Anion and cation permeability of the mouse tmem16f calcium-activated channel

TMEM16F is involved in several physiological processes, such as blood coagulation, bone development and virus infections. This protein acts both as a Ca2+-dependent phospholipid scram-blase and a Ca2+-activated ion channel but several studies have reported conflicting results about the ion selectivity of the TMEM16F-mediated current. Here, we have performed a detailed side-by-side comparison of the ion selectivity of TMEM16F using the whole-cell and inside-out excised patch configurations to directly compare the results. In inside-out configuration, Ca2+-dependent activation was fast and the TMEM16F-mediated current was activated in a few milliseconds, while in whole-cell recordings full activation required several minutes. We determined the relative permeability between Na+ and Cl¯ (PNa /PCl ) using the dilution method in both configurations. The TMEM16F-mediated current was highly nonselective, but there were differences depending on the configuration of the recordings. In whole-cell recordings, PNa /PCl was approximately 0.5, indicating a slight preference for Cl¯ permeation. In contrast, in inside-out experiments the TMEM16F channel showed a higher permeability for Na+ with PNa /PCl reaching 3.7. Our results demonstrate that the time dependence of Ca2+ activation and the ion selectivity of TMEM16F depend on the recording configuration

Due visioni della responsabilità sociale dell'impresa, con una applicazione alla società benefit

Il lavoro analizza due diverse concezioni della CSR e tenta una applicazione all'istituto della societ\ue0 benefit.The paper analyzes two different conceptions of CSR and attempts an application to the benefit corporation

Generation of donor-specific Tr1 cells to be used after kidney transplantation and definition of the timing of their in vivo infusion in the presence of immunosuppression

Background: Operational tolerance is an alternative to lifelong immunosuppression after transplantation. One strategy to achieve tolerance is by T regulatory cells. Safety and feasibility of a T regulatory type 1 (Tr1)-cell-based therapy to prevent graft versus host disease in patients with hematological malignancies has been already proven. We are now planning to perform a Tr1-cell-based therapy after kidney transplantation. Methods: Upon tailoring the lab-grade protocol to patients on dialysis, aims of the current work were to develop a clinical-grade compatible protocol to generate a donor-specific Tr1-cell-enriched medicinal product (named T10 cells) and to test the Tr1-cell sensitivity to standard immunosuppression in vivo to define the best timing of cell infusion. Results: We developed a medicinal product that was enriched in Tr1 cells, anergic to donor-cell stimulation, able to suppress proliferation upon donor- but not third-party stimulation in vitro, and stable upon cryopreservation. The protocol was reproducible upon up scaling to leukapheresis from patients on dialysis and was effective in yielding the expected number of T10 cells necessary for the planned infusions. The tolerogenic gene signature of circulating Tr1 cells was minimally compromised in kidney transplant recipients under standard immunosuppression and it eventually started to recover 36weeks post-transplantation, providing rationale for selecting the timings of the cell infusions. Conclusions: These data provide solid ground for proceeding with the trial and establish robust rationale for defining the correct timing of cell infusion during concomitant immunosuppressive treatment

Neutron personal dosimetry using polyallyl diglycol carbonate (PADC): Current status, best practices and proposed research

The objective of this paper is to provide an overview of the current status in neutron personal dosimetry based on poly allyl diglycol carbonate (PADC), also commonly known by the commercial name CR-39, to summarize the best practices in the field, and to point future research directions. An overview of the fundamentals of the technique is given, including a discussion on the PADC material, main parameters and characteristics, practical considerations, dosimetry approaches, and relevant standards. This work also summarizes the best practices adopted by individual monitoring services (IMSs) and discusses the research needed to improve the performance of this type of neutron dosimetry technique, as well as the challenges that make progress difficult. This work is based on the knowledge and experience of several laboratories and investigators and is part of the activities of the European Radiation Dosimetry Group (EURADOS) Working Group 2 – Harmonization of Individual Monitoring in Europe (WG2)

