Activation of the IκB Kinase Complex and Nuclear Factor-κB Contributes to Mutant Huntingtin Neurotoxicity

Transcriptional dysregulation by mutant huntingtin (Htt) protein has been implicated in the pathogenesis of Huntington's disease (HD). We find that cultured cells expressing mutant Htt and striatal cells from HD transgenic mice have elevated nuclear factor-κB (NF-κB) activity. Furthermore, NF-κB is concentrated in the nucleus of neurons in the brains of HD transgenic mice. In inducible PC12 cells and in HD transgenic mice, mutant Htt activates the IκB kinase complex (IKK), a key regulator of NF-κB. Activation of IKK is likely mediated by direct interaction with mutant Htt, because the expanded polyglutamine stretch and adjacent proline-rich motifs in mutant Htt interact with IKKγ, a regulatory subunit of IKK. Activation of IKK may also influence the toxicity of mutant Htt, because expression of IKKγ promotes aggregation and nuclear localization of mutant Htt exon-1. Moreover, in acute striatal slice cultures, inhibition of IKK activity with an N-terminally truncated form of IKKγ blocks mutant Htt-induced toxicity in medium-sized spiny neurons (MSNs). In addition, blocking degradation of NF-κB inhibitors with a dominant-negative ubiquitin ligase β-transducin repeat-containing protein also reduces the toxicity of mutant Htt in MSNs. Therefore, aberrant NF-κB activation may contribute to the neurodegeneration induced by mutant Htt

Elective Open Suprarenal Aneurysm Repair in England from 2000 to 2010 an Observational Study of Hospital Episode Statistics

Background: Open surgery is widely used as a benchmark for the results of fenestrated endovascular repair of complex abdominal aortic aneurysms (AAA). However, the existing evidence stems from single-centre experiences, and may not be reproducible in wider practice. National outcomes provide valuable information regarding the safety of suprarenal aneurysm repair. Methods: Demographic and clinical data were extracted from English Hospital Episodes Statistics for patients undergoing elective suprarenal aneurysm repair from 1 April 2000 to 31 March 2010. Thirty-day mortality and five-year survival were analysed by logistic regression and Cox proportional hazards modeling. Results: 793 patients underwent surgery with 14% overall 30-day mortality, which did not improve over the study period. Independent predictors of 30-day mortality included age, renal disease and previous myocardial infarction. 5-year survival was independently reduced by age, renal disease, liver disease, chronic pulmonary disease, and known metastatic solid tumour. There was significant regional variation in both 30-day mortality and 5-year survival after risk-adjustment. Regional differences in outcome were eliminated in a sensitivity analysis for perioperative outcome, conducted by restricting analysis to survivors of the first 30 days after surgery. Conclusions: Elective suprarenal aneurysm repair was associated with considerable mortality and significant regional variation across England. These data provide a benchmark to assess the efficacy of complex endovascular repair of supra-renal aneurysms, though cautious interpretation is required due to the lack of information regarding aneurysm morphology. More detailed study is required, ideally through the mandatory submission of data to a national registry of suprarenal aneurysm repair

Effectiveness of physiotherapy exercise following hip arthroplasty for osteoarthritis: a systematic review of clinical trials

Background: Physiotherapy has long been a routine component of patient rehabilitation following hip joint replacement. The purpose of this systematic review was to evaluate the effectiveness of physiotherapy exercise after discharge from hospital on function, walking, range of motion, quality of life and muscle strength, for osteoarthritic patients following elective primary total hip arthroplasty. Methods: Design: Systematic review, using the Cochrane Collaboration Handbook for Systematic Reviews of Interventions and the Quorom Statement. Database searches: AMED, CINAHL, EMBASE, KingsFund, MEDLINE, Cochrane library (Cochrane reviews, Cochrane Central Register of Controlled Trials, DARE), PEDro, The Department of Health National Research Register. Handsearches: Physiotherapy, Physical Therapy, Journal of Bone and Joint Surgery (Britain) Conference Proceedings. No language restrictions were applied. Selection: Trials comparing physiotherapy exercise versus usual/standard care, or comparing two types of relevant exercise physiotherapy, following discharge from hospital after elective primary total hip replacement for osteoarthritis were reviewed. Outcomes: Functional activities of daily living, walking, quality of life, muscle strength and range of hip joint motion. Trial quality was extensively evaluated. Narrative synthesis plus meta-analytic summaries were performed to summarise the data. Results: 8 trials were identified. Trial quality was mixed. Generally poor trial quality, quantity and diversity prevented explanatory meta-analyses. The results were synthesised and meta-analytic summaries were used where possible to provide a formal summary of results. Results indicate that physiotherapy exercise after discharge following total hip replacement has the potential to benefit patients. Conclusion: Insufficient evidence exists to establish the effectiveness of physiotherapy exercise following primary hip replacement for osteoarthritis. Further well designed trials are required to determine the value of post discharge exercise following this increasingly common surgical procedure

