The comparision of glybenclamide and metformin-loaded bacterial cellulose/gelatin nanofibres produced by a portable electrohydrodynamic gun for diabetic wound healing

Wound dressings made from natural polymers are an important aspect of biomaterials. Protein-based materials are less likely to instigate an immunogenic response and have the capacity to degrade in vivo, also without triggering an inflammatory response. Therefore, gelatin (GEL) was chosen and combined with bacterial cellulose (BC) to produce nanofibres and the potential of an all-natural polymer construct was determined. GEL and BC were successfully electrospun with metformin (Met) and glybenclamide (Gb) using a portable, point of need electrospinning set up. The virgin fibre group exhibited a significant effect on the proliferation of L929 (mouse fibroblast) cells but all fibre samples can safely be applied on wound site without risk of cytotoxicity. According to the results obtained by animal tests, the GEL-BC-Gb group showed better recovery than the GEL-BC-Met group. Diabetic wounds treated with GEL-BC-Met were characterized by moderate re-epithelialization and partially organized granulation tissue. Moderate to complete re-epithelialization and well-formed granulation tissue were observed in diabetic wounds treated with GEL-BC-Gb. The histologic scores obtained on day 14 confirmed that the GEL-BC-Gb group played a stronger wound-healing role compared to the GEL-BC-Met group. The highest decrease of TNF-α level was observed in the GEL-BC-Gb group at the end of the experiment but there is no significant difference between drug-loaded fibre groups. Therefore, topical administration of Met and Gb in a sustained release form has a high potential for diabetic wound healing with high bioavailability and fewer systemic side effects but Gb showed better improvement according to the results of the animal tests

Multi-institutional expert update on the use of laparoscopic bile duct exploration (LBDE) in the management of choledocholithiasis: lesson learned from 3950 procedures

Background: Recently there has been a growing interest in the laparoscopic management of common bile duct stones with gallbladder in situ (LBDE), which is favoring the expansion of this technique. Our study identified the standardization factors of LBDE and its implementation in the single-stage man agement of choledocholithiasis. Methods: A retrospective multi-institutional study among 17 centers with proven experience in LBDE was performed. A cross-sectional survey consisting of a semi-structured pretested questionnaire was distributed covering the main aspects on the use of LBDE in the management of choledocholithiasis. Results: A total of 3950 LBDEs were analyzed. The most frequent indication was jaundice (58.8%). LBDEs were performed after failed ERCP in 15.2%. The most common approach used was the transcystic (63.11%). The overall series failure rate of LBDE was 4% and the median rate for each center was 6% (IQR, 4.5-12.5). Median operative time ranged between 60-120 min (70.6%). Overall morbidity rate was 14.6%, with a postoperative bile leak and complications ≥3a rate of 4.5% and 2.5%, respectively. The operative time decreased with experience (P = .03) and length of hospital stay was longer in the presence of a biliary leak (P = .04). Current training of LBDE was defined as poor or very poor by 82.4%. Conclusion: Based on this multicenter survey, LBDE is a safe and effective ap proach when performed by experienced teams. The generalization of LBDE will be based on developing training programs

Evidence for Irradiation Triggered Nonuniform Defect Distribution In Multiharmonic Magnetic Susceptibility of Neutron Irradiated YBa2Cu3O7-x

Multiharmonic ac-magnetic susceptibility \ch11,\chi2,chi3, of neutron irradiated Li-doped YBa2Cu3O7-x has revealed a nonmonotonic dependence of all harmonics on the neutron fluence. The irradiation has a strongly depressive influence on the intergrain connection suggesting an increase of the effective thickness of the intergranular Josephson junction at aneutron fluence of 0.98x10$^{17}$ cm$_{-2}$. Less damaged are the intragrain properties. A spectacular enhancement of the superconducting intragranular properties reflected in the characteristics of all harmonics was observed at highest fluence \Phi = 9.98x10$^{17}$ cm$_{-2}$. We assume that this effect results from the development of a space inhomogeneous distribution with alternating defectless and defect rich regions.Comment: 24 pages, 9 figures, accepted to J. Supercon

Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease

Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1-/- and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-ɑ. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice

Meat consumption and K-ras mutations in sporadic colon and rectal cancer in The Netherlands Cohort Study