Exocrine pancreas function is impaired in adult relatives of patients with type 1 diabetes

Aims: Alterations of the exocrine pancreas have been reported in type 1 diabetes, but their contribution to the pathogenesis of the disease is poorly understood. Here, we investigated markers of exocrine pancreas dysfunction in individuals at-risk of developing type 1 diabetes. Methods: Serum P-amylase and lipase levels were assessed in samples obtained from healthy controls, patients with new onset type 1 diabetes, relatives participating to the TrialNet Pathway to Prevention who were, at blood collection, autoantibody negative or positive for a single autoantibody (low-risk individuals), and positive for multiple autoantibodies (high-risk individuals). Linear mixed models were adopted to estimate variation of pancreatic enzymes among the groups and to evaluate the influence of high-risk HLA genotypes and residual beta cell function on exocrine pancreas function. Results: In adults, but not children, reduced levels of P-amylase and lipase were shown in at-risk individuals, including (for P-amylase levels only) those at low-risk, and in T1Dnew. Furthermore, while high-risk HLA genotypes negatively affected P-amylase levels in autoantibody negative adult individuals, fasting C-peptide levels did not correlate with pancreatic enzyme levels. Conclusions: Exocrine pancreas dysfunction precedes the onset of type 1 diabetes in adult at-risk individuals and may be unrelated to fasting C-peptide levels

Neutron personal dosimetry using polyallyl diglycol carbonate (PADC): Current status, best practices and proposed research

The objective of this paper is to provide an overview of the current status in neutron personal dosimetry based on poly allyl diglycol carbonate (PADC), also commonly known by the commercial name CR-39, to summarize the best practices in the field, and to point future research directions. An overview of the fundamentals of the technique is given, including a discussion on the PADC material, main parameters and characteristics, practical considerations, dosimetry approaches, and relevant standards. This work also summarizes the best practices adopted by individual monitoring services (IMSs) and discusses the research needed to improve the performance of this type of neutron dosimetry technique, as well as the challenges that make progress difficult. This work is based on the knowledge and experience of several laboratories and investigators and is part of the activities of the European Radiation Dosimetry Group (EURADOS) Working Group 2 –Harmonization of Individual Monitoring in Europe (WG2)

Regulatory T-cells from pancreatic lymphnodes of patients with type-1 diabetes express increased levels of microRNA miR-125a-5p that limits CCR2 expression

Autoimmune type 1 diabetes (T1D) is thought to be caused by a defective immune regulation with regulatory T (Treg) cells playing a fundamental role in this process. Tolerance mechanisms depend on tunable responses that are sensitive to minor perturbations in the expression of molecules that can be carried out by multiple epigenetic mechanisms, including regulation by microRNAs. In this study, microRNA expression profile was investigated in Treg cells isolated from peripheral blood (PB) and from pancreatic draining lymph nodes (PLN) of T1D patients and non-diabetic subjects. Among 72 microRNAs analyzed, miR-125a-5p resulted specifically hyper-expressed in Treg cells purified from PLN of T1D patients. TNFR2 and CCR2 were identified as miR-125a-5p target genes. Elevated miR-125a-5p was detected in Treg cells isolated from PLN but not from PB of donors with T1D and was associated with reduced CCR2 expression. A specific beta-cell expression of the CCR2-ligand (CCL2) was observed in the pancreata of cadaveric donors, suggesting that beta-cells are prone to attract CCR2(+) Treg cells. These novel data propose a mechanism, occurring in PLNs of T1D patients, involving increased expression of miR-125a-5p on Treg cells which results into reduced expression of CCR2, thus limiting their migration and eventual function in the pancreas

Poor nutritional status is associated with other geriatric domain impairments and adverse postoperative outcomes in onco-geriatric surgical patients – a multicentre cohort study

