Harnessing the Vnn1 pantetheinase pathway boosts short chain fatty acids production and mucosal protection in colitis.

OBJECTIVE: In the management of patients with IBD, there is a need to identify prognostic markers and druggable biological pathways to improve mucosal repair and probe the efficacy of tumour necrosis factor alpha biologics. Vnn1 is a pantetheinase that degrades pantetheine to pantothenate (vitamin B5, a precursor of coenzyme A (CoA) biosynthesis) and cysteamine. Vnn1 is overexpressed by inflamed colonocytes. We investigated its contribution to the tolerance of the intestinal mucosa to colitis-induced injury. DESIGN: We performed an RNA sequencing study on colon biopsy samples from patients with IBD stratified according to clinical severity and modalities of treatment. We generated the VIVA mouse transgenic model, which specifically overexpresses Vnn1 on intestinal epithelial cells and explored its susceptibility to colitis. We developed a pharmacological mimicry of Vnn1 overexpression by administration of Vnn1 derivatives. RESULTS: VNN1 overexpression on colonocytes correlates with IBD severity. VIVA mice are resistant to experimentally induced colitis. The pantetheinase activity of Vnn1 is cytoprotective in colon: it enhances CoA regeneration and metabolic adaptation of colonocytes; it favours microbiota-dependent production of short chain fatty acids and mostly butyrate, shown to regulate mucosal energetics and to be reduced in patients with IBD. This prohealing phenotype is recapitulated by treating control mice with the substrate (pantethine) or the products of pantetheinase activity prior to induction of colitis. In severe IBD, the protection conferred by the high induction of VNN1 might be compromised because its enzymatic activity may be limited by lack of available substrates. In addition, we identify the elevation of indoxyl sulfate in urine as a biomarker of Vnn1 overexpression, also detected in patients with IBD. CONCLUSION: The induction of Vnn1/VNN1 during colitis in mouse and human is a compensatory mechanism to reinforce the mucosal barrier. Therefore, enhancement of vitamin B5-driven metabolism should improve mucosal healing and might increase the efficacy of anti-inflammatory therapy.

Identification of Cx43 variants predisposing to ventricular fibrillation in the acute phase of ST-elevation myocardial infarction.

AIMS: Ventricular fibrillation (VF) occurring in the acute phase of ST-elevation myocardial infarction (STEMI) is the leading cause of sudden cardiac death worldwide. Several studies showed that reduced connexin 43 (Cx43) expression and reduced conduction velocity increase the risk of VF in acute myocardial infarction (MI). Furthermore, genetic background might predispose individuals to primary VF (PVF). The primary objective was to evaluate the presence of GJA1 variants in STEMI patients. The secondary objective was to evaluate the arrhythmogenic impact of GJA1 variants in STEMI patients with VF. METHODS AND RESULTS: The MAP-IDM prospective cohort study included 966 STEMI patients and was designed to identify genetic predisposition to VF. A total of 483 (50.0%) STEMI patients with PVF were included. The presence of GJA1 variants increased the risk of VF in STEMI patients [from 49.1 to 70.8%, P = 0.0423; odds ratio (OR): 0.40; 95% confidence interval: 0.16-0.97; P = 0.04]. The risk of PVF decreased with beta-blocker intake (from 53.5 to 44.8%, P = 0.0085), atrial fibrillation (from 50.7 to 26.4%, P = 0.0022), and with left ventricular ejection fraction >50% (from 60.2 to 41.4%, P < 0.0001). Among 16 GJA1 variants, three novel heterozygous missense variants were identified in three patients: V236I, H248R, and I327M. In vitro studies of these variants showed altered Cx43 localization and decreased cellular communication, mainly during acidosis. CONCLUSION: Connexin 43 variants are associated with increased VF susceptibility in STEMI patients. Restoring Cx43 function may be a potential therapeutic target to prevent PVF in patients with acute MI. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00859300.

Endoscopic ultrasound-guided radiofrequency ablation for pancreatic neuroendocrine tumors and pancreatic cystic neoplasms: a prospective multicenter study.

