Sympathetic nervous system activity and anti-lipolytic response to iv-glucose load in subcutaneous adipose tissue of obese and obese type 2 diabetic subjects

The study aim was to investigate the effect of endogenous insulin release on lipolysis in subcutaneous adipose tissue after adrenergic stimulation in obese subjects diagnosed with type 2 diabetes (T2D). In 14 obese female T2D subjects, or 14 obese non-T2D controls, glycerol concentration was measured in response to the α1,2,ß-agonist norepinephrine, the α1-agonist norfenefrine and the ß2-agonist terbutaline (each 10-4 M), using the microdialysis technique. After 60 minutes of stimulation, an intravenous glucose load (0.5 g/kg lean body mass) was given. Local blood flow was monitored by means of the ethanol technique. Norepinephrine and norfenefrine induced a four and three fold rise in glycerol dialysate concentration (p\u3c0.001, each), with a similar pattern in adipose tissue. Following agonist stimulation and glucose infusion, endogenous insulin release inhibited lipolysis in the presence of norepinephrine, which was more rapid and pronounced in healthy obese controls than in T2D subjects (p = 0.024 obese vs T2D subjects). Insulin-induced inhibition of lipolysis in the presence of norfenefrine was similar in all study participants. In the presence of terbutaline the lipolysis rate increased two fold until the effect of endogenous insulin (p\u3c0.001). A similar insulin-induced decrease in lipolysis was observed for each of the norfenefrine groups and the terbutaline groups, respectively. Adipose tissue blood flow remained unchanged after the iv-glucose load. Both norepinephrine and norfenefrine diminished blood flow slightly, but insulin reversed this response (p\u3c0.001 over the entire time). Terbutaline alone and terbutaline plus increased endogenous insulin augmented local blood flow (p\u3c0.001 over the entire time). In conclusion, a difference in insulin-induced inhibition of lipolysis was observed in obese T2D subjects compared to obese healthy controls following modulation of sympathetic nervous system activity and is assumed to be due to ß1-adrenoceptor mediated stimulation by norepinephrine

Quantitation of Formoterol, Salbutamol, and Salbutamol-4′-O-Sulfate in Human Urine and Serum via UHPLC-MS/MS

The adrenergic beta-2 agonists formoterol and salbutamol are used for the treatment of asthma and COPD but are also misused in sports competitions. Therefore, they are included in WADA regulations. Both drugs are mainly excreted in urine after administration via inhalation. A four-armed, double-blind cross-over clinical trial was conducted involving endurance-trained participants (12 females and 12 males). Inhalation dosages of 36 μg formoterol, 1200 μg salbutamol, a combination of both, or a placebo were administered before exercise. Serum and urine were collected after exercise and 3 and 24 h after administration. Here, we show the successful quantitation of formoterol, salbutamol, and its phase II metabolite salbutamol-4′-O-sulfate in all urine and serum samples using ultra-high performance liquid chromatography–tandem mass spectrometry. In the serum analysis, results of up to 14.2 pg/mL formoterol, 10.0 ng/mL salbutamol, and 21.4 ng/mL salbutamol-4′-O-sulfate (calculated as salbutamol equivalent) were found. In urine, maximum concentrations (after deglucuronidation) were 17.2 ng/mL formoterol, 948.5 ng/mL salbutamol, and 2738.5 ng/mL salbutamol-4′-O-sulfate. Sex-specific differences in serum concentrations as well as in urinary excretion were observed. The results pronounce the importance of the implementation and elucidation of phase II metabolites to quantitation methods in antidoping

Fascial tissue research in sports medicine: from molecules to tissue adaptation, injury and diagnostics.

