Islet cell stress induced by insulin-degrading enzyme deficiency promotes regeneration and protection from autoimmune diabetes.

Tuning of protein homeostasis through mobilization of the unfolded protein response (UPR) is key to the capacity of pancreatic beta cells to cope with variable demand for insulin. Here, we asked how insulin-degrading enzyme (IDE) affects beta cell adaptation to metabolic and immune stress. C57BL/6 and autoimmune non-obese diabetic (NOD) mice lacking IDE were exposed to proteotoxic, metabolic, and immune stress. IDE deficiency induced a low-level UPR with islet hypertrophy at the steady state, rapamycin-sensitive beta cell proliferation enhanced by proteotoxic stress, and beta cell decompensation upon high-fat feeding. IDE deficiency also enhanced the UPR triggered by proteotoxic stress in human EndoC-ßH1 cells. In Ide-/- NOD mice, islet inflammation specifically induced regenerating islet-derived protein 2, a protein attenuating autoimmune inflammation. These findings establish a role of IDE in islet cell protein homeostasis, demonstrate how its absence induces metabolic decompensation despite beta cell proliferation, and UPR-independent islet regeneration in the presence of inflammation.

Risk factors for emergency surgery for diverticulitis: A retrospective multicentric French study at 41 hospitals.

BACKGROUND: The observed increase in the incidence of complicated diverticulitis may lead to the performance of more emergency surgeries. This study aimed to assess the rate and risk factors of emergency surgery for sigmoid diverticulitis. METHOD: The primary outcomes were the rate of emergency surgery for sigmoid diverticulitis and its associated risk factors. The urgent or elective nature of the surgical intervention was provided by the surgeon and in accordance with the indication for surgical treatment. A mixed logistic regression with a random intercept after multiple imputations by the chained equation was performed to consider the influence of missing data on the results. RESULTS: Between 2010 and 2021, 6,867 patients underwent surgery for sigmoid diverticulitis in the participating centers, of which one-third (n = 2317) were emergency cases. In multivariate regression analysis with multiple imputation by chained equation, increasing age, body mass index <18.5 kg/m2, neurologic and pulmonary comorbidities, use of anticoagulant drugs, immunocompromised status, and first attack of sigmoid diverticulitis were independent risk factors for emergency surgery. The likelihood of emergency surgery was significantly more frequent after national guidelines, which were implemented in 2017, only in patients with a history of sigmoid diverticulitis attacks. CONCLUSION: The present study highlights a high rate (33%) of emergency surgery for sigmoid diverticulitis in France, which was significantly associated with patient features and the first attack of diverticulitis.

Real-life data comparing the efficacy of vigabatrin and oral steroids given sequentially or combined for infantile epileptic spasms syndrome.

AIMS: The prognosis of Infantile epileptic spasm syndrome (IESS), relates to the underlying etiology and delay in controlling epileptic spasms. Based on the spasm-free rate, a randomized controlled trial has demonstrated the superiority of combining oral steroids and vigabatrin over oral steroids alone but confirmation in real-life conditions is mandatory. METHODS: We compared two real-life IESS cohorts: a multicenter, retrospective cohort of 40 infants treated with vigabatrin followed by a sequential (ST) addition of steroids, and a prospective, single-center cohort of 58 infants treated with an immediate combination of vigabatrin and steroids (CT). RESULTS: The two cohorts were similar. When the rate of spasm-free infants in the two cohorts was compared on day 14, a significant difference was observed between the ST (27,5 %) and CT cohorts (64 %) (p < 0.0004). This difference remained significant on day 30, with 55 % spasm-free patients in the ST cohort compared to 76 % in the CT cohort (p = 0.03). After the infants had received both vigabatrin and steroids, without taking into account the time point after treatment initiation, no significant difference was observed in the spasm-free rate between the two cohorts (p = 0.38). INTERPRETATION: Real-life data confirm the interest of combination therapy as a first-line treatment for IESS.

Impact of the first wave of COVID-19 epidemy on the surgical management of sigmoid diverticular disease in France: National French retrospective study.

