Substantial Decrease in Comorbidity 5 Years After Gastric Bypass : A Population-based Study From the Scandinavian Obesity Surgery Registry

OBJECTIVE:: To evaluate effect on comorbid disease and weight loss 5 years after Roux-en-Y gastric bypass (RYGB) surgery for morbid obesity in a large nationwide cohort. BACKGROUND:: The number patients having surgical procedures to treat obesity and obesity-related disease are increasing. Yet, population-based, long-term outcome studies are few. METHODS:: Data on 26,119 individuals [75.8% women, 41.0 years, and body mass index (BMI) 42.8?kg/m] undergoing primary RYGB between May 1, 2007 and June 30, 2012, were collected from 2 Swedish quality registries: Scandinavian Obesity Surgery Registry and the Prescribed Drug Registry. Weight, remission of type 2 diabetes mellitus, hypertension, dyslipidemia, depression, and sleep apnea, and changes in corresponding laboratory data were studied. Five-year follow-up was 100% (9774 eligible individuals) for comorbid diseases. RESULTS:: BMI decreased from 42.8?±?5.5 to 31.2?±?5.5?kg/m at 5 years, corresponding to 27.7% reduction in total body weight. Prevalence of type 2 diabetes mellitus (15.5%–5.9%), hypertension (29.7%–19.5%), dyslipidemia (14.0%–6.8%), and sleep apnea (9.6%–2.6%) was reduced. Greater weight loss was a positive prognostic factor, whereas increasing age or BMI at baseline was a negative prognostic factor for remission. The use of antidepressants increased (24.1%–27.5%). Laboratory status was improved, for example, fasting glucose and glycated hemoglobin decreased from 6.1 to 5.4?mmol/mol and 41.8% to 37.7%, respectively. CONCLUSIONS:: In this nationwide study, gastric bypass resulted in large improvements in obesity-related comorbid disease and sustained weight loss over a 5-year period. The increased use of antidepressants warrants further investigation

Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block

Congenital heart block develops in fetuses after placental transfer of Ro/SSA autoantibodies from rheumatic mothers. The condition is often fatal and the majority of live-born children require a pacemaker at an early age. The specific antibody that induces the heart block and the mechanism by which it mediates the pathogenic effect have not been elucidated. In this study, we define the cellular mechanism leading to the disease and show that maternal autoantibodies directed to a specific epitope within the leucine zipper amino acid sequence 200–239 (p200) of the Ro52 protein correlate with prolongation of fetal atrioventricular (AV) time and heart block. This finding was further confirmed experimentally in that pups born to rats immunized with p200 peptide developed AV block. p200-specific autoantibodies cloned from patients bound cultured cardiomyocytes and severely affected Ca2+ oscillations, leading to accumulating levels and overload of intracellular Ca2+ levels with subsequent loss of contractility and ultimately apoptosis. These findings suggest that passive transfer of maternal p200 autoantibodies causes congenital heart block by dysregulating Ca2+ homeostasis and inducing death in affected cells

Redox modifications of cysteine residues regulate the cytokine activity of HMGB1.

BACKGROUND: High mobility group box 1 (HMGB1) is a nuclear protein with extracellular inflammatory cytokine activity. It is passively released during cell death and secreted by activated cells of many lineages. HMGB1 contains three conserved redox-sensitive cysteine residues: cysteines in position 23 and 45 (C23 and C45) can form an intramolecular disulfide bond, whereas C106 is unpaired and is essential for the interaction with Toll-Like Receptor (TLR) 4. However, a comprehensive characterization of the dynamic redox states of each cysteine residue and of their impacts on innate immune responses is lacking. METHODS: Primary human macrophages or murine macrophage-like RAW 264.7 cells were activated in cell cultures by redox-modified or point-mutated (C45A) recombinant HMGB1 preparations or by lipopolysaccharide (E. coli.0111: B4). Cellular phosphorylated NF-κB p65 subunit and subsequent TNF-α release were quantified by commercial enzyme-linked immunosorbent assays. RESULTS: Cell cultures with primary human macrophages and RAW 264.7 cells demonstrated that fully reduced HMGB1 with all three cysteines expressing thiol side chains failed to generate phosphorylated NF-КB p65 subunit or TNF-α. Mild oxidation forming a C23-C45 disulfide bond, while leaving C106 with a thiol group, was required for HMGB1 to induce phosphorylated NF-КB p65 subunit and TNF-α production. The importance of a C23-C45 disulfide bond was confirmed by mutation of C45 to C45A HMGB1, which abolished the ability for cytokine induction. Further oxidation of the disulfide isoform also inactivated HMGB1. CONCLUSIONS: These results reveal critical post-translational redox mechanisms that control the proinflammatory activity of HMGB1 and its inactivation during inflammation