Impact of percutaneous coronary intervention timing on 5-year outcome in patients with non-ST-segment elevation acute coronary syndromes. The ‘wait a day’ approach might be safer

Background The OPTIMA trial was a randomised multicentre trial exploring the influence of the timing of percutaneous coronary intervention (PCI) on patient outcomes in an intermediate to high risk non-ST-elevation acute coronary syndrome (NSTE-ACS) population. In order to decide the best treatment strategy for patients presenting with NSTEACS, long-term outcomes are essential. Methods Five-year follow-up data from 133 of the 142 patients could be retrieved (94 %). The primary endpoint was a composite of death and spontaneous myocardial infarction (MI). Spontaneous MI was defined as MI occurring more than 30 days after randomisation. Secondary endpoints were the individual outcomes of death, spontaneous MI or re-PCI. Results No significant difference with respect to the primary endpoint was observed (17.8 vs. 10.1 %; HR 1.55, 95 % CI: 0.73–4.22, p = 0.21). There was no significant difference in mortality rate. However, spontaneous MI was significantly more common in the group receiving immediate PCI (11.0 vs. 1.4 %; HR 4.46, 95 % CI: 1.21–16.50, p = 0.02). We did not find a significant difference between the groups with respect to re-PCI rate. Conclusion There was no difference in the composite of death and spontaneous MI. The trial suggests an increased long-term risk of spontaneous MI for patients treated with immediate PCI

Climate-controlled submarine landslides on the Antarctic continental margin

Antarctica’s continental margins pose an unknown submarine landslidegenerated tsunami risk to Southern Hemisphere populations and infrastructure. Understanding the factors driving slope failure is essential to assessing future geohazards. Here, we present a multidisciplinary study of a major submarine landslide complex along the eastern Ross Sea continental slope (Antarctica) that identifies preconditioning factors and failure mechanisms. Weak layers, identified beneath three submarine landslides, consist of distinct packages of interbedded Miocene- to Pliocene-age diatom oozes and glaciomarine diamicts. The observed lithological differences, which arise from glacial to interglacial variations in biological productivity, ice proximity, and ocean circulation, caused changes in sediment deposition that inherently preconditioned slope failure. These recurrent Antarctic submarine landslides were likely triggered by seismicity associated with glacioisostatic readjustment, leading to failure within the preconditioned weak layers. Ongoing climate warming and ice retreat may increase regional glacioisostatic seismicity, triggering Antarctic submarine landslides

Predicting fitness to practise events in international medical graduates who registered as UK doctors via the Professional and Linguistic Assessments Board (PLAB) system: a national cohort study