OBJECTIVE: To analyze the surgical management of sigmoid diverticular disease (SDD) before, during, and after the first containment rules (CR) for the first wave of COVID-19. METHODS: From the French Surgical Association multicenter series, this study included all patients operated on between January 2018 and September 2021. Three groups were compared: A (before CR period: 01/01/18-03/16/20), B (CR period: 03/17/20-05/03/20), and C (post CR period: 05/04/20-09/30/21). RESULTS: A total of 1965 patients (A n = 1517, B n = 52, C n = 396) were included. The A group had significantly more previous SDD compared to the two other groups (p = 0.007), especially complicated (p = 0.0004). The rate of peritonitis was significantly higher in the B (46.1%) and C (38.4%) groups compared to the A group (31.7%) (p = 0.034 and p = 0.014). As regards surgical treatment, Hartmann's procedure was more often performed in the B group (44.2%, vs A 25.5% and C 26.8%, p = 0.01). Mortality at 90 days was significantly higher in the B group (9.6%, vs A 4% and C 6.3%, p = 0.034). This difference was also significant between the A and B groups (p = 0.048), as well as between the A and C groups (p = 0.05). There was no significant difference between the three groups in terms of postoperative morbidity. CONCLUSION: This study shows that the management of SDD was impacted by COVID-19 at CR, but also after and until September 2021, both on the initial clinical presentation and on postoperative mortality.

Right portal vein ligation is still relevant for left hemi-liver hypertrophy: results of a comparative study using a propensity score between right portal vein ligation and embolization.

BACKGROUND: In two-stage hepatectomy for bilobar liver metastases from colorectal cancer, future liver remnant (FLR) growth can be achieved using several techniques, such as right portal vein ligation (RPVL) or right portal vein embolization (RPVE). A few heterogeneous studies have compared these two techniques with contradictory results concerning FLR growth. The objective of this study was to compare FLR hypertrophy of the left hemi-liver after RPVL and RPVE. STUDY DESIGN: This was a retrospective comparative study using a propensity score of patients who underwent RPVL or RPVE prior to major hepatectomy between January 2010 and December 2020. The endpoints were FLR growth (%) after weighting using the propensity score, which included FLR prior to surgery and the number of chemotherapy cycles. Secondary endpoints were the percentage of patients undergoing simultaneous procedures, the morbidity and mortality, the recourse to other liver hypertrophy procedures, and the number of invasive procedures for the entire oncologic program in intention-to-treat analysis. RESULTS: Fifty-four consecutive patients were retrospectively included and analyzed, 18 in the RPVL group, and 36 in the RPVE group. The demographic characteristics were similar between the groups. After weighting, there was no significant difference between the RPVL and RPVE groups for FLR growth (%), respectively 32.5% [19.3-56.0%] and 34.5% [20.5-47.3%] (p = 0.221). There was no significant difference regarding the secondary outcomes except for the lower number of invasive procedures in RPVL group (median of 2 [2.0, 3.0] in RPVL group and 3 [3.0, 3.0] in RPVE group, p = 0.001)). CONCLUSION: RPVL and RPVE are both effective to provide required left hemi-liver hypertrophy before right hepatectomy. RPVL should be considered for the simultaneous treatment of liver metastases and the primary tumor.

Pancreatic islet cell stress induced by insulin-degrading enzyme deficiency promotes islet regeneration and protection from autoimmune diabetes.

Appropriate tuning of protein homeostasis through mobilization of the unfolded protein response (UPR) is key to the capacity of pancreatic beta cells to cope with highly variable demand for insulin synthesis. An efficient UPR ensures a sufficient beta cell mass and secretory output but can also affect beta cell resilience to autoimmune aggression. The factors regulating protein homeostasis in the face of metabolic and immune challenges are insufficiently understood. We examined beta cell adaptation to stress in mice deficient for insulin-degrading enzyme (IDE), a ubiquitous protease with high affinity for insulin and genetic association with type 2 diabetes. IDE deficiency induced a low-level UPR in both C57BL/6 and autoimmune non-obese diabetic (NOD) mice, associated with rapamycin-sensitive beta cell proliferation strongly enhanced by proteotoxic stress. Moreover, in NOD mice, IDE deficiency protected from spontaneous diabetes and triggered an additional independent pathway, conditional on the presence of islet inflammation but inhibited by proteotoxic stress, highlighted by strong upregulation of regenerating islet-derived protein 2, a protein attenuating autoimmune inflammation. Our findings establish a key role of IDE in islet cell protein homeostasis, identify a link between low-level UPR and proliferation, and reveal an UPR-independent anti-inflammatory islet cell response uncovered in the absence of IDE of potential interest in autoimmune diabetes.