BACKGROUND: Pancreatic neuroendocrine tumors (NETs) and intraductal pancreatic mucinous neoplasia (IPMN) with worrisome features are surgically managed. Endoscopic ultrasound (EUS)-guided radiofrequency ablation (RFA) has recently been developed. The safety of EUS-RFA was the primary end point of this study, its efficacy the secondary end point. METHODS: This was a prospective multicenter study that was planned to include 30 patients with a 1-year follow-up with either a NET < 2 cm or a pancreatic cystic neoplasm (PCN), either a branch duct IPMN with worrisome features or a mucinous cystadenoma (MCA). EUS-RFA was performed with an 18G RFA cooling needle. RESULTS: 12 patients had 14 NETs (mean size 13.1 mm, range 10 - 20 mm); 17 patients had cystic tumors (16 IPMNs, 1 MCA; mean size 28 mm, range 9 - 60 mm). Overall three adverse events occurred (10 %), two of these in the first two patients (one pancreatitis, one small-bowel perforation). After these initial patients, modifications in the protocol resulted in a decrease in complications (3.5 %), with one patient having a pancreatic ductal stenosis. Among the 14 NETs, at 1-year follow-up 12 had completely disappeared (86 % tumor resolution), with three patients having a delayed response. Among the 17 PCNs, at 12 months, there were 11 complete disappearances and one diameter that decreased by > 50 % (significant response rate 71 %). All 12 mural nodules showed complete resolution. CONCLUSIONS: EUS-RFA of pancreatic NETs or PCNs is safe with a 10 % complication rate, which can be decreased by improved prophylaxis for the procedure.

TWEAK-binding autoantibodies are generated during psoriatic arthritis and are not influenced by anti-TNF therapy.

BACKGROUND: TNF weakly inducer of apoptosis (TWEAK) is member of the TNF ligand superfamily. Various data support that TWEAK produced by synovial macrophages may contribute to synovitis observed in psoriatic arthritis (PsoA). In PsoA, anti-TNF therapy has been successful in agreement with the key role of TNF in the pathogenesis and the generation by PsoA patients of anti-TNF autoantibodies referred as "beneficial autoimmunity to pro-inflammatory mediators". However, the role of TNF-alpha in the regulation of TWEAK modulation of inflammation during PsoA remains unknown. METHODS: We have studied level course during anti-TNF therapy of serum soluble TWEAK. In the same cohort, we have investigated the generation of TWEAK-binding autoantibodies by PsoA patients before and after anti-TNF therapy. RESULTS: Patients with PsoA had significantly higher serum levels of TWEAK compared with controls [respective means (±SEM) were 645 pg/ml (64) and 467 pg/ml (23); (p = 0.006)] but serum soluble TWEAK levels were not correlated with BASDAI (Spearman's coefficients <0.003, p > 0.05). Our study showed that soluble TWEAK levels were not modulated by etanercept therapy [respective Means (±SEM) were 605 (95) (week 12) and 744 (97) (week 24) pg/ml; (p > 0.23)]. Anti-TWEAK autoantibodies were detected in 9/13 (69.2 %) PsoA patients at inclusion and only in 3/57 (5.3 %) healthy blood donors (p < 0.0001). These circulating antibodies were persistent in PsoA patients and detected at similar levels during etanercept therapy. Moreover we showed that they had a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro. CONCLUSION: Our study revealed that during psoriatic arthritis (1) serum TWEAK was up regulated and (2) TWEAK-binding autoantibodies are generated. Both parameters were not influenced by anti-TNF therapy and persisted at high levels during anti-TNF therapy. For the first time we described here TWEAK-binding IgG autoantibodies with a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro. Finally, our results suggest that TWEAK may be involved in PsoA pathogeny. Trial registration This clinical trial was approved by the local Ethics Committee "Comité de Protection des Personnes Sud-Méditerranée V" with the registration number: 2011-002954-29, and French health minister registration number AFSSAPS A110784-42 obtained the 08/22/2011. This clinical trial is registered in Clinical trial.gov under the number: NCT02164214.