The fascial system builds a three-dimensional continuum of soft, collagen-containing, loose and dense fibrous connective tissue that permeates the body and enables all body systems to operate in an integrated manner. Injuries to the fascial system cause a significant loss of performance in recreational exercise as well as high-performance sports, and could have a potential role in the development and perpetuation of musculoskeletal disorders, including lower back pain. Fascial tissues deserve more detailed attention in the field of sports medicine. A better understanding of their adaptation dynamics to mechanical loading as well as to biochemical conditions promises valuable improvements in terms of injury prevention, athletic performance and sports-related rehabilitation. This consensus statement reflects the state of knowledge regarding the role of fascial tissues in the discipline of sports medicine. It aims to (1) provide an overview of the contemporary state of knowledge regarding the fascial system from the microlevel (molecular and cellular responses) to the macrolevel (mechanical properties), (2) summarise the responses of the fascial system to altered loading (physical exercise), to injury and other physiological challenges including ageing, (3) outline the methods available to study the fascial system, and (4) highlight the contemporary view of interventions that target fascial tissue in sport and exercise medicine. Advancing this field will require a coordinated effort of researchers and clinicians combining mechanobiology, exercise physiology and improved assessment technologies

The Role of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 in the p38/TNF-α Pathway of Systemic and Cutaneous Inflammation

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a downstream molecule of p38, involved in the production of TNF-α, a key cytokine, and an established drug target for many inflammatory diseases. We investigated the role of MK2 in skin inflammation to determine its drug target potential. MK2 deficiency significantly decreased plasma TNF-α levels after systemic endotoxin application. Deficient mice showed decreased skin edema formation in chronic 2-O-tetradecanoylphorbol-13-acetate (TPA)-induced irritative dermatitis and in subacute 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity. Surprisingly, MK2 deficiency did not inhibit edema formation in subacute 2,4-dinitrochlorobenzene (DNCB)-induced contact allergy and even increased TNF-α and IL-1β levels as well as granulocyte infiltration in diseased ears. Ear inflammation in this model, however, was inhibited by TNF-α neutralization as it was in the subacute DNFB model. MK2 deficiency also did not show anti-inflammatory effects in acute DNFB-induced contact hypersensitivity, whereas the p38 inhibitor, SB203580, ameliorated skin inflammation supporting a pathophysiological role of p38. When evaluating possible mechanisms, we found that TNF-α production in MK2-deficient spleen cells was strongly diminished after TLR stimulation but less affected after T-cell receptor stimulation. Our data suggest that MK2, in contrast to its downstream effector molecule, TNF-α, has a rather elusive role in T-cell-dependent cutaneous inflammation

Failure of available scoring systems to predict ongoing infection in patients with abdominal sepsis after their initial emergency laparotomy

<p>Abstract</p> <p>Background</p> <p>To examine commonly used scoring systems, designed to predict overall outcome in critically ill patients, for their ability to select patients with an abdominal sepsis that have ongoing infection needing relaparotomy.</p> <p>Methods</p> <p>Data from a RCT comparing two surgical strategies was used. The study population consisted of 221 patients at risk for ongoing abdominal infection. The following scoring systems were evaluated with logistic regression analysis for their ability to select patients requiring a relaparotomy: APACHE-II score, SAPS-II, Mannheim Peritonitis Index (MPI), MODS, SOFA score, and the acute part of the APACHE-II score (APS).</p> <p>Results</p> <p>The proportion of patients requiring a relaparotomy was 32% (71/221). Only 2 scores had a discriminatory ability in identifying patients with ongoing infection needing relaparotomy above chance: the APS on day 1 (AUC 0.61; 95%CI 0.52-0.69) and the SOFA score on day 2 (AUC 0.60; 95%CI 0.52-0.69). However, to correctly identify 90% of all patients needing a relaparotomy would require such a low cut-off value that around 80% of all patients identified by these scoring systems would have negative findings at relaparotomy.</p> <p>Conclusions</p> <p>None of the widely-used scoring systems to predict overall outcome in critically ill patients are of clinical value for the identification of patients with ongoing infection needing relaparotomy. There is a need to develop more specific tools to assist physicians in their daily monitoring and selection of these patients after the initial emergency laparotomy.</p> <p>Trial registration number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN 51729393">ISRCTN 51729393</a></p

