Cohesin promotes the repair of ionizing radiation-induced DNA double-strand breaks in replicated chromatin

The cohesin protein complex holds sister chromatids together after synthesis until mitosis. It also contributes to post-replicative DNA repair in yeast and higher eukaryotes and accumulates at sites of laser-induced damage in human cells. Our goal was to determine whether the cohesin subunits SMC1 and Rad21 contribute to DNA double-strand break repair in X-irradiated human cells in the G2 phase of the cell cycle. RNA interference-mediated depletion of SMC1 sensitized HeLa cells to X-rays. Repair of radiation-induced DNA double-strand breaks, measured by γH2AX/53BP1 foci analysis, was slower in SMC1- or Rad21-depleted cells than in controls in G2 but not in G1. Inhibition of the DNA damage kinase DNA-PK, but not ATM, further inhibited foci loss in cohesin-depleted cells in G2. SMC1 depletion had no effect on DNA single-strand break repair in either G1 or late S/G2. Rad21 and SMC1 were recruited to sites of X-ray-induced DNA damage in G2-phase cells, but not in G1, and only when DNA damage was concentrated in subnuclear stripes, generated by partially shielded ultrasoft X-rays. Our results suggest that the cohesin complex contributes to cell survival by promoting the repair of radiation-induced DNA double-strand breaks in G2-phase cells in an ATM-dependent pathway

Vascular Health in American Football Players: Cardiovascular Risk Increased in Division III Players

Studies report that football players have high blood pressure (BP) and increased cardiovascular risk. There are over 70,000 NCAA football players and 450 Division III schools sponsor football programs, yet limited research exists on vascular health of athletes. This study aimed to compare vascular and cardiovascular health measures between football players and nonathlete controls. Twenty-three athletes and 19 nonathletes participated. Vascular health measures included flow-mediated dilation (FMD) and carotid artery intima-media thickness (IMT). Cardiovascular measures included clinic and 24 hr BP levels, body composition, VO2 max, and fasting glucose/cholesterol levels. Compared to controls, football players had a worse vascular and cardiovascular profile. Football players had thicker carotid artery IMT (0.49 ± 0.06 mm versus 0.46 ± 0.07 mm) and larger brachial artery diameter during FMD (4.3 ± 0.5 mm versus 3.7 ± 0.6 mm), but no difference in percent FMD. Systolic BP was significantly higher in football players at all measurements: resting (128.2 ± 6.4 mmHg versus 122.4 ± 6.8 mmHg), submaximal exercise (150.4 ± 18.8 mmHg versus 137.3 ± 9.5 mmHg), maximal exercise (211.3 ± 25.9 mmHg versus 191.4 ± 19.2 mmHg), and 24-hour BP (124.9 ± 6.3 mmHg versus 109.8 ± 3.7 mmHg). Football players also had higher fasting glucose (91.6 ± 6.5 mg/dL versus 86.6 ± 5.8 mg/dL), lower HDL (36.5±11.2 mg/dL versus 47.1±14.8 mg/dL), and higher body fat percentage (29.2±7.9% versus 23.2±7.0%). Division III collegiate football players remain an understudied population and may be at increased cardiovascular risk

Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end joining (NHEJ) pathway required for the repair of DNA double strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. Methods: We evaluated clinicopathological significance of DNA-PKcs protein expression in 1161 tumours and DNA-PKcs mRNA expression in 1950 tumours. We correlated DNA-PKcs to other markers of aggressive phenotypes, DNA repair, apoptosis and cell cycle regulation. Results: Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps<0.05). Absence of BRCA1, low XRCC1/SMUG1/APE1/Polβ were also more likely in low DNA-PKcs expressing tumours (ps<0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer specific survival (BCCS) in univariate and multivariate analysis (ps<0.01). At the mRNA level, low DNA-PKcs was associated with PAM50.Her2 and PAM50.LumA molecular phenotypes (ps<0.01) and poor BCSS. In patients with ER positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Conclusions: Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers

Early regular egg exposure in infants with eczema: a randomized controlled trial

BackgroundObservational studies suggest that early regular ingestion of allergenic foods might reduce the risk of food allergy.ObjectiveWe sought to determine whether early regular oral egg exposure will reduce subsequent IgE-mediated egg allergy in infants with moderate-to-severe eczema.MethodsIn a double-blind, randomized controlled trial infants were allocated to 1 teaspoon of pasteurized raw whole egg powder (n = 49) or rice powder (n = 37) daily from 4 to 8 months of age. Cooked egg was introduced to both groups after an observed feed at 8 months. The primary outcome was IgE-mediated egg allergy at 12 months, as defined based on the results of an observed pasteurized raw egg challenge and skin prick tests.ResultsA high proportion (31% [15/49]) of infants randomized to receive egg had an allergic reaction to the egg powder and did not continue powder ingestion. At 4 months of age, before any known egg ingestion, 36% (24/67) of infants already had egg-specific IgE levels of greater than 0.35 kilounits of antibody (kUA)/L. At 12 months, a lower (but not significant) proportion of infants in the egg group (33%) were given a diagnosis of IgE-mediated egg allergy compared with the control group (51%; relative risk, 0.65; 95% CI, 0.38-1.11; P = .11). Egg-specific IgG4 levels were significantly (P ConclusionInduction of immune tolerance pathways and reduction in egg allergy incidence can be achieved by early regular oral egg exposure in infants with eczema. Caution needs to be taken when these high-risk infants are first exposed to egg because many have sensitization already by 4 months of age.Debra J. Palmer, Jessica Metcalfe, Maria Makrides, Michael S. Gold, Patrick Quinn, Christina E. West, Richard Loh, and Susan L. Prescot

Seasonal dynamics of the wild rodent faecal virome

Viral discovery studies in wild animals often rely on cross-sectional surveys at a single time point. As a result, our understanding of the temporal stability of wild animal viromes remains poorly resolved. While studies of single host–virus systems indicate that host and environmental factors influence seasonal virus transmission dynamics, comparable insights for whole viral communities in multiple hosts are lacking. Utilizing noninvasive faecal samples from a long-term wild rodent study, we characterized viral communities of three common European rodent species (Apodemus sylvaticus, A. flavicollis and Myodes glareolus) living in temperate woodland over a single year. Our findings indicate that a substantial fraction of the rodent virome is seasonally transient and associated with vertebrate or bacteria hosts. Further analyses of one of the most common virus families, Picornaviridae, show pronounced temporal changes in viral richness and evenness, which were associated with concurrent and up to ~3-month lags in host density, ambient temperature, rainfall and humidity, suggesting complex feedbacks from the host and environmental factors on virus transmission and shedding in seasonal habitats. Overall, this study emphasizes the importance of understanding the seasonal dynamics of wild animal viromes in order to better predict and mitigate zoonotic risks

Lung-specific interleukin 6 mediated transglutaminase 2 activation and cardiopulmonary fibrogenesis

Pulmonary hypertension (PH) pathogenesis is driven by inflammatory and metabolic derangements as well as glycolytic reprogramming. Induction of both interleukin 6 (IL6) and transglutaminase 2 (TG2) expression participates in human and experimental cardiovascular diseases. However, little is known about the role of TG2 in these pathologic processes. The current study aimed to investigate the molecular interactions between TG2 and IL6 in mediation of tissue remodeling in PH. A lung-specific IL6 over-expressing transgenic mouse strain showed elevated right ventricular (RV) systolic pressure as well as increased wet and dry tissue weights and tissue fibrosis in both lungs and RVs compared to age-matched wild-type littermates. In addition, IL6 over-expression induced the glycolytic and fibrogenic markers, hypoxia-inducible factor 1α, pyruvate kinase M2 (PKM2), and TG2. Consistent with these findings, IL6 induced the expression of both glycolytic and pro-fibrogenic markers in cultured lung fibroblasts. IL6 also induced TG2 activation and the accumulation of TG2 in the extracellular matrix. Pharmacologic inhibition of the glycolytic enzyme, PKM2 significantly attenuated IL6-induced TG2 activity and fibrogenesis. Thus, we conclude that IL6-induced TG2 activity and cardiopulmonary remodeling associated with tissue fibrosis are under regulatory control of the glycolytic enzyme, PKM2