A Combination of Single-Nucleotide Polymorphisms Is Associated with Interindividual Variability in Cholecalciferol Bioavailability in Healthy Men.

BACKGROUND: Most people require dietary vitamin D to achieve the recommended concentration of 25-hydroxyvitamin D [25(OH)D] in the blood. However, the response to vitamin D supplementation is highly variable among individuals. OBJECTIVE: We assessed whether the variability in cholecalciferol bioavailability was associated with single-nucleotide polymorphisms (SNPs) in candidate genes. METHODS: In a single-group design, 39 healthy adult men with a mean ± SD age of 33 ± 2 y and mean ± SD body mass index (in kg/m2) of 22.9 ± 0.3 were genotyped with the use of whole-genome microarrays. After an overnight fast, plasma 25(OH)D status was measured, and the subjects then consumed a meal that provided 5 mg cholecalciferol as a supplement. Plasma chylomicron cholecalciferol concentration was measured over 8 h, and cholecalciferol response was assessed by calculating the postprandial area under the curve. Partial least squares regression was used to test the association of SNPs in or near candidate genes (61 genes representing 3791 SNPs) with the postprandial cholecalciferol response. RESULTS: The postprandial chylomicron cholecalciferol concentration peaked at 5.4 h. The cholecalciferol response was extremely variable among individuals (CV: 47%). It correlated with the chylomicron triglyceride (TG) response (r = 0.60; P < 0.001) but not with the fasting plasma 25(OH)D concentration (r = 0.04; P = 0.83). A significant (P = 1.32 × 10-4) partial least squares regression model that included 17 SNPs in 13 genes (including 5 that have been associated with chylomicron TG response) was associated with the variance in the cholecalciferol response. CONCLUSION: In healthy men, there is a high interindividual variability in cholecalciferol bioavailability that is associated with a combination of SNPs located in or near genes involved in both vitamin D and lipid metabolism. This trial was registered at clinicaltrials.gov as NCT02100774.

High Atopobium vaginae and Gardnerella vaginalis vaginal loads are associated with preterm birth.

BACKGROUND: Bacterial vaginosis is a risk factor for preterm birth. The various conventional methods for its diagnosis are laborious and not easily reproducible. Molecular quantification methods have been reported recently, but the specific risk factors they might identify remain unclear. METHODS: A prospective multicenter national study included pregnant women at risk of preterm birth. A quantitative molecular tool using a specific real-time polymerase chain reaction assay and serial dilutions of a plasmid suspension quantified Atopobium vaginae, Gardnerella vaginalis, lactobacilli, Mycoplasma hominis, and the human albumin gene (for quality control). RESULTS: In 813 pregnancies, high vaginal loads of either or both of A. vaginae and G. vaginalis were associated with preterm birth (hazard ratio [HR], 3.9; 95% confidence interval {CI}, 1.1-14.1; P = .031). A high vaginal load of A. vaginae was significantly associated with shortened time to delivery and therefore pregnancy length. These times were, respectively, 152.2 and 188.2 days (HR, 5.6; 95% CI, 1.5-21.3; P < .001) before 22 weeks, 149.0 and 183.2 days (HR, 2.8; 95% CI, 1.1-8.2; P = .048) before 28 weeks, and 132.6 and 170.4 days (HR, 2.2; 95% CI, 1.1-4.6; P = .033) before 32 weeks. After multivariate analysis, A. vaginae levels ≥10(8) copies/mL remained significantly associated with delivery before 22 weeks of gestation (adjusted HR, 4.7; 95% CI, .2-17.6; P = .014). CONCLUSIONS: High vaginal loads of A. vaginae and G. vaginalis are associated with late miscarriage and prematurity in high-risk pregnancies. A high vaginal load of A. vaginae (DNA level ≥10(8) copies/mL) identifies a population at high risk of preterm birth. Further studies that both screen for and then treat A. vaginae are needed. CLINICAL TRIALS REGISTRATION: NCT00484653.

High prevalence of laminopathies among patients with metabolic syndrome.