Case–cohort analyses were performed on meat and fish consumption in relation to K-ras mutations in 448 colon and 160 rectal cancers that occurred during 7.3 years of follow-up, excluding the first 2.3 years, and 2948 subcohort members of The Netherlands Cohort Study on diet and cancer. Adjusted incidence rate ratios and 95% confidence intervals were computed for colon and rectal cancer and for K-ras mutation status subgroups. Total fresh meat, most types of fresh meat and fish were not associated with colon or rectal cancer, neither overall nor with K-ras mutation status. However, several weak associations were observed for tumours with a wild-type K-ras, including beef and colon tumours, and an inverse association for pork with colon and rectal tumours; for meat products, an increased association was observed with wild-type K-ras tumours in the colon and possibly with G>A transitions in rectal tumours

CSF-Biomarkers in Olympic Boxing: Diagnosis and Effects of Repetitive Head Trauma

Background Sports-related head trauma is common but still there is no established laboratory test used in the diagnostics of minimal or mild traumatic brain injuries. Further the effects of recurrent head trauma on brain injury markers are unknown. The purpose of this study was to investigate the relationship between Olympic (amateur) boxing and cerebrospinal fluid (CSF) brain injury biomarkers. Methods The study was designed as a prospective cohort study. Thirty Olympic boxers with a minimum of 45 bouts and 25 non-boxing matched controls were included in the study. CSF samples were collected by lumbar puncture 1–6 days after a bout and after a rest period for at least 14 days. The controls were tested once. Biomarkers for acute and chronic brain injury were analysed. Results NFL (mean ± SD, 532±553 vs 135±51 ng/L p = 0.001), GFAP (496±238 vs 247±147 ng/L p<0.001), T-tau (58±26 vs 49±21 ng/L p<0.025) and S-100B (0.76±0.29 vs 0.60±0.23 ng/L p = 0.03) concentrations were significantly increased after boxing compared to controls. NFL (402±434 ng/L p = 0.004) and GFAP (369±113 ng/L p = 0.001) concentrations remained elevated after the rest period. Conclusion Increased CSF levels of T-tau, NFL, GFAP, and S-100B in >80% of the boxers demonstrate that both the acute and the cumulative effect of head trauma in Olympic boxing may induce CSF biomarker changes that suggest minor central nervous injuries. The lack of normalization of NFL and GFAP after the rest period in a subgroup of boxers may indicate ongoing degeneration. The recurrent head trauma in boxing may be associated with increased risk of chronic traumatic brain injury

Familiarity bias and physiological responses in contagious yawning by dogs support link to empathy

In humans, the susceptibility to yawn contagion has been theoretically and empirically related to our capacity for empathy. Because of its relevance to evolutionary biology, this phenomenon has been the focus of recent investigations in nonhuman species. In line with the empathic hypothesis, contagious yawning has been shown to correlate with the level of social attachment in several primate species. Domestic dogs (Canis familiaris) have also shown the ability to yawn contagiously. To date, however, the social modulation of dog contagious yawning has received contradictory support and alternative explanations (i.e., yawn as a mild distress response) could explain positive evidence. The present study aims to replicate contagious yawning in dogs and to discriminate between the two possible mediating mechanisms (i.e., empathic vs. distress related response). Twenty-five dogs observed familiar (dog’s owner) and unfamiliar human models (experimenter) acting out a yawn or control mouth movements. Concurrent physiological measures (heart rate) were additionally monitored for twenty-one of the subjects. The occurrence of yawn contagion was significantly higher during the yawning condition than during the control mouth movements. Furthermore, the dogs yawned more frequently when watching the familiar model than the unfamiliar one demonstrating that the contagiousness of yawning in dogs correlated with the level of emotional proximity. Moreover, subjects’ heart rate did not differ among conditions suggesting that the phenomenon of contagious yawning in dogs is unrelated to stressful events. Our findings are consistent with the view that contagious yawning is modulated by affective components of the behavior and may indicate that rudimentary forms of empathy could be present in domesticated dogs

Total Intermittent Pringle Maneuver during Liver Resection Can Induce Intestinal Epithelial Cell Damage and Endotoxemia

