High intensity interval training improves liver and adipose tissue insulin sensitivity

Objective: Endurance exercise training reduces insulin resistance, adipose tissue inflammation and non-alcoholic fatty liver disease (NAFLD), an effect often associated with modest weight loss. Recent studies have indicated that high-intensity interval training (HIIT) lowers blood glucose in individuals with type 2 diabetes independently of weight loss; however, the organs affected and mechanisms mediating the glucose lowering effects are not known. Intense exercise increases phosphorylation and inhibition of acetyl-CoA carboxylase (ACC) by AMP-activated protein kinase (AMPK) in muscle, adipose tissue and liver. AMPK and ACC are key enzymes regulating fatty acid metabolism, liver fat content, adipose tissue inflammation and insulin sensitivity but the importance of this pathway in regulating insulin sensitivity with HIIT is unknown. Methods: In the current study, the effects of 6 weeks of HIIT were examined using obese mice with serine–alanine knock-in mutations on the AMPK phosphorylation sites of ACC1 and ACC2 (AccDKI) or wild-type (WT) controls. Results: HIIT lowered blood glucose and increased exercise capacity, food intake, basal activity levels, carbohydrate oxidation and liver and adipose tissue insulin sensitivity in HFD-fed WT and AccDKI mice. These changes occurred independently of weight loss or reductions in adiposity, inflammation and liver lipid content. Conclusions: These data indicate that HIIT lowers blood glucose levels by improving adipose and liver insulin sensitivity independently of changes in adiposity, adipose tissue inflammation, liver lipid content or AMPK phosphorylation of ACC

Leucurogin, a new recombinant disintegrin cloned from Bothrops leucurus (white-tailed-jararaca) with potent activity upon platelet aggregation and tumor growth

Disintegrins and disintegrins-like proteins are able to inhibit platelet aggregation and integrin-mediated cell adhesion. the aim of this study was to produce one disintegrin-like cloned from Bothrops leucurus venom gland and to characterize it regarding biological activity. the recombinant protein was purified by one step procedure involving anion-exchange chromatography (DEAE-cellulose) and presented a molecular mass of 10.4 kDa. the purified protein was able to inhibit platelet aggregation induced by collagen (IC(50) = 0.65 mu M) and to inhibit growth of Ehrlich tumor implanted in mice by more than 50% after 7 days administration of 10 mu g/day. No effects were observed upon adenosine 5'diphosphate (ADP)-and arachidonic acid (AA)-induced platelet aggregation. the recombinant protein was recognized by an antibody specific for jararhagin one metalloproteinase isolated from Bothrops jararaca venom, and therefore it was named leucurogin. Anti-angiogenesis effect of leucurogin was evaluated by the sponge implant model. After 7 days administration leucurogin inhibited, in a dose dependent way, the vascularization process in the sponge. Leucurogin represents a new biotechnological tool to understand biological processes where disintegrins-like are involved and may help to characterize integrins that can be involved in development and progression of malignant cells. (C) 2011 Elsevier B.V. All rights reserved.FAEPFundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Fed Minas Gerais, Inst Ciencias Biol, BR-31270901 Belo Horizonte, MG, BrazilUniv Mogi das Cruzes, Ctr Civ, BR-08780911 São Paulo, BrazilProteobras Desenvolvimento Biotecnol Ltda, BR-13069310 São Paulo, BrazilFundacao Ezequiel Dias, BR-30510010 Belo Horizonte, MG, BrazilUniversidade Federal de São Paulo, Dept Biofis, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biofis, BR-04023062 São Paulo, BrazilWeb of Scienc

Behavioural activation therapy for depression in adults (Review)