Constitutional laminopathies, such as the Dunnigan familial partial lipodystrophy, are severe diseases caused by mutations in A-type lamins and share several features with metabolic syndrome (MS). In this study, we hypothesized that MS may be, in some cases, a mild form of laminopathies and use the abnormal cell nucleus phenotype observed in these diseases as a primary screening test in patients suffering from common MS. Nuclear shape and lamin A nucleoplasmic distribution abnormalities were systematically searched in lymphoblastoid cells of 87 consecutive patients with MS. In parallel, five genes encoding either the A-type lamins or the enzymes of the lamin A maturation pathway were systematically sequenced (LMNA, ZMPSTE24, ICMT, FNTA and FNTB). We identified 10 MS patients presenting abnormal nuclear shape and disturbed lamin A/C nuclear distribution. These patients were not clinically different from those without nuclear abnormalities except that they were younger, and had higher triglyceridemia and SGPT levels. Three of them carry a heterozygous mutation in LMNA or in ZMPSTE24, a gene encoding one of the lamin A processing enzymes. All three mutations are novel missense mutations predicted to be damaging. Both lymphoblastoid cells and skin fibroblasts from the patient carrying the mutation in ZMPSTE24, showed accumulation of lamin A precursor, indicating an alteration of the lamin A processing, confirmed by functional study. Together, these results show for the first time, that a significant proportion of MS patients exhibits laminopathies and suggest that systematic investigation of lamin A and its partners should be performed at the diagnosis of this syndrome.

Impact of Neuroeffector Adrenergic Receptor Polymorphisms on Incident Ventricular Fibrillation During Acute Myocardial Ischemia.

Background Cardiac adrenergic receptor gene polymorphisms have the potential to influence risk of developing ventricular fibrillation (VF) during ST-segment-elevation myocardial infarction, but no previous study has comprehensively investigated those most likely to alter norepinephrine release, signal transduction, or biased signaling. Methods and Results In a case-control study, we recruited 953 patients with ST-segment-elevation myocardial infarction without previous cardiac history, 477 with primary VF, and 476 controls without VF, and genotyped them for ADRB1 Arg389Gly and Ser49Gly, ADRB2 Gln27Glu and Gly16Arg, and ADRA2C Ins322-325Del. Within each minor allele-containing genotype, haplotype, or 2-genotype combination, patients with incident VF were compared with non-VF controls by odds ratios (OR) of variant frequencies referenced against major allele homozygotes. Of 156 investigated genetic constructs, 19 (12.2%) exhibited significantly (P<0.05) reduced association with incident VF, and none was associated with increased VF risk except for ADRB1 Gly389 homozygotes in the subset of patients not receiving ß-blockers. ADRB1 Gly49 carriers (prevalence 23.0%) had an OR (95% CI) of 0.70 (0.49-0.98), and the ADRA2C 322-325 deletion (Del) carriers (prevalence 13.5%) had an OR of 0.61 (0.39-0.94). When present in genotype combinations (8 each), both ADRB1 Gly49 carriers (OR, 0.67 [0.56-0.80]) and ADRA2C Del carriers (OR, 0.57 [0.45- 0.71]) were associated with reduced VF risk. Conclusions In ST-segment-elevation myocardial infarction, the adrenergic receptor minor alleles ADRB1 Gly49, whose encoded receptor undergoes enhanced agonist-mediated internalization and ß-arrestin interactions leading to cardioprotective biased signaling, and ADRA2C Del322-325, whose receptor causes disinhibition of norepinephrine release, are associated with a lower incidence of VF. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT00859300.

Hypoxia-inducible factor (HIF1α) gene expression in human shock states.