Contains fulltext : 110009.pdf (publisher's version ) (Open Access)OBJECTIVES: The intermittent Pringle maneuver (IPM) is frequently applied to minimize blood loss during liver transection. Clamping the hepatoduodenal ligament blocks the hepatic inflow, which leads to a non circulating (hepato)splanchnic outflow. Also, IPM blocks the mesenteric venous drainage (as well as the splenic drainage) with raising pressure in the microvascular network of the intestinal structures. It is unknown whether the IPM is harmful to the gut. The aim was to investigate intestinal epithelial cell damage reflected by circulating intestinal fatty acid binding protein levels (I-FABP) in patients undergoing liver resection with IPM. METHODS: Patients who underwent liver surgery received total IPM (total-IPM) or selective IPM (sel-IPM). A selective IPM was performed by selectively clamping the right portal pedicle. Patients without IPM served as controls (no-IPM). Arterial blood samples were taken immediately after incision, ischemia and reperfusion of the liver, transection, 8 hours after start of surgery and on the first post-operative day. RESULTS: 24 patients (13 males) were included. 7 patients received cycles of 15 minutes and 5 patients received cycles of 30 minutes of hepatic inflow occlusion. 6 patients received cycles of 15 minutes selective hepatic occlusion and 6 patients underwent surgery without inflow occlusion. Application of total-IPM resulted in a significant increase in I-FABP 8 hours after start of surgery compared to baseline (p<0.005). In the no-IPM group and sel-IPM group no significant increase in I-FABP at any time point compared to baseline was observed. CONCLUSION: Total-IPM in patients undergoing liver resection is associated with a substantial increase in arterial I-FABP, pointing to intestinal epithelial injury during liver surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT01099475

Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2

Deregulated redox metabolism in cancer leads to oxidative damage to cellular components including deoxyribonucleoside triphosphates (dNTPs). Targeting dNTP pool sanitizing enzymes, such as MTH1, is a highly promising anticancer strategy. The MTH2 protein, known as NUDT15, is described as the second human homologue of bacterial MutT with 8-oxo-dGTPase activity. We present the first NUDT15 crystal structure and demonstrate that NUDT15 prefers other nucleotide substrates over 8-oxo-dGTP. Key structural features are identified that explain different substrate preferences for NUDT15 and MTH1. We find that depletion of NUDT15 has no effect on incorporation of 8-oxo-dGTP into DNA and does not impact cancer cell survival in cell lines tested. NUDT17 and NUDT18 were also profiled and found to have far less activity than MTH1 against oxidized nucleotides. We show that NUDT15 is not a biologically relevant 8-oxo-dGTPase, and that MTH1 is the most prominent sanitizer of the cellular dNTP pool known to date

Epigenetic perturbations in the pathogenesis of mustard toxicity; hypothesis and preliminary results

Among the most readily available chemical warfare agents, sulfur mustard (SM), also known as mustard gas, has been the most widely used chemical weapon. SM causes debilitating effects that can leave an exposed individual incapacitated for days to months; therefore delayed SM toxicity is of much greater importance than its ability to cause lethality. Although not fully understood, acute toxicity of SM is related to reactive oxygen and nitrogen species, oxidative stress, DNA damage, poly(ADP-ribose) polymerase (PARP) activation and energy depletion within the affected cell. Therefore several antioxidants and PARP inhibitors show beneficial effects against acute SM toxicity. The delayed toxicity of SM however, currently has no clear mechanistic explanation. One third of the 100,000 Iranian casualties are still suffering from the detrimental effects of SM in spite of the extensive treatment. We, therefore, made an attempt whether epigenetic aberrations may contribute to pathogenesis of mustard poisoning. Preliminary evidence reveals that mechlorethamine (a nitrogen mustard derivative) exposure may not only cause oxidative stress, DNA damage, but epigenetic perturbations as well. Epigenetic refers to the study of changes that influence the phenotype without causing alteration of the genotype. It involves changes in the properties of a cell that are inherited but do not involve a change in DNA sequence. It is now known that in addition to mutations, epimutations contribute to a variety of human diseases. Under light of preliminary results, the current hypothesis will focus on epigenetic regulations to clarify mustard toxicity and the use of drugs to correct possible epigenetic defects