rifampin, but CD39 was shown to be toxic to eukaryotic cells. The compounds inhibit InhA as well the fatty acid synthase type I, and CD117 was found to also inhibit tuberculostearic acid synthesis. This study provides the TB drug development community with two chemical scaffolds that are suitable for structure-activity relationship study to improve on their cytotoxicities and bactericidal activities in vitro and in vivo

HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat.

BackgroundA single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4(+) T cells of treated, aviremic human immunodeficiency virus (HIV)-positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge.MethodsFive participants in whom resting CD4(+) T-cell-associated HIV RNA (rc-RNA) increased after a single dose of VOR agreed to receive daily VOR Monday through Wednesday for 8 weekly cycles. VOR serum levels, peripheral blood mononuclear cell histone acetylation, plasma HIV RNA single-copy assays, rc-RNA, total cellular HIV DNA, and quantitative viral outgrowth assays from resting CD4(+) T cells were assayed.ResultsVOR was well tolerated, with exposures within expected parameters. However, rc-RNA measured after dose 11 (second dose of cycle 4) or dose 22 (second dose of cycle 8) increased significantly in only 3 of the 5 participants, and the magnitude of the rc-RNA increase was much reduced compared with that after a single dose. Changes in histone acetylation were blunted. Results of quantitative viral outgrowth and other assays were unchanged.ConclusionsAlthough HIV latency is disrupted by an initial VOR dose, the effect of subsequent doses in this protocol was much reduced. We hypothesize that the global effect of VOR results in a refractory period of ≥ 24 hours. The optimal schedule for VOR administration is still to be defined