Increased Sensitivity of DNA Damage Response-Deficient Cells to Stimulated Microgravity-Induced DNA Lesions

Microgravity is a major stress factor that astronauts have to face in space. In the past, the effects of microgravity on genomic DNA damage were studied, and it seems that the effect on genomic DNA depends on cell types and the length of exposure time to microgravity or simulated microgravity (SMG). In this study we used mouse embryonic stem (MES) and mouse embryonic fibroblast (MEF) cells to assess the effects of SMG on DNA lesions. To acquire the insight into potential mechanisms by which cells resist and/or adapt to SMG, we also included Rad9-deleted MES and Mdc1-deleted MEF cells in addition to wild type cells in this study. We observed significant SMG-induced DNA double strand breaks (DSBs) in Rad9 ^-/- MES and Mdc1 ^-/- MEF cells but not in their corresponding wild type cells. A similar pattern of DNA single strand break or modifications was also observed in Rad9 ^-/- MES. As the exposure to SMG was prolonged, Rad9 ^-/- MES cells adapted to the SMG disturbance by reducing the induced DNA lesions. The induced DNA lesions in Rad9 ^-/- MES were due to SMG-induced reactive oxygen species (ROS). Interestingly, Mdc1 ^-/- MEF cells were only partially adapted to the SMG disturbance. That is, the induced DNA lesions were reduced over time, but did not return to the control level while ROS returned to a control level. In addition, ROS was only partially responsible for the induced DNA lesions in Mdc1 ^-/- MEF cells. Taken together, these data suggest that SMG is a weak genomic DNA stress and can aggravate genomic instability in cells with DNA damage response (DDR) defects.     

First-In-Human,Double-Blind,Placebo-Controlled,Randomized, Dose-Escalation Study of BG00010, a Glial Cell Line-Derived Neurotrophic Factor Family Member,in Subjects with Unilateral Sciatica

ObjectiveTo evaluate the safety, tolerability, and pharmacokinetics of single doses of BG00010 (neublastin, artemin, enovin) in subjects with unilateral sciatica.MethodsThis was a single-center, blinded, placebo-controlled, randomized Phase 1 sequential-cohort, dose-escalation study (ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00961766","term_id":"NCT00961766"}}NCT00961766; funded by Biogen Idec). Adults with unilateral sciatica were enrolled at The Royal Adelaide Hospital, Australia. Four subjects were assigned to each of eleven cohorts (intravenous BG00010 0.3, 1, 3, 10, 25, 50, 100, 200, 400, or 800 μg/kg, or subcutaneous BG00010 50 μg/kg) and were randomized 3:1 to receive a single dose of BG00010 or placebo. The primary safety and tolerability assessments were: adverse events; clinical laboratory parameters and vital signs; pain as measured by a Likert rating scale; intra-epidermal nerve fiber density; and longitudinal assessment of quantitative sensory test parameters. Blood, serum, and plasma samples were collected for pharmacokinetic and pharmacodynamic assessments. Subjects were blinded to treatment assignment throughout the study. The investigator was blinded to treatment assignment until the Data Safety Review Committee review of unblinded data, which occurred after day 28.ResultsBeyond the planned enrollment of 44 subjects, four additional subjects were enrolled into to the intravenous BG00010 200 μg/kg cohort after one original subject experienced mild generalized pruritus. Therefore, a total of 48 subjects were enrolled between August 2009 and December 2011; all were included in the safety analyses. BG00010 was generally well tolerated: in primary analyses, the most common treatment-emergent adverse events were changes in temperature perception, pruritus, rash, or headache; no trends were observed in clinical laboratory parameters, vital signs, intra-epidermal nerve fiber density, or quantitative sensory testing. BG00010 was not associated with any clear, dose-dependent trends in Likert pain scores. BG00010 was rapidly distributed, with a prolonged terminal elimination phase.ConclusionsThese data support the development of BG00010 for the treatment of neuropathic pain.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00961766","term_id":"NCT00961766"}}NCT00961766     

Nevirapine Concentration in Hair Samples Is a Strong Predictor of Virologic Suppression in a Prospective Cohort of HIV-Infected Patients