Cross-presentation by the others.

The critical role of conventional dendritic cells in physiological cross-priming of immune responses to tumors and pathogens is widely documented and beyond doubt. However, there is ample evidence that a wide range of other cell types can also acquire the capacity to cross-present. These include not only other myeloid cells such as plasmacytoid dendritic cells, macrophages and neutrophils, but also lymphoid populations, endothelial and epithelial cells and stromal cells including fibroblasts. The aim of this review is to provide an overview of the relevant literature that analyzes each report cited for the antigens and readouts used, mechanistic insight and in vivo experimentation addressing physiological relevance. As this analysis shows, many reports rely on the exceptionally sensitive recognition of an ovalbumin peptide by a transgenic T cell receptor, with results that therefore cannot always be extrapolated to physiological settings. Mechanistic studies remain basic in most cases but reveal that the cytosolic pathway is dominant across many cell types, while vacuolar processing is most encountered in macrophages. Studies addressing physiological relevance rigorously remain exceptional but suggest that cross-presentation by non-dendritic cells may have significant impact in anti-tumor immunity and autoimmunity.

Benefit of a flash dose of corticosteroids in digestive surgical oncology: a multicenter, randomized, double blind, placebo-controlled trial (CORTIFRENCH).

BACKGROUND: The modulation of perioperative inflammation seems crucial to improve postoperative morbidity and cancer-related outcomes in patients undergoing oncological surgery. Data from the literature suggest that perioperative corticosteroids decrease inflammatory markers and might be associated with fewer complications in esophageal, liver, pancreatic and colorectal surgery. Their benefit on cancer-related outcomes has not been assessed. METHODS: The CORTIFRENCH trial is a phase III multicenter randomized double-blind placebo-controlled trial to assess the impact of a flash dose of preoperative corticosteroids versus placebo on postoperative morbidity and cancer-related outcomes after elective curative-intent surgery for digestive cancer. The primary endpoint is the frequency of patients with postoperative major complications occurring within 30 days after surgery (defined as all complications with Clavien-Dindo grade > 2). The secondary endpoints are the overall survival at 3 years, the disease-free survival at 3 years, the frequency of patients with intraabdominal infections and postoperative infections within 30 days after surgery and the hospital length of stay. We hypothesize a reduced risk of major complications and a better disease-survival at 3 years in the experimental group. Allowing for 5% of drop-out, 1 200 patients (600 per arm) should be included. DISCUSSION: This will be the first trial focusing on the impact of perioperative corticosteroids on cancer related outcomes. If significant, it might be a strong improvement on oncological outcomes for patients undergoing surgery for digestive cancers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03875690, Registered on March 15, 2019, URL: https://clinicaltrials.gov/ct2/show/NCT03875690 .

Role of protective stoma after primary anastomosis for generalized peritonitis due to perforated diverticulitis-DIVERTI 2 (a prospective multicenter randomized trial): rationale and design (nct04604730).

BACKGROUND: Traditionally, patients with peritonitis Hinchey III and IV due to perforated diverticulitis were treated with Hartmann's procedure. In the past decade, resection and primary anastomosis have gained popularity over Hartmann's procedure and recent guidelines recommend Hartmann's procedure in two situations only: critically ill patients and in selected patients with multiple comorbidity (at high risk of complications). The protective stoma (PS) is recommended after resection with primary anastomosis, however its interest has never been studied. The aim of this trial is to define the role of systematic PS after resection and primary anastomosis for peritonitis Hinchey III and IV due to perforated diverticulitis. METHODS/DESIGN: This DIVERTI 2 trial is a multicenter, randomized, controlled, superiority trial comparing resection and primary anastomosis with (control group) or without (experimental group) PS in patients with peritonitis Hinchey III and IV due to perforated diverticulitis. Primary endpoint is the overall 1 year morbidity according to the Clavien-Dindo classification of surgical complications. All complications occurring during hospitalization will be collected. Late complications occurring after hospitalization will be collected during follow-up. In order to obtain 80% power for a difference given by respective main probabilities of 67% and 47% in the protective stoma and no protective stoma groups respectively, with a two-sided type I error of 5%, 96 patients will have to be included in each group, hence 192 patients overall. Expecting a 5% rate of patients not assessable for the primary end point (lost to follow-up), 204 patients will be enrolled. Secondary endpoints are postoperative mortality, unplanned reinterventions, incisional surgical site infection (SSI), organ/space SSI, wound disruption, anastomotic leak, operating time, length of hospital stay, stoma at 1 year after initial surgery, quality of life, costs and quality-adjusted life years (QALYs). DISCUSSION: The DIVERTI 2 trial is a prospective, multicenter, randomized, study to define the best strategy between PS and no PS in resection and primary anastomosis for patients presenting with peritonitis due to perforated diverticulitis. TRIAL REGISTRATION: ClinicalTrial.gov: NCT04604730 date of registration October 27, 2020. https://clinicaltrials.gov/ct2/show/NCT04604730?recrs=a&cond=Diverticulitis&draw=2&rank=12 .

