Influence of oxidative stress, diaphragm fatigue, and inspiratory muscle training on the plasma cytokine response to maximum sustainable voluntary ventilation

The influence of oxidative stress, diaphragm fatigue, and inspiratory muscle training (IMT) on the cytokine response to maximum sustainable voluntary ventilation (MSVV) is unknown. Twelve healthy males were divided equally into an IMT or placebo (PLA) group, and before and after a 6-wk intervention they undertook, on separate days, 1h of (1) passive rest and (2) MSVV, whereby participants undertook volitional hyperpnea at rest that mimicked the breathing and respiratory muscle recruitment patterns commensurate with heavy cycling exercise. Plasma cytokines remained unchanged during passive rest. There was a main effect of time (P < 0.01) for plasma interleukin-1 (IL-1) and interleukin-6 (IL-6) concentrations and a strong trend (P = 0.067) for plasma interleukin-1 receptor antagonist concentration during MSVV. Plasma IL-6 concentration was reduced after IMT by 27 + 18% (main effect of intervention, P = 0.029), whereas there was no change after PLA (P = 0.753). There was no increase in a systemic marker of oxidative stress [DNA damage in peripheral blood mononuclear cells (PBMC)], and diaphragm fatigue was not related to the increases in plasma IL-1 and IL-6 concentrations. A dose-response relationship was observed between respiratory muscle work and minute ventilation and increases in plasma IL-6 concentration. In conclusion, increases in plasma IL-1 and IL-6 concentrations during MSVV were not due to diaphragm fatigue or DNA damage in PBMC. Increases in plasma IL-6 concentration during MSVV are attenuated following IMT, and the plasma IL-6 response is dependent upon the level of respiratory muscle work and minute ventilation

Efficacy, Safety, and Timing of Anticoagulant Thromboprophylaxis for the Prevention of Venous Thromboembolism in Patients With Acute Spinal Cord Injury: A Systematic Review

Study Design: Systematic review. Objectives: The objective of this study was to answer 5 key questions: What is the comparative effectiveness and safety of (1a) anticoagulant thromboprophylaxis compared to no prophylaxis, placebo, or another anticoagulant strategy for preventing deep vein thrombosis (DVT) and pulmonary embolism (PE) after acute spinal cord injury (SCI)? (1b) Mechanical prophylaxis strategies alone or in combination with other strategies for preventing DVT and PE after acute SCI? (1c) Prophylactic inferior vena cava filter insertion alone or in combination with other strategies for preventing DVT and PE after acute SCI? (2) What is the optimal timing to initiate and/or discontinue anticoagulant, mechanical, and/or prophylactic inferior vena cava filter following acute SCI? (3) What is the cost-effectiveness of these treatment options? Methods: A systematic literature search was conducted to identify studies published through February 28, 2015. We sought randomized controlled trials evaluating efficacy and safety of antithrombotic strategies. Strength of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Results: Nine studies satisfied inclusion criteria. We found a trend toward lower risk of DVT in patients treated with enoxaparin. There were no significant differences in rates of DVT, PE, bleeding, and mortality between patients treated with different types of low-molecular-weight heparin or between low-molecular-weight heparin and unfractionated heparin. Combined anticoagulant and mechanical prophylaxis initiated within 72 hours of SCI resulted in lower risk of DVT than treatment commenced after 72 hours of injury. Conclusion: Prophylactic treatments can be used to lower the risk of venous thromboembolic events in patients with acute SCI, without significant increase in risk of bleeding and mortality and should be initiated within 72 hours. © 2017, © The Author(s) 2017

Primary Care Screening and Treatment for Latent Tuberculosis Infection in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force