Effective antiretroviral (ARV) therapy depends on adequate drug exposure, yet methods to assess ARV exposure are limited. Concentrations of ARV in hair are the product of steady-state pharmacokinetics factors and longitudinal adherence. We investigated nevirapine (NVP) concentrations in hair as a predictor of treatment response in women receiving ARVs. In participants of the Women’s Interagency HIV Study, who reported NVP use for >1 month from 2003–2008, NVP concentrations in hair were measured via liquid-chromatography-tandem mass-spectrometry. The outcome was virologic suppression (plasma HIV RNA below assay threshold) at the time of hair sampling and the primary predictor was nevirapine concentration categorized into quartiles. We controlled for age, race/ethnicity, pre-treatment HIV RNA, CD4 cell count, and self-reported adherence over the 6-month visit interval (categorized ≤ 74%, 75%–94% or ≥ 95%). We also assessed the relation of NVP concentration with changes in hepatic transaminase levels via multivariate random intercept logistic regression and linear regression analyses. 271 women contributed 1089 person-visits to the analysis (median 3 of semi-annual visits). Viral suppression was least frequent in concentration quartile 1 (86/178 (48.3%)) and increased in higher quartiles (to 158/204 (77.5%) for quartile 4). The odds of viral suppression in the highest concentration quartile were 9.17 times (95% CI 3.2–26, P < 0.0001) those in the lowest. African-American race was associated with lower rates of virologic suppression independent of NVP hair concentration. NVP concentration was not significantly associated with patterns of serum transaminases. Concentration of NVP in hair was a strong independent predictor of virologic suppression in women taking NVP, stronger than self-reported adherence, but did not appear to be strongly predictive of hepatotoxicity.     

Decline in Coronary Mortality in Sweden between 1986 and 2002: Comparing Contributions from Primary and Secondary Prevention

BackgroundThe relative importance of risk factor reduction in healthy people (primary prevention) versus that in patients with coronary heart disease (secondary prevention) has been debated. We aimed to quantify the contribution of the two.MethodologyWe used the previously validated IMPACT model to estimate contributions from primary prevention (reducing risk factors in the population, particularly smoking, cholesterol and systolic blood pressure) and from secondary prevention (reducing risk factors in coronary heart disease patients) in the Swedish population.ConclusionsThe largest effects on mortality came from primary prevention, giving markedly larger mortality reductions than secondary prevention.     

Multimodal Discrimination of Alzheimer’s Disease Based on Regional Cortical Atrophy and Hypometabolism

Structural MR image (MRI) and ¹⁸F-Fluorodeoxyglucose-positron emission tomography (FDG-PET) have been widely employed in diagnosis of both Alzheimer’s disease (AD) and mild cognitive impairment (MCI) pathology, which has led to the development of methods to distinguish AD and MCI from normal controls (NC). Synaptic dysfunction leads to a reduction in the rate of metabolism of glucose in the brain and is thought to represent AD progression. FDG-PET has the unique ability to estimate glucose metabolism, providing information on the distribution of hypometabolism. In addition, patients with AD exhibit significant neuronal loss in cerebral regions, and previous AD research has shown that structural MRI can be used to sensitively measure cortical atrophy. In this paper, we introduced a new method to discriminate AD from NC based on complementary information obtained by FDG and MRI. For accurate classification, surface-based features were employed and 12 predefined regions were selected from previous studies based on both MRI and FDG-PET. Partial least square linear discriminant analysis was employed for making diagnoses. We obtained 93.6% classification accuracy, 90.1% sensitivity, and 96.5% specificity in discriminating AD from NC. The classification scheme had an accuracy of 76.5% and sensitivity and specificity of 46.5% and 89.6%, respectively, for discriminating MCI from AD. Our method exhibited a superior classification performance compared with single modal approaches and yielded parallel accuracy to previous multimodal classification studies using MRI and FDG-PET.     

Helicobacter pylori,HIV and Gastric Hypochlorhydria in the Malawian Population

Background

HIV and Helicobacter pylori are common chronic infections in sub-Saharan Africa. Both conditions can predispose to gastric hypochlorhydria that may be a risk factor for enteric infections and reduced drug absorption. We have investigated to what extent HIV and H. pylori infections are associated with hypochlorhydria in a Malawian cohort of patients undergoing endoscopy.

Methods

104 sequential symptomatic adults referred for gastroscopy at Queen Elizabeth Central Hospital, Blantyre, Malawi, had blood taken for rapid HIV testing and fasting serum gastrin analysis. Gastric fluid was aspirated for pH testing, and gastric biopsies were taken.

