Skeletal muscle dysfunction is associated with derangements in mitochondrial bioenergetics (but not UCP3) in a rodent model of sepsis

Muscle dysfunction is a common feature of severe sepsis and multi-organ failure. Recent evidence implicates bioenergetic dysfunction and oxidative damage as important underlying pathophysiological mechanisms. Increased abundance of uncoupling protein-3 (UCP-3) in sepsis suggests increased mitochondrial proton leak, which may reduce mitochondrial coupling efficiency but limit ROS production. Using a murine model, we examined metabolic, cardiovascular and skeletal muscle contractile changes following induction of peritoneal sepsis in wild-type and Ucp3(-/-) mice. Mitochondrial membrane potential (Δψm) was measured using two-photon microscopy in living diaphragm, and contractile function was measured in diaphragm muscle strips. The kinetic relationship between membrane potential and oxygen consumption was determined using a modular kinetic approach in isolated mitochondria. Sepsis was associated with significant whole body metabolic suppression, hypothermia and cardiovascular dysfunction. Maximal force generation was reduced and fatigue accelerated in ex vivo diaphragm muscle strips from septic mice. Mitochondrial membrane potential was lower in the isolated diaphragm from septic mice despite normal substrate oxidation kinetics and proton leak in skeletal muscle mitochondria. Even though wild-type mice exhibited an absolute 26 ± 6% higher UCP-3 protein abundance at 24 hours, no differences were seen in whole animal or diaphragm physiology, nor in survival rates, between wild-type and Ucp3(-/-) mice. In conclusion, this murine sepsis model shows a hypometabolic phenotype with evidence of significant cardiovascular and muscle dysfunction. This was associated with lower Δψm and alterations in mitochondrial ATP turnover and phosphorylation pathway. However, UCP-3 does not play an important functional role, despite its upregulation

A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing

BACKGROUND: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. METHODS: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. RESULTS: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p<6.7 × 10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge. CONCLUSIONS: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. FUNDING: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study

Development of the interRAI Pressure Ulcer Risk Scale (PURS) for use in long-term care and home care settings

<p>Abstract</p> <p>Background</p> <p>In long-term care (LTC) homes in the province of Ontario, implementation of the Minimum Data Set (MDS) assessment and The Braden Scale for predicting pressure ulcer risk were occurring simultaneously. The purpose of this study was, using available data sources, to develop a bedside MDS-based scale to identify individuals under care at various levels of risk for developing pressure ulcers in order to facilitate targeting risk factors for prevention.</p> <p>Methods</p> <p>Data for developing the interRAI Pressure Ulcer Risk Scale (interRAI PURS) were available from 2 Ontario sources: three LTC homes with 257 residents assessed during the same time frame with the MDS and Braden Scale for Predicting Pressure Sore Risk, and eighty-nine Ontario LTC homes with 12,896 residents with baseline/reassessment MDS data (median time 91 days), between 2005-2007. All assessments were done by trained clinical staff, and baseline assessments were restricted to those with no recorded pressure ulcer. MDS baseline/reassessment samples used in further testing included 13,062 patients of Ontario Complex Continuing Care Hospitals (CCC) and 73,183 Ontario long-stay home care (HC) clients.</p> <p>Results</p> <p>A data-informed Braden Scale cross-walk scale using MDS items was devised from the 3-facility dataset, and tested in the larger longitudinal LTC homes data for its association with a future new pressure ulcer, giving a c-statistic of 0.676. Informed by this, LTC homes data along with evidence from the clinical literature was used to create an alternate-form 7-item additive scale, the interRAI PURS, with good distributional characteristics and c-statistic of 0.708. Testing of the scale in CCC and HC longitudinal data showed strong association with development of a new pressure ulcer.</p> <p>Conclusions</p> <p>interRAI PURS differentiates risk of developing pressure ulcers among facility-based residents and home care recipients. As an output from an MDS assessment, it eliminates duplicated effort required for separate pressure ulcer risk scoring. Moreover, it can be done manually at the bedside during critical early days in an admission when the full MDS has yet to be completed. It can be calculated with established MDS instruments as well as with the newer interRAI suite instruments designed to follow persons across various care settings (interRAI Long-Term Care Facilities, interRAI Home Care, interRAI Palliative Care).</p

Polymorphisms in immunoregulatory genes and the risk of histologic chorioamnionitis in Caucasoid women: a case control study

BACKGROUND: Chorioamnionitis is a common underlying cause of preterm birth (PTB). It is hypothesised that polymorphisms in immunoregulatory genes influence the host response to infection and subsequent preterm birth. The relationship between histologic chorioamnionitis and 22 single nucleotide polymorphisms in 11 immunoregulatory genes was examined in a case-control study. METHODS: Placentas of 181 Caucasoid women with spontaneous PTB prior to 35 weeks were examined for histologic chorioamnionitis. Polymorphisms in genes IL1A, IL1B, IL1RN, IL1R1, tumour necrosis factor (TNF), IL4, IL6, IL10, transforming growth factor beta-1 (TGFB1), Fas (TNFRSF6), and mannose-binding lectin (MBL2) were genotyped by polymerase chain reaction and sequence specific primers. Multivariable logistic regression including demographic and genetic variables and Kaplan-Meier survival analyses of genotype frequencies and pregnancy outcome were performed. RESULTS: Sixty-nine (34%) women had histologic evidence of acute chorioamnionitis. Carriage of the IL10-1082A/-819T/592A (ATA) haplotype [Multivariable Odds ratio (MOR) 1.9, P = 0.05] and MBL2 codon 54Asp allele (MOR 2.0, P = 0.04), were positively associated with chorioamnionitis, while the TNFRSF6-1377A/-670G (AG) haplotype (MOR 0.4, P = 0.03) and homozygosity for TGFB1-800G/509T (GT) haplotype (MOR 0.2, P = 0.04) were negatively associated. CONCLUSION: These findings demonstrate that polymorphisms in immunoregulatory genes IL10, MBL2, TNFRSF6 and TGFB1 may influence susceptibility to chorioamnionitis

Emergence of rationally designed therapeutic strategies for breast cancer targeting DNA repair mechanisms

Accumulating evidence suggests that many cancers, including BRCA1- and BRCA2-associated breast cancers, are deficient in DNA repair processes. Both hereditary and sporadic breast cancers have been found to have significant downregulation of repair factors. This has provided opportunities to exploit DNA repair deficiencies, whether acquired or inherited. Here, we review efforts to exploit DNA repair deficiencies in tumors, with a focus on breast cancer. A variety of agents, including PARP (poly [ADP-ribose] polymerase) inhibitors, are currently under investigation in clinical trials and available results will be reviewed