INTRODUCTION: Hypoxia-inducible factor-1 (HIF1) controls the expression of genes involved in the cellular response to hypoxia. No information is available on its expression in critically ill patients. Thus, we designed the first clinical study in order to evaluate the role of HIF1α as a prognosis marker in patients with shock. METHODS: 50 consecutive adult patients with shock and 11 healthy volunteers were prospectively included. RNA was extracted from whole blood samples and expression of HIF1α was assessed over the first 4 hours of shock. The primary objective was to assess HIF1α as a prognostic marker in shock. Secondary objectives were to evaluate the role of HIF1α as a diagnostic and follow-up marker. Patient survival was evaluated at day 28. RESULTS: The causes of shock were sepsis (78%), hemorrhage (18%), and cardiac dysfunction (4%). The HIF1α expression was significantly higher in the shock patients than in the healthy volunteers (121 [72-168] vs. 48 [38-54] normalized copies, p < 0.01), whatever the measured isoforms. It was similar in non-survivors and survivors (108 [range 84-183] vs. 121 [range 72-185] normalized copies, p = 0.92), and did not significantly change within the study period. CONCLUSIONS: The present study is the first to demonstrate the increased expression of HIF1α in patients with shock. Further studies are needed to clarify the potential association with outcome. Our findings reinforce the value of monitoring plasma lactate levels to guide the treatment of shock.

Long-term outcome after EUS-guided radiofrequency ablation: Prospective results in pancreatic neuroendocrine tumors and pancreatic cystic neoplasms.

Background and study aims Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) for pancreatic neuroendocrine tumors (NETs) and intraductal pancreatic mucinous neoplasia (IPMN) with worrisome features or high-risk stigmata (WF/HRS) has been evaluated in few series with short-term outcomes. This study's primary endpoint was to assess the long-term efficacy of EUS-RFA in patients with NETs or pancreatic cystic neoplasms (PCNs) over at least 3 years. Patients and methods Twelve patients had 14 NETs with a mean 13.4-mm size (10-20) and 17 patients had a cystic tumor (16 IPMN, 1 MCA) with a 29.1-mm mean size (9-60 were included. They were treated with EUS-guided RFA, evaluated prospectively at 1 year, and followed annually for at least 3 years. Results The mean duration of follow-up was 42.9 months (36-53). Four patients died during follow-up (17-42 months) from unrelated diseases. At 1-year follow-up, and 85.7 % complete disappearance was seen in 12 patients with 14 NETs. At the end of follow-up (45.6 months), complete disappearance of tumors was seen in 85.7 % of cases. One case of late liver metastasis occurred in a patient with initial failure of EUS-RFA. At 1-year follow-up, a significant response was seen in 70.5 % of 15 patients with PCNs. At the end of the follow-up, there was a significant response in 66.6 % with no mural nodules. Two cases of distant pancreatic adenocarcinoma unrelated to IPMN occurred. Conclusions EUS-RFA results for pancreatic NETs or PCNs appear to be stable during 42 months of follow-up.

Corrigendum: Factors Predicting the Presence of Maternal Cells in Cord Blood and Associated Changes in Immune Cell Composition.

[This corrects the article DOI: 10.3389/fimmu.2021.651399.].

Grandmaternal cells in cord blood.

BACKGROUND: During pregnancy a feto-maternal exchange of cells through the placenta conducts to maternal microchimerism (Mc) in the child and fetal Mc in the mother. Because of this bidirectional traffic of cells, pregnant women have also acquired maternal cells in utero from their mother and could transfer grandmaternal (GdM) cells to their child through the maternal bloodstream during pregnancy. Thus, cord blood (CB) samples could theoretically carry GdMMc. Nevertheless this has never been demonstrated. METHODS: Using Human Leukocyte Antigen (HLA)-specific quantitative PCR assays on three-generation families, we were able to test 28 CB samples from healthy primigravid women for GdMMc in whole blood (WB) and isolated cells (PBMC, T, B, granulocytes, stem cells). FINDINGS: Five CB samples (18%) had GdMMc which could not be confounded with maternal source, with quantities 100 fold lower than maternal Mc in WB and PBMC. Risk of aneuploidies and/or related invasive prenatal procedures significantly correlated with the presence of GdMMc in CB (p=0.024). Significantly decreased HLA compatibility was observed in three-generation families from CB samples carrying GdMMc (p=0.019). INTERPRETATION: Transgenerational transfer of cells could have implications in immunology and evolution. Further analyses will be necessary to evaluate whether GdMMc in CB is a passive or immunologically active transfer and whether invasive prenatal procedures could trigger GdMMc. FUNDING: Provence-Alpes-Côte d'Azur APEX grant # 2012_06549E, 2012_11786F and 2014_03978) and the Foundation for Medical Research (FRM Grant #ING20140129045).