This is the final version. Available from Cochrane Collaboration via the DOI in this record. BACKGROUND: Behavioural activation is a brief psychotherapeutic approach that seeks to change the way a person interacts with their environment. Behavioural activation is increasingly receiving attention as a potentially cost-effective intervention for depression, which may require less resources and may be easier to deliver and implement than other types of psychotherapy. OBJECTIVES: To examine the effects of behavioural activation compared with other psychological therapies for depression in adults. To examine the effects of behavioural activation compared with medication for depression in adults. To examine the effects of behavioural activation compared with treatment as usual/waiting list/placebo no treatment for depression in adults. SEARCH METHODS: We searched CCMD-CTR (all available years), CENTRAL (current issue), Ovid MEDLINE (1946 onwards), Ovid EMBASE (1980 onwards), and Ovid PsycINFO (1806 onwards) on the 17 January 2020 to identify randomised controlled trials (RCTs) of 'behavioural activation', or the main elements of behavioural activation for depression in participants with clinically diagnosed depression or subthreshold depression. We did not apply any restrictions on date, language or publication status to the searches. We searched international trials registries via the World Health Organization's trials portal (ICTRP) and ClinicalTrials.gov to identify unpublished or ongoing trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of behavioural activation for the treatment of depression or symptoms of depression in adults aged 18 or over. We excluded RCTs conducted in inpatient settings and with trial participants selected because of a physical comorbidity. Studies were included regardless of reported outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all titles/abstracts and full-text manuscripts for inclusion. Data extraction and 'Risk of bias' assessments were also performed by two review authors in duplicate. Where necessary, we contacted study authors for more information. MAIN RESULTS: Fifty-three studies with 5495 participants were included; 51 parallel group RCTs and two cluster-RCTs. We found moderate-certainty evidence that behavioural activation had greater short-term efficacy than treatment as usual (risk ratio (RR) 1.40, 95% confidence interval (CI) 1.10 to 1.78; 7 RCTs, 1533 participants), although this difference was no longer evident in sensitivity analyses using a worst-case or intention-to-treat scenario. Compared with waiting list, behavioural activation may be more effective, but there were fewer data in this comparison and evidence was of low certainty (RR 2.14, 95% CI 0.90 to 5.09; 1 RCT, 26 participants). No evidence on treatment efficacy was available for behavioural activation versus placebo and behavioural activation versus no treatment. We found moderate-certainty evidence suggesting no evidence of a difference in short-term treatment efficacy between behavioural activation and CBT (RR 0.99, 95% CI 0.92 to 1.07; 5 RCTs, 601 participants). Fewer data were available for other comparators. No evidence of a difference in short term-efficacy was found between behavioural activation and third-wave CBT (RR 1.10, 95% CI 0.91 to 1.33; 2 RCTs, 98 participants; low certainty), and psychodynamic therapy (RR 1.21, 95% CI 0.74 to 1.99; 1 RCT,60 participants; very low certainty). Behavioural activation was more effective than humanistic therapy (RR 1.84, 95% CI 1.15 to 2.95; 2 RCTs, 46 participants; low certainty) and medication (RR 1.77, 95% CI 1.14 to 2.76; 1 RCT; 141 participants; moderate certainty), but both of these results were based on a small number of trials and participants. No evidence on treatment efficacy was available for comparisons between behavioural activation versus interpersonal, cognitive analytic, and integrative therapies. There was moderate-certainty evidence that behavioural activation might have lower treatment acceptability (based on dropout rate) than treatment as usual in the short term, although the data did not confirm a difference and results lacked precision (RR 1.64, 95% CI 0.81 to 3.31; 14 RCTs, 2518 participants). Moderate-certainty evidence did not suggest any difference in short-term acceptability between behavioural activation and waiting list (RR 1.17, 95% CI 0.70 to 1.93; 8 RCTs. 359 participants), no treatment (RR 0.97, 95% CI 0.45 to 2.09; 3 RCTs, 187 participants), medication (RR 0.52, 95% CI 0.23 to 1.16; 2 RCTs, 243 participants), or placebo (RR 0.72, 95% CI 0.31 to 1.67; 1 RCT; 96 participants; low-certainty evidence). No evidence on treatment acceptability was available comparing behavioural activation versus psychodynamic therapy. Low-certainty evidence did not show a difference in short-term treatment acceptability (dropout rate) between behavioural activation and CBT (RR 1.03, 95% CI 0.85 to 1.25; 12 RCTs, 1195 participants), third-wave CBT (RR 0.84, 95% CI 0.33 to 2.10; 3 RCTs, 147 participants); humanistic therapy (RR 1.06, 95% CI 0.20 to 5.55; 2 RCTs, 96 participants) (very low certainty), and interpersonal, cognitive analytic, and integrative therapy (RR 0.84, 95% CI 0.32 to 2.20; 4 RCTs, 123 participants). Results from medium- and long-term primary outcomes, secondary outcomes, subgroup analyses, and sensitivity analyses are summarised in the text. AUTHORS' CONCLUSIONS: This systematic review suggests that behavioural activation may be more effective than humanistic therapy, medication, and treatment as usual, and that it may be no less effective than CBT, psychodynamic therapy, or being placed on a waiting list. However, our confidence in these findings is limited due to concerns about the certainty of the evidence. We found no evidence of a difference in short-term treatment acceptability (based on dropouts) between behavioural activation and most comparison groups (CBT, humanistic therapy, waiting list, placebo, medication, no treatment or treatment as usual). Again, our confidence in all these findings is limited due to concerns about the certainty of the evidence. No data were available about the efficacy of behaioural activation compared with placebo, or about treatment acceptability comparing behavioural activation and psychodynamic therapy, interpersonal, cognitive analytic and integrative therapies. The evidence could be strengthened by better reporting and better quality RCTs of behavioural activation and by assessing working mechanisms of behavioural activation.National Institute for Health Research (NIHR