Results

After 9/104 HIV-infected patients who were already established on anti-retroviral therapy were excluded, 17/95 (25.0%) were seropositive for untreated HIV, and 68/95 (71.6%) patients were H. pylori positive by histology. Hypochlorhydria (fasting gastric pH>4.0) was present in 55.8% (53/95) of patients. H. pylori infection was significantly associated with hypochlorhydria (OR 2.91, [1.02-7.75], p=0.046). While single infection with HIV was not significantly independently associated with hypochlorhydria. H. pylori and HIV co-infection was more strongly associated with hypochlorhydria (OR 6.25, [1.33-29.43], p=0.020) than either infection alone, suggesting an additive effect of co-infection. HIV infection was associated with higher serum gastrin levels (91.3pM vs. 53.1pM, p=0.040), while H. pylori infection was not (63.1pM vs. 55.1pM, p=0.610). Irrespective of H. pylori and HIV status, most patients (>90%) exhibited pangastritis. Only three patients had histological evidence of gastric atrophy, of which only one was HIV-infected.

Conclusion

H. pylori infection was associated with fasting hypochlorhydria, while HIV was not independently associated. HIV and H. pylori co-infection, however, was more strongly associated with hypochlorhydria than H. pylori infection alone. The mechanism of this apparent additive effect between HIV and H. pylori remains unclear, but appears to be related to chronic pangastritis rather than gastric atrophy, and associated with hypergastrinaemia in HIV-infected individuals.     

Stable individual differences in separation calls during early development in cats and mice

Background

The development of ethologically meaningful test paradigms in young animals is an essential step in the study of the ontogeny of animal personality. Here we explore the possibility to integrate offspring separation (distress) calls into the study of consistent individual differences in behaviour in two species of mammals, the domestic cat (Felis silvestris catus) and the mound-building mouse (Mus spicilegus). Such vocal responses in young mammals are a potentially useful test option as they represent an important element of mother-offspring communication with strong implications for offspring survival. In addition, the neural control of vocalisation is closely associated with emotional state.

Results

We found marked similarities in the pattern of individual responses of the young of both species to separation from their mother and littermates. In the domestic cat as well as in the mound-building mouse, individual differences in the frequency of calls and to a lesser extent in locomotor activity were repeatable across age, indicating the existence of personality types. Such consistencies across age were also apparent when only considering relative individual differences among litter siblings. In both species, however, individual patterns of vocalisation and locomotor activity were unrelated. This suggests that these two forms of behavioural responses to isolation represent different domains of personality, presumably based on different underlying neurophysiological mechanisms.

Conclusions

Brief separation experiments in young mammals, and particularly the measurement of separation calls, provide a promising approach to study the ontogeny of personality traits. Future long-term studies are needed to investigate the association of these traits with biologically meaningful and potentially repeatable elements of behaviour during later life.

     

Gender difference in N170 elicited under oddball task

Background

Some studies have reported gender differences in N170, a face-selective event-related potential (ERP) component. This study investigated gender differences in N170 elicited under oddball paradigm in order to clarify the effect of task demand on gender differences in early facial processing.

Findings

Twelve males and 10 females discriminated targets (emotional faces) from non-targets (emotionally neutral faces) under an oddball paradigm, pressing a button as quickly as possible in response to the target. Clear N170 was elicited in response to target and non-target stimuli in both males and females. However, females showed more negative amplitude of N170 in response to target compared with non-target, while males did not show different N170 responses between target and non-target.

Conclusions

The present results suggest that females have a characteristic of allocating attention at an early stage when responding to faces actively (target) compared to viewing faces passively (non-target). This supports previous findings suggesting that task demand is an important factor in gender differences in N170.     

Exploration of Chronic Kidney Disease Prevalence Estimates Using New Measures of Kidney Function in the Health Survey for England

BackgroundChronic kidney disease (CKD) diagnosis relies on glomerular filtration rate (eGFR) estimation, traditionally using the creatinine-based Modification of Diet in Renal Disease (MDRD) equation. The Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equation performs better in estimating eGFR and predicting mortality and CKD progression risk. Cystatin C is an alternative glomerular filtration marker less influenced by muscle mass. CKD risk stratification is improved by combining creatinine eGFR with cystatin C and urinary albumin to creatinine ratio (uACR). We aimed to identify the impact of introducing CKDEPI and cystatin C on the estimated prevalence and risk stratification of CKD in England and to describe prevalence and associations of cystatin C.LimitationsCross sectional study, single eGFR measure, no measured (‘true’) GFR.ConclusionsIntroducing the CKDEPI equation and targeted cystatin C measurement reduces estimated CKD prevalence and improves risk stratification.