Cutaneous nociception and neurogenic inflammation evoked by PACAP38 and VIP

Pituitary adenylate cyclase-activating peptide-38 (PACAP38) and vasoactive intestinal peptide (VIP) belong to the same secretin–glucagon superfamily and are present in nerve fibers in dura and skin. Using a model of acute cutaneous pain we explored differences in pain perception and vasomotor responses between PACAP38 and VIP in 16 healthy volunteers in a double-blind, placebo-controlled, crossover study. All participants received intradermal injections of 200 pmol PACAP38, 200 pmol VIP and placebo into the volar forearm. Measurements included pain intensity on a visual analog scale (VAS), blood flow by laser Doppler flowmetry, visual flare and wheal. Pain intensities after PACAP38 and VIP were mild and limited to a short time of about 100 s after injection. The area under the VAS-time curve was larger following PACAP38 (P = 0.004) and VIP (P = 0.01) compared to placebo. We found no statistical difference in pain perception between PACAP38 and VIP. Skin blood flow increase, flare and wheal were larger after both PACAP38 (P = 0.011) and VIP (P = 0.001) compared to placebo. VIP induced a considerably larger increase in skin blood flow, flare and wheal than PACAP38 (P = 0.002). In conclusion, we found that peripheral nociceptive cutaneous responses elicited by PACAP38 and VIP are similar in healthy volunteers. This suggests that acute pain and vasomotor responses following intradermal injections of PACAP38 and VIP are primarily mediated by VPAC receptors

The biophysical climate mitigation potential of boreal peatlands during the growing season

Peatlands and forests cover large areas of the boreal biome and are critical for global climate regulation. They also regulate regional climate through heat and water vapour exchange with the atmosphere. Understanding how land-atmosphere interactions in peatlands differ from forests may therefore be crucial for modelling boreal climate system dynamics and for assessing climate benefits of peatland conservation and restoration. To assess the biophysical impacts of peatlands and forests on peak growing season air temperature and humidity, we analysed surface energy fluxes and albedo from 35 peatlands and 37 evergreen needleleaf forests-the dominant boreal forest type-and simulated air temperature and vapour pressure deficit (VPD) over hypothetical homogeneous peatland and forest landscapes. We ran an evapotranspiration model using land surface parameters derived from energy flux observations and coupled an analytical solution for the surface energy balance to an atmospheric boundary layer (ABL) model. We found that peatlands, compared to forests, are characterized by higher growing season albedo, lower aerodynamic conductance, and higher surface conductance for an equivalent VPD. This combination of peatland surface properties results in a similar to 20% decrease in afternoon ABL height, a cooling (from 1.7 to 2.5 degrees C) in afternoon air temperatures, and a decrease in afternoon VPD (from 0.4 to 0.7 kPa) for peatland landscapes compared to forest landscapes. These biophysical climate impacts of peatlands are most pronounced at lower latitudes (similar to 45 degrees N) and decrease toward the northern limit of the boreal biome (similar to 70 degrees N). Thus, boreal peatlands have the potential to mitigate the effect of regional climate warming during the growing season. The biophysical climate mitigation potential of peatlands needs to be accounted for when projecting the future climate of the boreal biome, when assessing the climate benefits of conserving pristine boreal peatlands, and when restoring peatlands that have experienced peatland drainage and mining.Peer reviewe

Molecular characterization of the Ro52 autoantigen and its disease related epitopes

The presence of high titers of autoantibodies in patient sera is characteristic for the autoimmune disorder Sjögren s syndrome. The major targets for these autoantibodies are three intracellular proteins Ro52, Ro60 and La. It is still unclear why these proteins become targets for the immune system, and how this autoreactivity is triggered. Antibodies to the Ro52 protein have also been shown to associate with the development of congenital heart block in fetuses of anti-Ro52 positive mothers. The focus of this thesis has been to characterize the Ro52 protein at the molecular level, and to analyze the role of anti-Ro52 antibodies in congenital heart block. By combining immunologic, biophysical and biochemical methods we have determined the protein domain composition of Ro52. The stable domains found in recombinant Ro52 correspond well with bioinformatic predictions. We have confirmed that the predicted RING-finger, B-box and coiled-coil domains are all functional in Ro52, based on secondary structure analysis and functional studies. The RING and B-box together form a single folding unit. Two Zn2+-binding sites with nanomolar affinities were found within the RING-finger, while the B-box contains one independent Zn2+-binding site with micromolar affinity. The region between RING and B-box appears crucial for Zn2+-dependent subdomain interactions within Ro52. Secondary structure analysis of the coiled-coil domain by circular dichroism confirmed that the domain has a predominant alpha-helical fold. This domain of Ro52 was determined to consist of two structurally stable coiled-coil formations, separated by a short stretch of exposed amino acid residues. The coiled-coil domain of Ro52 forms weak homodimers, which does not exclude possible heterodimerization with an unknown interaction partner. As a tool for studying congenital heart block, we identified and cloned two human monoclonal antibodies directed against the stretch of Ro52 recognized by antibodies associated with congenital heart block. The monoclonal antibodies were isolated from an antibody library from autoimmune patients by phage display technology. The specificities of these antibodies were fine mapped and one antibody clone was found to recognize a conformational epitope within the Ro52 coiled-coil domain. This antibody specificity was found in high frequency of sera from children affected by congenital heart block. In vitro studies with rat cardiomyocytes and in vivo studies in a rat model confirmed the importance of the certain antibody specificity in development of congenital heart block. The antibodies were found to interact with an antigen on the surface of cardiomyocytes, leading to disrupted Ca2+-homeostasis in response to antibody binding. After initial increase of calcium oscillation frequency, the cells were overloaded with Ca2+ and died via apoptosis. This mechanism is proposed as the initiating event in congenital heart block. In conclusion, this thesis work has revealed the presence and functionality of stable domains found in Ro52. We also suggest a mechanism for the induction of congenital heart block, and further characterized the role of specific anti-Ro52 autoantibodies in this process