Methylenetetrahydrofolate Reductase Gene Variant (MTHFR C677T) and Migraine: A Case Control Study and Meta-analysis

Extent: 9p.Background: Migraine is a common disorder that often coexists with depression. While a functional polymorphism in methyleneterahydrofolate reductase gene (MTHFR C677T) has been implicated in depression; the evidence to support an association of MTHFR with migraine has been inconclusive. We aim to investigate the effect of this variant on propensity for migraine and to perform a systematic review and meta-analysis of studies of MTHFR and migraine to date. Methods: Individuals with migraine (n = 447) were selected from the Depression Case Control (DeCC) study to investigate the association between migraine and MTHFR C677T single nucleotide polymorphism (SNP) rs1801133 using an additive model compared to non-migraineurs adjusting for depression status. A meta-analysis was performed and included 15 studies of MTHFR and migraine. Results: MTHFR C677T polymorphism was associated with migraine with aura (MA) (OR 1.31, 95% CI 1.01-1.70, p = 0.039) that remained significant after adjusting for age, sex and depression status. A meta-analysis of 15 case-control studies showed that T allele homozygosity is significantly associated with MA (OR = 1.42; 95% CI, 1.10-1.82) and total migraine (OR = 1.37; 95% CI, 1.07-1.76), but not migraine without aura (OR = 1.16; 95% CI, 0.36-3.76). In studies of non-Caucasian population, the TT genotype was associated with total migraine (OR= 3.46; 95% CI, 1.22-9.82), whereas in studies of Caucasians this variant was associated with MA only (OR = 1.28; 95% CI, 1.002-1.63). Conclusions: MTHFR C677T is associated with MA in individuals selected for depression study. A meta-analysis of 15 studies supports this association and demonstrated effects across ethnic groups.Zainab Samaan, Daria Gaysina, Sarah Cohen-Woods, Nick Craddock, Lisa Jones, Ania Korszun, Mike Owen, Andrew Mente, Peter McGuffin and Anne Farme

Methods and processes for development of a CONSORT extension for reporting pilot randomized controlled trials.

