Inactivation of glycogen synthase kinase-3 beta (GSK-3 beta) enhances skeletal muscle oxidative metabolism

Background: Aberrant skeletal muscle mitochondrial oxidative metabolism is a debilitating feature of chronic diseases such as chronic obstructive pulmonary disease, type 2 diabetes and chronic heart failure. Evidence in non-muscle cells suggests that glycogen synthase kinase-3 beta (GSK-3 beta) represses mitochondrial biogenesis and inhibits PPAR-gamma co-activator 1 (PGC-1), a master regulator of cellular oxidative metabolism. The role of GSK-3 beta in the regulation of skeletal muscle oxidative metabolism is unknown. Aims: We hypothesized that inactivation of GSK-3 beta stimulates muscle oxidative metabolism by activating PGC-1 signaling and explored if GSK-3 beta inactivation could protect against physical inactivity-induced alterations in skeletal muscle oxidative metabolism. Methods: GSK-3 beta was modulated genetically and pharmacologically in C2C12 myotubes in vitro and in skeletal muscle in vivo. Wild-type and muscle-specific GSK-3 beta knock-out (KO) mice were subjected to hind limb suspension for 14 days. Key constituents of oxidative metabolism and PGC-1. signaling were investigated. Results: In vitro, knock-down of GSK-3 beta increased mitochondrial DNA copy number, protein and mRNA abundance of oxidative phosphorylation (OXPHOS) complexes and activity of oxidative metabolic enzymes but also enhanced protein and mRNA abundance of key PGC-1 signaling constituents. Similarly, pharmacological inhibition of GSK-3 beta increased transcript and protein abundance of key constituents and regulators of mitochondrial energy metabolism. Furthermore, GSK-3 beta KO animals were protected against unloading-induced decrements in expression levels of these constituents. Conclusion: Inactivation of GSK-3 beta up-regulates skeletal muscle mitochondrial metabolism and increases expression levels of PGC-1 signaling constituents. In vivo, GSK-3 beta KO protects against inactivity-induced reductions in muscle metabolic gene expression

The effects of treatment with chemotherapy on energy metabolism and inflammatory mediators in small-cell lung carcinoma.

A disturbed energy balance has been demonstrated in lung cancer patients. Both an enhanced resting energy expenditure (REE) and a decreased energy intake contribute to weight loss. Enhanced systemic levels of inflammatory mediators were found to be related to the enhanced REE in lung cancer. The aim of the present study was to investigate energy metabolism and systemic levels of inflammatory mediators in small-cell lung carcinoma (SCLC) patients before and after treatment with chemotherapy. Hypermetabolism and an enhanced inflammatory response have already been demonstrated in SCLC by our group before. Twelve newly diagnosed SCLC patients were consecutively included in the study. REE was measured by indirect calorimetry and body composition was determined by bioelectrical impedance (BIA) before and 1 month after treatment. To assess the inflammatory state the acute-phase proteins, C-reactive protein (CRP) and lipopolysaccharide-binding protein (LBP), both soluble tumour necrosis factor (TNF) receptors, (sTNF-R)-55 and sTNF-R75, and soluble intercellular adhesion molecule (sICAM)-1 were measured in plasma before and 1 month after treatment. CRP was assessed by turbidemetry, whereas the other inflammatory parameters were measured by enzyme-linked immunosorbent assay (ELISA). A significant reduction in REE was found irrespective of therapeutic outcome, whereas body weight and body composition remained stable. The acute-phase proteins CRP and LBP were reduced significantly after treatment with chemotherapy, whereas both sTNF receptors and sICAM-1 remained enhanced. No correlation, however, existed between the decrease in REE and the decrease in the acute-phase proteins. In conclusion, chemotherapeutic treatment attenuates the tumour-related metabolic derangements and acute-phase response

Deep sternal wound infection after open heart surgery: current treatment insights. A retrospective study of 36 cases

