The Hydroxylase Inhibitor Dimethyloxallyl Glycine Attenuates Endotoxic Shock Via Alternative Activation of Macrophages and IL-10 Production by B1 Cells

Localized tissue hypoxia is a feature of infection and inflammation, resulting in the upregulation of the transcription factors HIF-1α and NF-κB via inhibition of oxygen sensing hydroxylase enzymes. Previous studies have demonstrated a beneficial role for the hydroxylase inhibitor dimethyloxallyl glycine (DMOG) in inflammatory conditions, including experimental colitis, by regulating the activity of HIF-1 and NF-κB. We have demonstrated in vivo that pre-treatment with DMOG attenuates systemic LPS-induced activation of the NF-κB pathway. Furthermore, mice treated with DMOG had significantly increased survival in LPS-induced shock. Conversely, in models of polymicrobial sepsis, DMOG exacerbates disease severity. DMOG treatment of mice promotes M2 polarization in macrophages within the peritoneal cavity, resulting in the downregulation of pro-inflammatory cytokines such as TNFα. In addition, in vivo DMOG treatment upregulates IL-10 expression, specifically in the peritoneal B-1 cell population. This study demonstrates cell type specific roles for hydroxylase inhibition in vivo and provides insight into the mechanism underlying the protection conveyed by DMOG in models of endotoxic shock

Exclusively cephalic venous access for cardiac resynchronisation: A prospective multi-centre evaluation.

BACKGROUND: Small series has shown that cardiac resynchronisation therapy (CRT) can be achieved in a majority of patients using exclusively cephalic venous access. We sought to determine whether this method is suitable for widespread use. METHODS: A group of 19 operators including 11 trainees in three pacing centres attempted to use cephalic access alone for all CRT device implants over a period of 8 years. The access route for each lead, the procedure outcome, duration, and complications were collected prospectively. Data were also collected for 105 consecutive CRT device implants performed by experienced operators not using the exclusively cephalic method. RESULTS: A new implantation of a CRT device using exclusively cephalic venous access was attempted in 1091 patients (73.6% male, aged 73 ± 12 years). Implantation was achieved using cephalic venous access alone in 801 cases (73.4%) and using a combination of cephalic and other access in a further 180 (16.5%). Cephalic access was used for 2468 of 3132 leads implanted (78.8%). Compared to a non-cephalic reference group, complications occurred less frequently (69/1091 vs 12/105; P = .0468), and there were no pneumothoraces with cephalic implants. Procedure and fluoroscopy duration were shorter (procedure duration 118 ± 45 vs 144 ± 39 minutes, P < .0001; fluoroscopy duration 15.7 ± 12.9 vs 22.8 ± 12.2 minutes, P < .0001). CONCLUSIONS: CRT devices can be implanted using cephalic access alone in a substantial majority of cases. This approach is safe and efficient

Type Ia Supernovae as Stellar Endpoints and Cosmological Tools

Empirically, Type Ia supernovae are the most useful, precise, and mature tools for determining astronomical distances. Acting as calibrated candles they revealed the presence of dark energy and are being used to measure its properties. However, the nature of the SN Ia explosion, and the progenitors involved, have remained elusive, even after seven decades of research. But now new large surveys are bringing about a paradigm shift --- we can finally compare samples of hundreds of supernovae to isolate critical variables. As a result of this, and advances in modeling, breakthroughs in understanding all aspects of SNe Ia are finally starting to happen.Comment: Invited review for Nature Communications. Final published version. Shortened, update

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years

Upregulation of the cell-cycle regulator RGC-32 in Epstein-Barr virus-immortalized cells

Epstein-Barr virus (EBV) is implicated in the pathogenesis of multiple human tumours of lymphoid and epithelial origin. The virus infects and immortalizes B cells establishing a persistent latent infection characterized by varying patterns of EBV latent gene expression (latency 0, I, II and III). The CDK1 activator, Response Gene to Complement-32 (RGC-32, C13ORF15), is overexpressed in colon, breast and ovarian cancer tissues and we have detected selective high-level RGC-32 protein expression in EBV-immortalized latency III cells. Significantly, we show that overexpression of RGC-32 in B cells is sufficient to disrupt G2 cell-cycle arrest consistent with activation of CDK1, implicating RGC-32 in the EBV transformation process. Surprisingly, RGC-32 mRNA is expressed at high levels in latency I Burkitt's lymphoma (BL) cells and in some EBV-negative BL cell-lines, although RGC-32 protein expression is not detectable. We show that RGC-32 mRNA expression is elevated in latency I cells due to transcriptional activation by high levels of the differentially expressed RUNX1c transcription factor. We found that proteosomal degradation or blocked cytoplasmic export of the RGC-32 message were not responsible for the lack of RGC-32 protein expression in latency I cells. Significantly, analysis of the ribosomal association of the RGC-32 mRNA in latency I and latency III cells revealed that RGC-32 transcripts were associated with multiple ribosomes in both cell-types implicating post-initiation translational repression mechanisms in the block to RGC-32 protein production in latency I cells. In summary, our results are the first to demonstrate RGC-32 protein upregulation in cells transformed by a human tumour virus and to identify post-initiation translational mechanisms as an expression control point for this key cell-cycle regulator