Background International medical graduates working in the UK are more likely to be censured in relation to fitness to practise compared to home graduates. Performance on the General Medical Council’s (GMC’s) Professional and Linguistic Assessments Board (PLAB) tests and English fluency have previously been shown to predict later educational performance in this group of doctors. It is unknown whether the PLAB system is also a valid predictor of unprofessional behaviour and malpractice. The findings would have implications for regulatory policy. Methods This was an observational study linking data relating to fitness to practise events (referral or censure), PLAB performance, demographic variables and English language competence, as evaluated via the International English Language Test System (IELTS). Data from 27,330 international medical graduates registered with the GMC were analysed, including 210 doctors who had been sanctioned in relation to at least one fitness to practise issue. The main outcome was risk of eventual censure (including a warning). Results The significant univariable educational predictors of eventual censure (versus no censures or referrals) were lower PLAB part 1 (hazard ratio [HR], 0.99; 95% confidence interval, 0.98 to 1.00) and part 2 scores (HR, 0.94; 0.91 to 0.97) at first sitting, multiple attempts at both parts of the PLAB, lower IELTS reading (HR, 0.79; 0.65 to 0.94) and listening scores (HR, 0.76; 0.62 to 0.93) and higher IELTS speaking scores (HR, 1.28; 1.04 to 1.57). Multiple resits at either part of the PLAB and higher IELTS speaking score (HR, 1.49; 1.20 to 1.84) were also independent predictors of censure. We estimated that the proposed limit of four attempts at both parts of the PLAB would reduce the risk in this entire group by only approximately two censures per 5 years in this group of doctors. Conclusions Making the PLAB, or any replacement assessment, more stringent and raising the required standards of English reading and listening may result in fewer fitness to practice events in international medical graduates. However, the number of PLAB resits permitted would have to be further capped to meaningfully impact the risk of sanctions in this group of doctor

Defining Responses to Therapy and Study Outcomes in Clinical Trials of Invasive Fungal Diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer Consensus Criteria

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledg

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

The Skin Microbiome in Healthy and Allergic Dogs

Changes in the microbial populations on the skin of animals have traditionally been evaluated using conventional microbiology techniques. The sequencing of bacterial 16S rRNA genes has revealed that the human skin is inhabited by a highly diverse and variable microbiome that had previously not been demonstrated by culture-based methods. The goals of this study were to describe the microbiome inhabiting different areas of the canine skin, and to compare the skin microbiome of healthy and allergic dogs. DNA extracted from superficial skin swabs from healthy (n = 12) and allergic dogs (n = 6) from different regions of haired skin and mucosal surfaces were used for 454-pyrosequencing of the 16S rRNA gene. Principal coordinates analysis revealed clustering for the different skin sites across all dogs, with some mucosal sites and the perianal regions clustering separately from the haired skin sites. The rarefaction analysis revealed high individual variability between samples collected from healthy dogs and between the different skin sites. Higher species richness and microbial diversity were observed in the samples from haired skin when compared to mucosal surfaces or mucocutaneous junctions. In all examined regions, the most abundant phylum and family identified in the different regions of skin and mucosal surfaces were Proteobacteria and Oxalobacteriaceae. The skin of allergic dogs had lower species richness when compared to the healthy dogs. The allergic dogs had lower proportions of the Betaproteobacteria Ralstonia spp. when compared to the healthy dogs. The study demonstrates that the skin of dogs is inhabited by much more rich and diverse microbial communities than previously thought using culture-based methods. Our sequence data reveal high individual variability between samples collected from different patients. Differences in species richness was also seen between healthy and allergic dogs, with allergic dogs having lower species richness when compared to healthy dogs.The open access fee for this work was funded through the Texas A&M University Open Access to Knowledge (OAK) Fund

Trajectories of Delinquency and Parenting Styles

We investigated trajectories of adolescent delinquent development using data from the Pittsburgh Youth Study and examined the extent to which these different trajectories are differentially predicted by childhood parenting styles. Based on self-reported and official delinquency seriousness, covering ages 10–19, we identified five distinct delinquency trajectories differing in both level and change in seriousness over time: a nondelinquent, minor persisting, moderate desisting, serious persisting, and serious desisting trajectory. More serious delinquents tended to more frequently engage in delinquency, and to report a higher proportion of theft. Proportionally, serious persistent delinquents were the most violent of all trajectory groups. Using cluster analysis we identified three parenting styles: authoritative, authoritarian (moderately supportive), and neglectful (punishing). Controlling for demographic characteristics and childhood delinquency, neglectful parenting was more frequent in moderate desisters, serious persisters, and serious desisters, suggesting that parenting styles differentiate non- or minor delinquents from more serious delinquents