Feasibility and Effectiveness of an Enhanced Recovery Program after Early Cholecystectomy for Acute Calculous Cholecystitis: A 2-Step Study.

BACKGROUND: Enhanced recovery programs (ERPs) are associated with a lower morbidity rate and a shorter length of stay. The present study's objective was to determine whether an ERP is feasible and effective for patients undergoing early cholecystectomy for grade I or II acute calculous cholecystitis. STUDY DESIGN: A 2-step multicenter study was performed. In the first step (the feasibility study), patients were consecutively included in a dedicated, prospective database from March 2019 until January 2020. The primary endpoint was the ERP's feasibility, evaluated in terms of the number and nature of the ERP components applied. During the second step, the ERP's effectiveness in acute calculous cholecystitis was evaluated in a case-control study. The ERP+ group comprised consecutive patients who were prospectively included from March 2019 to November 2020 and compared with a control (ERP-) group of patients extracted from the ABCAL randomized controlled trial treated between May 2010 and August 2012 and who had not participated in a dedicated ERP. RESULTS: During the feasibility study, 101 consecutive patients entered the ERP with 17 of the 20 ERP components applied. During the effectiveness study, 209 patients (ERP+ group) were compared with 414 patients (ERP- group). The median length of stay was significantly shorter in the ERP+ group (3.1 vs 5 days; p < 0.001). There were no intergroup differences in the severe morbidity rate, mortality rate, readmission rate, and reoperation rate. CONCLUSIONS: Implementation of an ERP after early cholecystectomy for acute calculous cholecystitis appeared to be feasible, effective, and safe for patients. The ERP significantly decreased the length of stay and did not increase the morbidity rate.

Impact of a procalcitonin-based algorithm on the quality of management of patients with uncomplicated adhesion-related small bowel obstruction assessed by a textbook outcome: a multicenter cluster-randomized open-label controlled trial.

BACKGROUND: Acute adhesion-related small bowel obstruction (ASBO) is a common digestive emergency, accounting for 1 to 3% of all digestive emergencies. The efficacy of conservative management in this setting is a subject of debate, as it may delay the decision to perform surgery and increase the frequency of bowel resection (e.g., in the presence of bowel necrosis) or, in contrast, prompt an excessive number of unnecessary laparotomies. Thus, the decision to perform surgery is difficult. We propose that the introduction of the procalcitonin (PCT)-based algorithm improves the quality of the management of patients with ASBO by aiding the decision of whether or not to perform surgery. METHODS: This is a 1:1 cluster-randomized clinical trial (use of algorithm: no algorithm) using an independent computer to ensure that investigators cannot interfere with the randomization. Each cluster will correspond to one investigating center. All patients in a center will be managed in the same way. Before randomization, each principal investigator will provide a commitment to participate in the study to avoid the risk of "empty clusters". The patients included will constitute two parallel arms (use of algorithm versus no algorithm), with no expected crossover between arms. The inclusion criteria are being an adult with uncomplicated acute ASBO (i.e., absence of fever, abdominal pain and distension, nausea and/or vomiting, and the absence of gas and/or stool, in conjunction with a contrast-enhanced CT scan, for patients with previous abdominal surgery) who is able to express consent with a signed written informed consent form. Patients with complicated acute ASBO (strangulation or peritonitis) will be excluded. DISCUSSION: There is an ongoing debate on the management of uncomplicated ASBO. The main points are to avoid a surgery if it is unnecessary and to avoid delayed surgery if it is necessary. Currently, there are no robust criteria to objectively determine the failure of non-surgical treatment or to establish the indications for surgery in acute ASBO. Our team proposes the use of procalcitonin (PCT) to help distinguish patients for whom conservative management is likely to be successful from those for whom surgical management is required. The results from a randomized control trial could help in the selection of patients through clear inclusion and exclusion criteria and simplify or clarify the management algorithm. In conclusion, PCT may be useful in evaluating the proper strategy for ASBO. Trial registration The trial is registered at clinical trials under the reference: NCT03905239.

Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis.

LPIN1 mutations are responsible for inherited recurrent rhabdomyolysis, a life-threatening condition with no efficient therapeutic intervention. Here, we conduct a bedside-to-bench-and-back investigation to study the pathophysiology of lipin1 deficiency. We find that lipin1-deficient myoblasts exhibit a reduction in phosphatidylinositol-3-phosphate close to autophagosomes and late endosomes that prevents the recruitment of the GTPase Armus, locks Rab7 in the active state, inhibits vesicle clearance by fusion with lysosomes, and alters their positioning and function. Oxidized mitochondrial DNA accumulates in late endosomes, where it activates Toll-like receptor 9 (TLR9) and triggers inflammatory signaling and caspase-dependent myolysis. Hydroxychloroquine blocks TLR9 activation by mitochondrial DNA in vitro and may attenuate flares of rhabdomyolysis in 6 patients treated. We suggest a critical role for defective clearance of oxidized mitochondrial DNA that activates TLR9-restricted inflammation in lipin1-related rhabdomyolysis. Interventions blocking TLR9 activation or inflammation can improve patient care in vivo.

Cross-sectional case-control study of the relationships between pharyngeal compliance and heart rate variability indices in childhood obstructive sleep apnoea.

A combination of noradrenergic and antimuscarinic agents reduces the apnea-hypopnea index (AHI) in adult patients with obstructive sleep apnoea (OSA) via reduced upper airway collapsibility, suggesting that a shift in the sympathovagal balance improves OSA. The objectives of our present case-control study were to assess heart rate variability (HRV) indices in the stages of sleep in children with and without OSA to evaluate OSA-induced sleep HRV modifications and to assess whether increased collapsibility measured during wakefulness is associated with reduced sympathetic activity during non-rapid eye movement (NREM) sleep. Three groups of 15 children were matched by sex, age, z-score of body mass index and ethnicity: non-OSA (obstructive AHI [OAHI] <2 events/hr), mild (OAHI ≥2 to <5 events/hr) or moderate-severe (OAHI ≥5 events/hr) OSA. Pharyngeal compliance was measured during wakefulness using acoustic pharyngometry. HRV indices (time and frequency domain variables) were calculated on 5-min electrocardiography recordings from polysomnography during wakefulness, NREM and REM sleep in periods free of any event. As compared to children without OSA, those with OSA (n = 30) were characterised by increased compliance and no physiological parasympathetic tone increase in REM sleep. Children with increased pharyngeal compliance (n = 21) had a higher OAHI due to higher AHI in NREM sleep, whereas their sympathetic tone was lower than that of those with normal compliance (n = 24). In conclusion, children with increased pharyngeal compliance exhibit decreased sympathetic tone associated with increased AHI in NREM sleep. Therapeutics directed at sympathovagal balance modifications should be tested in childhood OSA.

Are colorectal cancer patients at risk for COVID-19 infection during the postoperative period? The Covid-GRECCAR study.