Distinct Neurocognitive Strategies for Comprehensions of Human and Artificial Intelligence

Although humans have inevitably interacted with both human and artificial intelligence in real life situations, it is unknown whether the human brain engages homologous neurocognitive strategies to cope with both forms of intelligence. To investigate this, we scanned subjects, using functional MRI, while they inferred the reasoning processes conducted by human agents or by computers. We found that the inference of reasoning processes conducted by human agents but not by computers induced increased activity in the precuneus but decreased activity in the ventral medial prefrontal cortex and enhanced functional connectivity between the two brain areas. The findings provide evidence for distinct neurocognitive strategies of taking others' perspective and inhibiting the process referenced to the self that are specific to the comprehension of human intelligence

Esophageal cooling for protection during left atrial ablation: a systematic review and meta-analysis.

PURPOSE: Thermal damage to the esophagus is a risk from radiofrequency (RF) ablation of the left atrium for the treatment of atrial fibrillation (AF). The most extreme type of thermal injury results in atrio-esophageal fistula (AEF) and a correspondingly high mortality rate. Various strategies for reducing esophageal injury have been developed, including power reduction, esophageal deviation, and esophageal cooling. One method of esophageal cooling involves the direct instillation of cold water or saline into the esophagus during RF ablation. Although this method provides limited heat-extraction capacity, studies of it have suggested potential benefit. We sought to perform a meta-analysis of published studies evaluating the use of esophageal cooling via direct liquid instillation for the reduction of thermal injury during RF ablation. METHODS: We searched PubMed for studies that used esophageal cooling to protect the esophagus from thermal injury during RF ablation. We then performed a meta-analysis using a random effects model to calculate estimated effect size with 95% confidence intervals, with an outcome of esophageal lesions stratified by severity, as determined by post-procedure endoscopy. RESULTS: A total of 9 studies were identified and reviewed. After excluding preclinical and mathematical model studies, 3 were included in the meta-analysis, totaling 494 patients. Esophageal cooling showed a tendency to shift lesion severity downward, such that total lesions did not show a statistically significant change (OR 0.6, 95% CI 0.15 to 2.38). For high-grade lesions, a significant OR of 0.39 (95% CI 0.17 to 0.89) in favor of esophageal cooling was found, suggesting that esophageal cooling, even with a low-capacity thermal extraction technique, reduces the severity of lesions resulting from RF ablation. CONCLUSIONS: Esophageal cooling reduces the severity of the lesions that may result from RF ablation, even when relatively low heat extraction methods are used, such as the direct instillation of small volumes of cold liquid. Further investigation of this approach is warranted, particularly with higher heat extraction capacity techniques

The Inviscid Limit and Boundary Layers for Navier-Stokes Flows

The validity of the vanishing viscosity limit, that is, whether solutions of the Navier-Stokes equations modeling viscous incompressible flows converge to solutions of the Euler equations modeling inviscid incompressible flows as viscosity approaches zero, is one of the most fundamental issues in mathematical fluid mechanics. The problem is classified into two categories: the case when the physical boundary is absent, and the case when the physical boundary is present and the effect of the boundary layer becomes significant. The aim of this article is to review recent progress on the mathematical analysis of this problem in each category.Comment: To appear in "Handbook of Mathematical Analysis in Mechanics of Viscous Fluids", Y. Giga and A. Novotn\'y Ed., Springer. The final publication is available at http://www.springerlink.co

Prevalence of low back pain and associated occupational factors among Chinese coal miners

<p>Abstract</p> <p>Background</p> <p>Very few studies have evaluated the association between occupational factors and low back pain (LBP) among miners. The epidemiological data on LBP in Chinese miners are limited. The aim of this study was to measure the prevalence of low back pain in Chinese coal miners and to investigate the role of occupational factors.</p> <p>Methods</p> <p>A cross-sectional survey was conducted to examine 1573 coal miners in northern China. The prevalence of LBP over a 12-month period was assessed using the Nordic Musculoskeletal Questionnaire. Odds ratios were calculated to examine the association between the prevalence of LBP over a 12-month period and occupational factors using logistic regression.</p> <p>Results</p> <p>Among the coal miners, 64.9% self-reported LBP in a 12-month period. Occupational factors associated with LBP were identified, including tasks with a high degree of repetitiveness (OR 1.3, 95%CI 1.0-1.6), tasks characterized by a high level of physical demand (OR 1.4, 95% CI 1.1-1.8), posture requiring extreme bending (OR 1.6, 95% CI 1.2-1.7) and insufficient recovery time (OR 1.4, 95% CI 1.0-1.8).</p> <p>Conclusion</p> <p>Low back pain is common among Chinese miners. There were strong associations with occupational factors.</p