BACKGROUND: Feasibility and pilot studies are essential components of planning or preparing for a larger randomized controlled trial (RCT). They are intended to provide useful information about the feasibility of the main RCT-with the goal of reducing uncertainty and thereby increasing the chance of successfully conducting the main RCT. However, research has shown that there are serious inadequacies in the reporting of pilot and feasibility studies. Reasons for this include a lack of explicit publication policies for pilot and feasibility studies in many journals, unclear definitions of what constitutes a pilot or feasibility RCT/study, and a lack of clarity in the objectives and methodological focus. All these suggest that there is an urgent need for new guidelines for reporting pilot and feasibility studies. OBJECTIVES: The aim of this paper is to describe the methods and processes in our development of an extension to the Consolidated Standards of Reporting Trials (CONSORT) Statement for reporting pilot and feasibility RCTs, that are executed in preparation for a future, more definitive RCT. METHODS/DESIGN: There were five overlapping parts to the project: (i) the project launch-which involved establishing a working group and conducting a review of the literature; (ii) stakeholder engagement-which entailed consultation with the CONSORT group, journal editors and publishers, the clinical trials community, and funders; (iii) a Delphi process-used to assess the agreement of experts on initial definitions and to generate a reporting checklist for pilot RCTs, based on the 2010 CONSORT statement extension applicable to reporting pilot studies; (iv) a consensus meeting-to discuss, add, remove, or modify checklist items, with input from experts in the field; and (v) write-up and implementation-which included a guideline document which gives an explanation and elaboration (E&E) and which will provide advice for each item, together with examples of good reporting practice. This final part also included a plan for dissemination and publication of the guideline. CONCLUSIONS: We anticipate that implementation of our guideline will improve the reporting completeness, transparency, and quality of pilot RCTs, and hence benefit several constituencies, including authors of journal manuscripts, funding agencies, educators, researchers, and end-users

THE VALUE TO THE SURGEON OF PARATHYROID HORMONE ASSAYS IN PRIMARY HYPERPARATHYROIDISM

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72424/1/j.1445-2197.1988.tb01084.x.pd

Central nervous system relapse in patients with breast cancer is associated with advanced stages, with the presence of circulating occult tumor cells and with the HER2/neu status

INTRODUCTION: To evaluate the incidence of central nervous system (CNS) involvement in patients with breast cancer treated with a taxane-based chemotherapy regimen and to determine predictive factors for CNS relapse. METHODS: The medical files of patients with early breast cancer (n = 253) or advanced stage breast cancer (n = 239) as well of those with other solid tumors (n = 336) treated with or without a taxane-based chemotherapy regimen during a 42-month period were reviewed. HER2/neu overexpression was identified by immunohistochemistry, whereas cytokeratin 19 (CK-19) mRNA-positive circulating tumor cells (CTCs) in the peripheral blood were identified by real-time PCR. RESULTS: The incidence of CNS relapse was similar in patients suffering from breast cancer or other solid tumors (10.4% and 11.4%, respectively; P = 0.517). The incidence of CNS relapse was significantly higher in breast cancer patients with advanced disease (P = 0.041), visceral disease and bone disease (P = 0.036), in those who were treated with a taxane-containing regimen (P = 0.024), in those with HER2/neu-overexpressing tumors (P = 0.022) and, finally, in those with detectable CK-19 mRNA-positive CTCs (P = 0.008). Multivariate analysis revealed that the stage of disease (odds ratio, 0.23; 95% confidence interval, 0.007–0.23; P = 0.0001), the HER2/neu status (odds ratio, 29.4; 95% confidence interval, 7.51–101.21; P = 0.0001) and the presence of CK-19 mRNA-positive CTCs (odds ratio, 8.31; 95% confidence interval, 3.97–12.84; P = 0.001) were independent predictive factors for CNS relapse. CONCLUSION: CNS relapses are common among breast cancer patients treated with a taxane-based chemotherapy regimen, patients with HER2/neu-positive tumor and patients with CK-19 mRNA-positive CTCs

A tutorial on sensitivity analyses in clinical trials : the what, why, when and how

Background: Sensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations - such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers - on the overall conclusions of a study. The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials. Discussion. In this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials. Summary. When reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study