Lifestyle and self-rated health: a cross-sectional study of 3,601 citizens of Athens, Greece

<p>Abstract</p> <p>Background</p> <p>Self-rated health (SRH) is a popular health measure determined by multiple factors. International literature is increasingly focusing on health-related behaviors such as smoking, dietary habits, physical activity, even religiosity. However, population-based studies taking into account multiple putative determinants of SRH in Greece are scarce. The aim of this study was to clarify possible determinants of SRH with an emphasis on the relationship between SRH and lifestyle variables in a large sample of urban citizens.</p> <p>Methods</p> <p>In this one-year cross-sectional study, a stratified random sample of 3,601 urban citizens was selected. Data were collected using an interview-based questionnaire about various demographic, socioeconomic, disease- and lifestyle related factors such as smoking, physical activity, dietary habits, sleep quality and religiosity. Multivariate logistic regression was used separately in three age groups [15-29 (N = 1,360), 30-49 (N = 1,122) and 50+ (N = 1,119) years old] in order to identify putative lifestyle and other determinants of SRH.</p> <p>Results</p> <p>Reporting of good SRH decreased with age (97.1%, 91.4% and 74.8%, respectively). Overall, possible confounders of the lifestyle-SRH relationship among age groups were sex, education, hospitalization during the last year, daily physical symptoms and disease status. Poor SRH was associated with less physical activity in the 15-29 years old (OR 2.22, 95%CI 1.14-4.33), with past or heavy smoking, along with no sleep satisfaction in the 30-49 years old (OR 3.23, 95%CI 1.35-7.74, OR 2.56, 95%CI 1.29-5.05, OR 1.79, 95%CI 1.1-2.92, respectively) and with obesity and no sleep satisfaction in the 50+ years old individuals (OR 1.83, 95%CI 1.19-2.81, OR 2.54, 95%CI 1.83-3.54). Sleep dissatisfaction of the 50+ years old was the only variable associated with poor SRH at the 0.001 p level of significance (OR 2.45, 99%CI 1.59 to 3.76). Subgroup analyses of the 15-19 years old individuals also revealed sleep dissatisfaction as the only significant variable correlated with SRH.</p> <p>Conclusions</p> <p>Slight differences in lifestyle determinants of SRH were identified among age groups. Sleep quality emerged as an important determinant of SRH in the majority of participants.</p

Self-rated health of primary care house officers and its relationship to psychological and spiritual well-being

<p/> <p>Background</p> <p>The stress associated with residency training may place house officers at risk for poorer health. We sought to determine the level of self-reported health among resident physicians and to ascertain factors that are associated with their reported health.</p> <p>Methods</p> <p>A questionnaire was administered to house officers in 4 residency programs at a large Midwestern medical center. Self-rated health was determined by using a health rating scale (ranging from 0 = death to 100 = perfect health) and a Likert scale (ranging from "poor" health to "excellent" health). Independent variables included demographics, residency program type, post-graduate year level, current rotation, depressive symptoms, religious affiliation, religiosity, religious coping, and spirituality.</p> <p>Results</p> <p>We collected data from 227 subjects (92% response rate). The overall mean (SD) health rating score was 87 (10; range, 40–100), with only 4 (2%) subjects reporting a score of 100; on the Likert scale, only 88 (39%) reported excellent health. Lower health rating scores were significantly associated (P < 0.05) with internal medicine residency program, post-graduate year level, depressive symptoms, and poorer spiritual well-being. In multivariable analyses, lower health rating scores were associated with internal medicine residency program, depressive symptoms, and poorer spiritual well-being.</p> <p>Conclusion</p> <p>Residents' self-rated health was poorer than might be expected in a cohort of relatively young physicians and was related to program type, depressive symptoms, and spiritual well-being. Future studies should examine whether treating depressive symptoms and attending to spiritual needs can improve the overall health and well-being of primary care house officers.</p