Five to ten percent of individuals with latent tuberculosis infection (LTBI) progress to active tuberculosis (TB) disease. Identifying and treating LTBI is a key component of the strategy for reducing the burden of TB disease. To review the evidence about targeted screening and treatment for LTBI among adults in primary care settings to support the US Preventive Services Task Force in updating its 1996 recommendation. MEDLINE, Cochrane Library, and trial registries, searched through August 3, 2015; references from pertinent articles; and experts. Literature surveillance was conducted through May 31, 2016. English-language studies of LTBI screening, LTBI treatment with recommended pharmacotherapy, or accuracy of the tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). Studies of individuals for whom LTBI screening and treatment is part of public health surveillance or disease management were excluded. Two investigators independently reviewed abstracts and full-text articles. When at least 3 similar studies were available, random-effects meta-analysis was used to generate pooled estimates of outcomes. Sensitivity, specificity, reliability, active TB disease, mortality, hepatotoxicity, and other harms. The review included 72 studies (n = 51 711). No studies evaluated benefits and harms of screening compared with no screening. Pooled estimates for sensitivity of the TST at both 5-mm and 10-mm induration thresholds were 0.79 (5-mm: 95% CI, 0.69-0.89 [8 studies, n = 803]; 10 mm: 95% CI, 0.71-0.87 [11 studies; n = 988]), and those for IGRAs ranged from 0.77 to 0.90 (57 studies; n = 4378). Pooled estimates for specificity of the TST at the 10-mm and 15-mm thresholds and for IGRAs ranged from 0.95 to 0.99 (34 studies; n = 23 853). A randomized clinical trial (RCT) of 24 weeks of isoniazid in individuals with pulmonary fibrotic lesions and LTBI (n = 27 830) found a reduction in absolute risk of active TB at 5 years from 1.4% to 0.5% (relative risk [RR], 0.35 [95% CI, 0.24-0.52]) and an increase in absolute risk for hepatoxicity from 0.1% to 0.5% (RR, 4.59 [95% CI, 2.03-10.39]) for 24 weeks of daily isoniazid compared with placebo. An RCT (n = 6886) found that 3 months of once-weekly rifapentine plus isoniazid was noninferior to 9 months of isoniazid alone for preventing active TB. The risk difference for hepatoxicity comparing isoniazid with rifampin ranged from 3% to 7%, with a pooled RR of 3.29 (95% CI, 1.72-6.28 [3 RCTs; n = 1327]). No studies evaluated the benefits and harms of screening compared with no screening. Both the TST and IGRAs are moderately sensitive and highly specific within countries with low TB burden. Treatment reduced the risk of active TB among the populations included in this review. Isoniazid is associated with higher rates of hepatotoxicity than placebo or rifampin

Emergence of qualia from brain activity or from an interaction of proto-consciousness with the brain: which one is the weirder? Available evidence and a research agenda

This contribution to the science of consciousness aims at comparing how two different theories can explain the emergence of different qualia experiences, meta-awareness, meta-cognition, the placebo effect, out-of-body experiences, cognitive therapy and meditation-induced brain changes, etc. The first theory postulates that qualia experiences derive from specific neural patterns, the second one, that qualia experiences derive from the interaction of a proto-consciousness with the brain\u2019s neural activity. From this comparison it will be possible to judge which one seems to better explain the different qualia experiences and to offer a more promising research agenda

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44.

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating&nbsp;levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health

Pooled analysis of the association of PTGS2 rs5275 polymorphism and NSAID use with invasive ovarian carcinoma risk

Inflammation is postulated to play an important role in ovarian carcinogenesis. Prostaglandin endoperoxide synthase 2 (PTGS2) is responsible for the conversion of arachidonic acid to prostaglandins in response to inflammation. We examined the association of the PTGS2 rs5275 polymorphism with the risk of invasive ovarian carcinoma and the joint effect of rs5275 and use of nonsteroidal antiinflammatory drugs (NSAIDs) on risk in a pooled analysis of two population-based studies, the Hawaii Ovarian Cancer Case-Control Study and the New England Case-Control Study, including 1025 women with invasive ovarian carcinoma and 1687 cancer-free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. In the pooled analysis, the CC genotype was associated with a reduced risk of nonserous ovarian carcinoma (OR=0.66; CI: 0.44-0.98). In addition, the lowest risk was observed among carriers of the CC genotype who were users of nonaspirin NSAIDs (OR=0.43; CI:0.20-0.93) in all women combined. The association of PTGS2 rs5275 with nonserous ovarian carcinoma and possible effect modification by NSAID use needs further validation, preferably in the prospective studies

A clinical practice guideline for the management of patients with acute spinal cord injury: recommendations on the use of methylprednisolone sodium succinate

Introduction: The objective of this guideline is to outline the appropriate use of methylprednisolone sodium succinate (MPSS) in patients with acute spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions related to the use of MPSS in acute SCI. A multidisciplinary Guideline Development Group used this information, in combination with their clinical expertise, to develop recommendations for the use of MPSS. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as "we recommend," whereas a weaker recommendation is indicated by "we suggest." Results: The main conclusions from the systematic review included the following: (1) there were no differences in motor score change at any time point in patients treated with MPSS compared to those not receiving steroids; (2) when MPSS was administered within 8 hours of injury, pooled results at 6- and 12-months indicated modest improvements in mean motor scores in the MPSS group compared with the control group; and (3) there was no statistical difference between treatment groups in the risk of complications. Our recommendations were: (1) "We suggest not offering a 24-hour infusion of high-dose MPSS to adult patients who present after 8 hours with acute SCI"; (2) "We suggest a 24-hour infusion of high-dose MPSS be offered to adult patients within 8 hours of acute SCI as a treatment option"; and (3) "We suggest not offering a 48-hour infusion of high-dose MPSS to adult patients with acute SCI." Conclusions: These guidelines should be implemented into clinical practice to improve outcomes and reduce morbidity in SCI patients

A clinical practice guideline for the management of patients with acute spinal cord injury and central cord syndrome: recommendations on the timing (<= 24 hours versus > 24 hours) of decompressive surgery