Chlamydia trachomatis Infection and Anti-Hsp60 Immunity: The Two Sides of the Coin

Chlamydia trachomatis (CT) infection is one of the most common causes of reproductive tract diseases and infertility. CT-Hsp60 is synthesized during infection and is released in the bloodstream. As a consequence, immune cells will produce anti-CT-Hsp60 antibodies. Hsp60, a ubiquitous and evolutionarily conserved chaperonin, is normally sequestered inside the cell, particularly into mitochondria. However, upon cell stress, as well as during carcinogenesis, the chaperonin becomes exposed on the cell surface (sf-Hsp60) and/or is secreted from cells into the extracellular space and circulation. Reports in the literature on circulating Hsp and anti-Hsp antibodies are in many cases short on details about Hsp60 concentrations, and about the specificity spectra of the antibodies, their titers, and their true, direct, pathogenetic effects. Thus, more studies are still needed to obtain a definitive picture on these matters. Nevertheless, the information already available indicates that the concurrence of persistent CT infection and appearance of sf-Hsp60 can promote an autoimmune aggression towards stressed cells and the development of diseases such as autoimmune arthritis, multiple sclerosis, atherosclerosis, vasculitis, diabetes, and thyroiditis, among others. At the same time, immunocomplexes composed of anti-CT-Hsp60 antibodies and circulating Hsp60 (both CT and human) may form deposits in several anatomical locations, e.g., at the glomerular basal membrane. The opposite side of the coin is that pre-tumor and tumor cells with sf-Hsp60 can be destroyed with participation of the anti-Hsp60 antibody, thus stopping cancer progression before it is even noticed by the patient or physician

Association between trends in clinical variables and outcome in intensive care patients with faecal peritonitis: analysis of the GenOSept cohort

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

Characterization of vitamin D receptor ligands with cell-specific and dissociated activity

13 pages, 6 figures.Although the main role of 1{alpha},25-dihydroxyvitamin D3 [1,25-(OH)2D3] is to regulate calcium homeostasis, the valuable therapeutic applications of this compound have led to the search of new 1,25-(OH)2D3-vitamin D receptor (VDR) ligands with less side effects. In this work we have characterized seven 1,25-(OH)2D3 derivatives (ZK136607, ZK161422, ZK157202, ZK159222, ZK168492, ZK191732, and ZK168289). ZK157202 is an agonist that gives a pattern similar to that of 1,25-(OH)2D3 or ZK161422 in limited trypsin digestion assays, is able to recruit p160 and VDR-interacting protein 205 coactivators, is as potent as 1,25-(OH)2D3 to stimulate vitamin D response element-dependent transcription in HeLa cells, and acts as a superagonist in human embryonic kidney 293T cells. This compound is also more potent than the natural ligand to transrepress the activation of the retinoic acid receptor ß2 promoter by retinoic acid and the response of the collagenase promoter to 4{alpha}-12-O-tetradecanoylphorbol 13-acetate. ZK136607, ZK168492, ZK191732, and ZK168289 have a profile similar to that of the partial antagonist ZK159222. They induce an antagonistic-type proteolytic pattern, do not recruit classical coactivators, and have little transactivation potency. However, they act in a cell context-dependent manner because they lack activity in HeLa cells while presenting some agonistic activity in human embryonic kidney 293T cells, or vice versa. Furthermore, some of these compounds have a dissociated activity: they cannot transactivate but they are as potent as 1,25-(OH)2D3 in transrepression assays. Together our results demonstrate the existence of novel VDR ligands with variable biological functions and dissociated activity. They should represent useful tools for studying VDR function and could have therapeutic utility.This work was supported by the Spanish Grants BFU2004 03165 from the Ministerio de Educación y Ciencia and FIS C03/10, and from the European Grant CRESCENDO (FP-018652). A.I.C was supported by a postdoctoral fellowship of the Ernst Schering Research Foundation.Peer reviewe