Background: Nutritional status (NS), though frequently affected in onco-geriatric patients, is no standard part of a geriatric assessment. The aim of this study was to analyse the association between a preoperatively impaired NS and geriatric domain impairments and adverse postoperative outcomes in onco-geriatric surgical patients. Methods: 309 patients ≥70 years undergoing surgery for solid tumours were prospectively recruited. Nine screening tools were preoperatively administered as part of a geriatric assessment. NS was based on BMI, weight loss and food intake. Odds ratio’s (OR) and 95% confidence intervals (95%CI) were estimated using logistic regression analysis. The occurrence of 30-day adverse postoperative outcomes was recorded. Results: At a median age of 76 years, 107 patients (34.6%) had an impaired NS. Decreased performance status and depression were associated with an impaired NS, when adjusted for tumour characteristics and comorbidities (ORPS>1 3.46; 95%CI 1.56-7.67. ORGDS>5 2.11; 95%CI 1.05-4.26). An impaired NS was an independent predictor for major complications (OR 3.3; 95%CI 1.6-6.8). Ten out of 11 patients who deceased had an impaired NS. Conclusion: An impaired NS is prevalent in onco-geriatric patients considered to be fit for surgery. It is associated with decreased performance status and depression. An impaired NS is a predictor for adverse postoperative outcomes. NS should be incorporated in a geriatric assessment

Preventing incisional ventral hernias: important for patients but ignored by surgical specialities? A critical review.

Purpose Incisional ventral hernias (IHs) are a common complication across all surgical specialities requiring access to the abdomen, pelvis, and retroperitoneum. This public health issue continues to be widely ignored, resulting in appreciable morbidity and expenses. In this critical review, the issue is explored by an interdisciplinary group. Methods A group of European surgeons encompassing representatives from abdominal wall, vascular, urological, gynecological, colorectal and hepato-pancreatico-biliary surgery have reviewed the occurrence of His in these disciplines. Results Incisional hernias are a major public health issue with appreciable morbidity and cost implications. General surgeons are commonly called upon to repair IHs following an initial operation by others. Measures that may collectively reduce the frequency of IH across specialities include better planning and preparation (e.g. a fit patient, no time pressure, an experienced operator). A minimally invasive technique should be employed where appropriate. Our main recommendations in midline incisions include using the ‘small bites’ suture technique with a ≥ 4:1 suture-to-wound length, and adding prophylactic mesh augmentation in patients more likely to suffer herniation. For off-midline incisions, more research of this problem is essential. Conclusion Meticulous closure of the incision is significant for every patient. Raising awareness of the His is necessary in all surgical disciplines that work withing the abdomen or retroperitoneum. Across all specialties, surgeons should aim for a < 10% IH rate.pre-print146 K

Protocol for EHS Rapid Guideline: Systematic Review, Meta-Analysis, GRADE Assessment, and European Recommendations on Parastomal Hernia Prevention

Background: Parastomal hernia presents frequently after construction of a permanent end colostomy. Previous guidelines recommend using a prophylactic mesh for hernia prevention. Randomized controlled trials (RCTs) published hereafter demonstrate conflicting outcomes.Methods and Analysis: A rapid guideline will be developed and reported in accordance with GRADE, GIN and AGREE-S standards. The steering group will consist of general and colorectal surgeons, members of the EHS Scientific Advisory Board with expertise and experience in guideline development, advanced medical statistics and evidence synthesis, and a certified guideline methodologist. The guideline panel will consist of three general surgeons, three colorectal surgeons, two stoma care nurses, and two patient representatives. A single question will address the safety and efficacy of the use of a prophylactic mesh in patients with a permanent end colostomy, and sensitivity analyses will focus on the use of non-absorbable versus absorbable meshes, and on different anatomical spaces for mesh placement. A systematic review will be conducted and evidence synthesis will be performed by statisticians independently. The results of evidence synthesis will be summarized in summary of findings tables. Recommendation(s) will be finalized through Delphi process of the guideline panel within an evidence-to-decision framework.Ethics and Dissemination: The funding body will not be involved in the development of this guideline. Conflicts of interest, if any, will be addressed by re-assigning functions or replacing participants with direct conflicts, according to Guidelines International Network recommendations