Objective: To develop recommendations on the timing of surgical decompression in patients with traumatic spinal cord injury (SCI) and central cord syndrome. Methods: A systematic review of the literature was conducted to address key relevant questions. A multidisciplinary guideline development group used this information, along with their clinical expertise, to develop recommendations for the timing of surgical decompression in patients with SCI and central cord syndrome. Based on GRADE, a strong recommendation is worded as "we recommend," whereas a weak recommendation is presented as "we suggest." Results: Conclusions from the systematic review included (1) isolated studies reported statistically significant and clinically important improvements following early decompression at 6 months and following discharge from inpatient rehabilitation; (2) in one study on acute central cord syndrome without instability, a marginally significant improvement in total motor scores was reported at 6 and 12 months in patients managed with early versus late surgery; and (3) there were no significant differences in length of acute care/rehabilitation stay or in rates of complications between treatment groups. Our recommendations were: "We suggest that early surgery be considered as a treatment option in adult patients with traumatic central cord syndrome" and "We suggest that early surgery be offered as an option for adult acute SCI patients regardless of level." Quality of evidence for both recommendations was considered low. Conclusions: These guidelines should be implemented into clinical practice to improve outcomes in patients with acute SCI and central cord syndrome by promoting standardization of care, decreasing the heterogeneity of management strategies, and encouraging clinicians to make evidence-informed decisions

Association of oestrogen receptor beta 2 (ERβ2/ERβcx) with outcome of adjuvant endocrine treatment for primary breast cancer – a retrospective study

<p>Abstract</p> <p>Background</p> <p>Oestrogen receptor beta (ERβ) modulates ERα activity; wild type ERβ (ERβ1) and its splice variants may therefore impact on hormone responsiveness of breast cancer. ERβ2/ERβcx acts as a dominant negative inhibitor of ERα and expression of ERβ2 mRNA has been proposed as a candidate marker for outcome in primary breast cancer following adjuvant endocrine therapy. We therefore now assess ERβ2 protein by immunostaining and mRNA by quantitative RT-PCR in relation to treatment outcome.</p> <p>Methods</p> <p>ERβ2-specific immunostaining was quantified in 141 primary breast cancer cases receiving adjuvant endocrine therapy, but no neoadjuvant therapy or adjuvant chemotherapy. The expression of mRNA for ERβ2/ERβcx was measured in 100 cases by quantitative RT-PCR. Statistical analysis of breast cancer relapse and breast cancer survival was performed using Kaplan Meier log-rank tests and Cox's univariate and multivariate survival analysis.</p> <p>Results</p> <p>High ERβ2 immunostaining (Allred score >5) and high ERβ2 mRNA levels were independently associated with significantly better outcome across the whole cohort, including both ERα positive and negative cases (Log-Rank P < 0.05). However, only ERβ2 mRNA levels were significantly associated with better outcome in the ERα + subgroup (Log-Rank P = 0.01) and this was independent of grade, size, nodal status and progesterone receptor status (Cox hazard ratio 0.31 P = 0.02 for relapse; 0.17 P = 0.01 for survival). High ERβ2 mRNA was also associated with better outcome in node negative cases (Log Rank P < 0.001).</p> <p>ERβ2 protein levels were greater in ERα positive cases (T-test P = 0.00001), possibly explaining the association with better outcome. Levels of ERβ2 protein did not correlate ERβ2 mRNA levels, but 34% of cases had both high mRNA and protein and had a significantly better outcome (Log-Rank relapse P < 0.005).</p> <p>Conclusion</p> <p>High ERβ2 protein levels were associated with ERα expression. Although most cases with high ERβ2 mRNA had strong ERβ2 immunostaining, mRNA levels but not protein levels were independently predictive of outcome in tamoxifen-treated ERα + tumours. Post-transcriptional control needs to be considered when assessing the biological or clinical importance of ERβ proteins.</p

ERK1/2 phosphorylation is an independent predictor of complete remission in newly diagnosed adult acute lymphoblastic leukemia

Abstract Extracellular signal-regulated kinase-1/2 (ERK1/2) is frequently found constitutively activated (p-ERK1/2) in hematopoietic diseases, suggesting a role in leukemogenesis. The aim of this study was to assess the expression and clinical role of p-ERK1/2 in adult acute lymphoblastic leukemia (ALL). In 131 primary samples from adult de novo ALL patients enrolled in the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) Leucemia Acute Linfoide (LAL) 2000 protocol and evaluated by flow cytometry, constitutive ERK1/2 activation was found in 34.5% of cases; these results were significantly associated with higher white blood cell (WBC) values (P = .013). In a multivariate analysis, p-ERK1/2 expression was an independent predictor of complete remission achievement (P = .027). Effective approaches toward MEK inhibition need to be explored in order to evaluate whether this may represent a new therapeutic strategy for adult ALL patients