INTRODUCTION: During the COVID-19 pandemic, cancer patients have been regarded as having a high risk of severe events if they are infected with SARS-CoV-2, particularly those under medical or surgical treatment. The aim of this study was to assess the posttreatment risk of infection by SARS-CoV-2 in a population of patients operated on for colorectal cancer 3 months before the COVID-19 outbreak and who after hospitalization returned to an environment where the virus was circulating. MATERIALS AND METHODS: This French, multicenter cohort study included consecutive patients undergoing elective surgery for colorectal cancer between January 1 and March 31, 2020, at 19 GRECCAR hospitals. The outcome was the rate of COVID-19 infection in this group of patients who were followed until June 15, 2020. RESULTS: This study included 448 patients, 262 male (58.5%) and 186 female (41.5%), who underwent surgery for colon cancer (n = 290, 64.7%), rectal cancer (n = 155, 34.6%), or anal cancer (n = 3, 0.7%). The median age was 68 years (19-95). Comorbidities were present in nearly half of the patients, 52% were at least overweight, and the median BMI was 25 (12-42). At the end of the study, 448 were alive. Six patients (1.3%) developed COVID-19 infection; among them, 3 were hospitalized in the conventional ward, and none of them died. CONCLUSION: The results are reassuring, with only a 1.3% infection rate and no deaths related to COVID-19. We believe that we can operate on colorectal cancer patients without additional mortality from COVID-19, applying all measures aimed at reducing the risk of infection.

Kinesin-1 regulates antigen cross-presentation through the scission of tubulations from early endosomes in dendritic cells.

Dendritic cells (DCs) constitute a specialized population of immune cells that present exogenous antigen (Ag) on major histocompatibility complex (MHC) class I molecules to initiate CD8 + T cell responses against pathogens and tumours. Although cross-presentation depends critically on the trafficking of Ag-containing intracellular vesicular compartments, the molecular machinery that regulates vesicular transport is incompletely understood. Here, we demonstrate that mice lacking Kif5b (the heavy chain of kinesin-1) in their DCs exhibit a major impairment in cross-presentation and thus a poor in vivo anti-tumour response. We find that kinesin-1 critically regulates antigen cross-presentation in DCs, by controlling Ag degradation, the endosomal pH, and MHC-I recycling. Mechanistically, kinesin-1 appears to regulate early endosome maturation by allowing the scission of endosomal tubulations. Our results highlight kinesin-1's role as a molecular checkpoint that modulates the balance between antigen degradation and cross-presentation.

Are the recommendations for post-operative antibiotics in patients with grade I or II acute calculous cholecystitis being applied in clinical practice?

BACKGROUND: There is a level-1 evidence indicating that postoperative antibiotics are unnecessary following cholecystectomy for grade I or II acute calculous cholecystitis (ACC). We wanted to evaluate the applications of this recommendation in clinical practice four years after the original publication in ABCAL-participating centers. METHODS: A retrospective analysis of patients operated for grade I or II ACC from January to December 2016 in ABCAL-participating centers was performed. Inclusion criteria were the same as for the ABCAL-study. The primary endpoint was the postoperative antibiotic administration rate. The secondary endpoints were postoperative outcomes. RESULTS: Of the 283 patients included, 64% received postoperative antibiotics. Only 19% received antibiotics after POD1. The perioperative outcomes were similar between those that did or did not receive antibiotics after POD1. The median [range] length of stay was significantly shorter in patients who did not receive postoperative antibiotics (4 days [1-20]) compared to the others (6 days [1-50], p > 0.001). CONCLUSION: Despite strong recommendations included in the Tokyo 2018 guidelines, the results of the ABCAL-study are poorly applied even if the absence of postoperative antibiotics has no impact on morbidity. It is important to stress that postoperative antibiotics are not necessary after cholecystectomy for grade I or II ACC.

IRAP Endosomes Control Phagosomal Maturation in Dendritic Cells.

Dendritic cells (DCs) contribute to the immune surveillance by sampling their environment through phagocytosis and endocytosis. We have previously reported that, rapidly following uptake of extracellular antigen into phagosomes or endosomes in DCs, a specialized population of storage endosomes marked by Rab14 and insulin-regulated aminopeptidase (IRAP) is recruited to the nascent antigen-containing compartment, thereby regulating its maturation and ultimately antigen cross-presentation to CD8+ T lymphocytes. Here, using IRAP-/- DCs, we explored how IRAP modulates phagosome maturation dynamics and cross-presentation. We find that in the absence of IRAP, phagosomes acquire more rapidly late endosomal markers, are more degradative, and show increased microbicidal activity. We also report evidence for a role of vesicle trafficking from the endoplasmic reticulum (ER)-Golgi intermediate compartment to endosomes for the formation or stability of the IRAP compartment. Moreover, we dissect the dual role of IRAP as a trimming peptidase and a critical constituent of endosome stability. Experiments using a protease-dead IRAP mutant and pharmacological IRAP inhibition suggest that IRAP expression but not proteolytic activity is required for the formation of storage endosomes and for DC-typical phagosome maturation, whereas proteolysis is required for fully efficient cross-presentation. These findings identify IRAP as a key factor in cross-presentation, trimming peptides to fit the major histocompatibility complex class-I binding site while preventing their destruction through premature phagosome maturation.