The aim of this study was to retrospectively evaluate the results of reconstructing infected post-sternotomy wounds, with either sternal plating and/or pectoralis major flap transposition or pedicled omentoplasty after previous vacuum-assisted closure (VAC) therapy. Between January 2005 and December 2010, 36 patients, suffering from deep sternal wound infection (DSWI) after coronary artery bypass grafting procedure, received (plastic) reconstructive surgery. All patients, treated in the Maastricht University Medical Centre (Departments of Plastic Surgery and Cardiothoracic Surgery), were selected for this study. For 22 patients, sternal refixation and reconstruction were obtained by sternal internal plate fixation combined with bilateral pectoralis major advancement flap. In 11 patients, a pedicled omentoplasty was performed, with or without split-skin graft and additional VAC therapy. Three patients only received a pectoralis plasty. We evaluated preoperative characteristics and post-operative course. Twenty-four patients (66.7%) had an uneventful post-operative course. Complications in the other patients included wound dehiscence, herniation of the donor site and infection of sternal plating material. Average sternal wound healing after sternal plating plus pectoralis plasty, pectoralis plasty and omentoplasty respectively accounted 7.7, 8.0 and 11.6 weeks. From our experience, we recommend VAC therapy plus delayed sternal plating and additional bilateral pectoralis major flap advancement as first repair option in case of DSWI. However, individual clinical conditions need to be taken into account when making a decision between the different available reconstructive options. Omentoplasty should be reserved for cases in which the sternum has recurrently fallen open after previous sternal plate refixation, or for cases in which the sternum defect is too extended

Aerobic and strength exercises for youngsters aged 12 to 15: what do parents think?

BACKGROUND: Although strength exercises evidently have both physiological and psychological health benefits across all ages, they are erroneously considered to adversely affect health status in youngsters. The aim of this study was to examine parental attitudes towards their child's physical activity in general, as well as aerobic and strength exercises in particular. METHODS: In total, 314 parents from an online panel representative of the Dutch population completed an online survey about their own physical activity and that of their child (12-15 years old). The study also explored reasons for non-participation, and attitudes about the parents' own and their child's physical activity level. RESULTS: Parents consistently reported a positive attitude towards aerobic exercises, but a less positive attitude regarding strength exercises. Parents were more likely to indicate that their child was not allowed to participate in strength exercises (29.6 %) than aerobic exercises (4.0 %). They thought that strength exercises could interfere with optimal physical development. CONCLUSIONS: This study consistently shows that parents have a positive attitude towards aerobic exercises, but a less positive attitude regarding strength exercises. We suggest testing interventions to increase parental understanding of the advantages of and possibilities for (e.g., facilities) strength training on their child's health

Cognitive impairment in chronic obstructive pulmonary disease:disease burden, determinants and possible future interventions

Introduction: Cognitive impairment (CI) is an important but an under-recognized extra-pulmonary feature of chronic obstructive pulmonary disease (COPD). It is related to the burden of disability, worse health outcomes, and impaired self-management. Areas covered: CI includes deterioration of a wide range of cognitive functions, such as memory and various executive functions. Risk of hospitalization might be higher in patients with COPD compared to those without, with CI negatively impacting the wellbeing of patients with COPD. Disease-specific factors such as hypoxemia and inflammation, lifestyle factors such as dietary insufficiencies and lack of physical activity, and comorbidities such as obstructive sleep apnea and depression are likely to synergistically contribute to the development of CI in COPD. Tailored interventions can possibly improve CI in COPD, but this needs further investigation. Expert commentary: Further research is warranted involving the optimization of neuropsychological testing for screening and outcome assessment, longitudinal studies to investigate the development of CI in COPD over time, and randomized clinical trials to test the feasibility and efficacy of promising interventions.</p

Corrigendum: Septum resection in women with a septate uterus:a cohort study

The authors of the above article would like to apologise for an error in one of the authors' names. W. Kuchenbecker should be W.K.H. Kuchenbecker, as above. The electronic version of this article has been updated at https:// doi.org/10.1093/humrep/dez284. The print version is correct. The Authors would like to assure readers that this does not affect any other content of the article.</p

Perioperative Hyperspectral Imaging to Assess Mastectomy Skin Flap and DIEP Flap Perfusion in Immediate Autologous Breast Reconstruction: A Pilot Study.

Mastectomy skin flap necrosis (MSFN) and partial DIEP (deep inferior epigastric artery perforator) flap loss represent two frequently reported complications in immediate autologous breast reconstruction. These complications could be prevented when areas of insufficient tissue perfusion are detected intraoperatively. Hyperspectral imaging (HSI) is a relatively novel, non-invasive imaging technique, which could be used to objectively assess tissue perfusion through analysis of tissue oxygenation patterns (StO2%), near-infrared (NIR%), tissue hemoglobin (THI%), and tissue water (TWI%) perfusion indices. This prospective clinical pilot study aimed to evaluate the efficacy of HSI for tissue perfusion assessment and to identify a cut-off value for flap necrosis. Ten patients with a mean age of 55.4 years underwent immediate unilateral autologous breast reconstruction. Prior, during and up to 72 h after surgery, a total of 19 hyperspectral images per patient were acquired. MSFN was observed in 3 out of 10 patients. No DIEP flap necrosis was observed. In all MSFN cases, an increased THI% and decreased StO2%, NIR%, and TWI% were observed when compared to the vital group. StO2% was found to be the most sensitive parameter to detect MSFN with a statistically significant lower mean StO2% (51% in the vital group versus 32% in the necrosis group, p < 0.0001) and a cut-off value of 36.29% for flap necrosis. HSI has the potential to accurately assess mastectomy skin flap perfusion and discriminate between vital and necrotic skin flap during the early postoperative period prior to clinical observation. Although the results should be confirmed in future studies, including DIEP flap necrosis specifically, these findings suggest that HSI can aid clinicians in postoperative mastectomy skin flap and DIEP flap monitoring

Spatial Distribution of Factor Xa, Thrombin, and Fibrin(ogen) on Thrombi at Venous Shear

The generation of thrombin is a critical process in the formation of venous thrombi. In isolated plasma under static conditions, phosphatidylserine (PS)-exposing platelets support coagulation factor activation and thrombin generation; however, their role in supporting coagulation factor binding under shear conditions remains unclear. We sought to determine where activated factor X (FXa), (pro)thrombin, and fibrin(ogen) are localized in thrombi formed under venous shear.Fluorescence microscopy was used to study the accumulation of platelets, FXa, (pro)thrombin, and fibrin(ogen) in thrombi formed in vitro and in vivo. Co-perfusion of human blood with tissue factor resulted in formation of visible fibrin at low, but not at high shear rate. At low shear, platelets demonstrated increased Ca(2+) signaling and PS exposure, and supported binding of FXa and prothrombin. However, once cleaved, (pro)thrombin was observed on fibrin fibers, covering the whole thrombus. In vivo, wild-type mice were injected with fluorescently labeled coagulation factors and venous thrombus formation was monitored in mesenteric veins treated with FeCl(3). Thrombi formed in vivo consisted of platelet aggregates, focal spots of platelets binding FXa, and large areas binding (pro)thrombin and fibrin(ogen).FXa bound in a punctate manner to thrombi under shear, while thrombin and fibrin(ogen) distributed ubiquitously over platelet-fibrin thrombi. During thrombus formation under venous shear, thrombin may relocate from focal sites of formation (on FXa-binding platelets) to dispersed sites of action (on fibrin fibers)

Developing a pressure ulcer risk factor minimum data set and risk assessment framework

AIM: To agree a draft pressure ulcer risk factor Minimum Data Set to underpin the development of a new evidenced-based Risk Assessment Framework.BACKGROUND: A recent systematic review identified the need for a pressure ulcer risk factor Minimum Data Set and development and validation of an evidenced-based pressure ulcer Risk Assessment Framework. This was undertaken through the Pressure UlceR Programme Of reSEarch (RP-PG-0407-10056), funded by the National Institute for Health Research and incorporates five phases. This article reports phase two, a consensus study.DESIGN: Consensus study.METHOD: A modified nominal group technique based on the Research and Development/University of California at Los Angeles appropriateness method. This incorporated an expert group, review of the evidence and the views of a Patient and Public Involvement service user group. Data were collected December 2010-December 2011.FINDINGS: The risk factors and assessment items of the Minimum Data Set (including immobility, pressure ulcer and skin status, perfusion, diabetes, skin moisture, sensory perception and nutrition) were agreed. In addition, a draft Risk Assessment Framework incorporating all Minimum Data Set items was developed, comprising a two stage assessment process (screening and detailed full assessment) and decision pathways.CONCLUSION: The draft Risk Assessment Framework will undergo further design and pre-testing with clinical nurses to assess and improve its usability. It will then be evaluated in clinical practice to assess its validity and reliability. The Minimum Data Set could be used in future for large scale risk factor studies informing refinement of the Risk Assessment Framework