Evaluation of a one-piece soft convex ostomy appliance: a prospective, multicentre, open-label pilot study.

Leakage of stomal effluent is considered by people living with a stoma to be the key factor that negatively impacts their quality of life (QoL). This non-randomised pilot study evaluated the performance of a new stoma appliance, Flexima® Active O Convex in 40 ostomy patients with a flat, flush or slightly retracted stoma over a 14-day period. Leakage was reported for the wear time of each pouch by the patients. On 79% of occasions, the patient reported no leakage under the skin protector. The appliance was very well tolerated and the condition of the patients' peristomal skin was maintained throughout the study. The performance was rated as 'good' or 'very good' by most of the patients. The results of this study have shown that the design of this one-piece soft convex appliance can prevent leakage and protect peristomal skin by providing a safe seal around the stoma. It was also reported as being flexible and comfortable to wear.

Innate Immune Signals Induce Anterograde Endosome Transport Promoting MHC Class I Cross-Presentation.

Both cross-presentation of antigens by dendritic cells, a key pathway triggering T cell immunity and immune tolerance, and survival of several pathogens residing in intracellular vacuoles are intimately linked to delayed maturation of vesicles containing internalized antigens and microbes. However, how early endosome or phagosome identity is maintained is incompletely understood. We show that Toll-like receptor 4 (TLR4) and Fc receptor ligation induces interaction of the GTPase Rab14 with the kinesin KIF16b mediating plus-end-directed microtubule transport of endosomes. As a result, Rab14 recruitment to phagosomes delays their maturation and killing of an internalized pathogen. Enhancing anterograde transport by overexpressing Rab14, promoting the GTP-bound Rab14 state, or inhibiting retrograde transport upregulates cross-presentation. Conversely, reducing Rab14 expression, destabilizing Rab14 endosomes, and inhibiting anterograde microtubule transport by Kif16b knockdown compromise cross-presentation. Therefore, regulation of early endosome trafficking by innate immune signals is a critical parameter in cross-presentation by dendritic cells.

Cardiac function and exercise adaptation in 8 children with LPIN1 mutations.

INTRODUCTION: Lipin-1 deficiency is a major cause of rhabdomyolysis that are precipitated by febrile illness. The prognosis is poor, with one-third of patients dying from cardiac arrest during a crisis episode. Apart from acute rhabdomyolysis, most patients are healthy, showing normal clinical and cardiac ultrasound parameters. PATIENTS AND METHODS: We report cardiac and exercise examinations of 8 children carrying two LPIN1 mutations. The examinations were performed outside of a myolysis episode, but one patient presented with fever during one examination. RESULTS: All but one patient displayed normal resting cardiac function, as determined by echocardiography. One patient exhibited slight left ventricular dysfunction at rest and a lack of increased stroke volume during cycle ramp exercise. During exercise, peripheral muscle adaptation was impaired in 2 patients compared to healthy controls: they presented an abnormal increase in cardiac output relative to oxygen uptake: dQ/dVO2=8.2 and 9.5 (>2DS of controls population). One patient underwent 2 exercise tests; during one test, the patient was febrile, leading to acute rhabdomyolysis in the following hours. He exhibited changes in recovery muscle reoxygenation parameters and an increased dQ/dVO2 during exercise compared with that under normothermia (7.9 vs 6), which did not lead to acute rhabdomyolysis. The four patients assessed by cardiac 1H-magnetic resonance spectroscopy exhibited signs of intracardiac steatosis. CONCLUSION: We observed abnormal haemodynamic profiles during exercise in 3/8 patients with lipin-1 deficiency, suggesting impaired muscle oxidative phosphorylation during exercise. Fever appeared to be an aggravating factor. One patient exhibited moderate cardiac dysfunction, which was possibly related to intracardiac stored lipid toxicity.