Factors Predicting the Presence of Maternal Cells in Cord Blood and Associated Changes in Immune Cell Composition.

Background: Cord blood (CB) samples are increasingly used as a source of hematopoietic stem cells in transplantation settings. Maternal cells have been detected in CB samples and their presence is associated with a better graft outcome. However, we still do not know what influences the presence of maternal microchimerism (MMc) in CB samples and whether their presence influences CB hematopoietic cell composition. Patients and Methods: Here we test whether genetic, biological, anthropometric and/or obstetrical parameters influence the frequency and/or quantity of maternal Mc in CB samples from 55 healthy primigravid women. Mc was evaluated by targeting non-shared, non-inherited Human Leukocyte Antigen (HLA)-specific real-time quantitative PCR in whole blood and four cell subsets (T, B lymphocytes, granulocytes and/or hematopoietic progenitor cells). Furthermore CB samples were analyzed for their cell composition by flow cytometry and categorized according to their microchimeric status. Results: MMc was present in 55% of CB samples in at least one cell subset or whole blood, with levels reaching up to 0.3% of hematopoietic progenitor cells. Two factors were predictive of the presence of MMc in CB samples: high concentrations of maternal serological Pregnancy-Associated-Protein-A at first trimester of pregnancy (p=0.018) and feto-maternal HLA-A and/or -DR compatibility (p=0.009 and p=0.01 respectively). Finally, CB samples positive for MMc were significantly enriched in CD56+ cells compared to CB negative for MMc. Conclusions: We have identified two factors, measurable at early pregnancy, predicting the presence of maternal cells in CB samples at delivery. We have shown that MMc in CB samples could have an influence on the hematopoietic composition of fetal cells. CD56 is the phenotypic marker of natural killer cells (NK) and NK cells are known to be the main effector for graft versus leukemia reactions early after hematopoietic stem cell transplantation. These results emphasize the importance of MMc investigation for CB banking strategies.

Atelectasis prevention during anaesthesia using high-flow nasal cannula therapy: A paediatric randomised trial using MRI images.

BACKGROUND: Atelectasis frequently occurs early on during anaesthesia in children. We hypothesised that positive expiratory pressure (PEP) generated via high-flow nasal cannula (HFNC) could prevent atelectasis in non-intubated children under general anaesthesia. The objective was to compare the volume of atelectasis present in patients treated via HFNC to that of patients treated via a face bag-mask without PEP. The outcome used for this comparison was the ratio of the atelectasis volume to the total pulmonary volume. METHODS: A prospective single-centre, single-blind, randomised trial was conducted in a tertiary hospital from November 2018 through May 2019. The trial subjects were infants and children between six months and six years of age who required anaesthesia for an MRI. The children were randomised to receive sevoflurane for maintenance of anaesthesia either via a classic face bag-mask or by HFNC. The atelectasis volume was measured from thoracic MRI images. The judgement criterion was the ratio of the atelectasis volume to the lung volume. RESULTS: Of a trial group of 42 patients, 21 received anaesthesia via a face bag-mask and 21 via HFNC. After three patients were excluded for technical issues, the data for 39 patients were analysed. The atelectasis volume to the lung volume ratio in the HFNC group was significantly smaller than the ratio for the face bag-mask group (1.6% vs 6.8%, respectively; p=0.002). CONCLUSION: HFNC was associated with a lower atelectasis lung ratio compared to using a face bag-mask during anaesthesia for children maintained with spontaneous ventilation. Registered on Clinicaltrials.gov: NCT03592589.

Is endoscopic sphincterotomy avoidable in patients with sphincter of Oddi dysfunction?

AIM: Endoscopic sphincterotomy is an efficient means of treating sphincter of Oddi dysfunction (SOD), but it is associated with a morbidity rate of 20%. The aim of this study was to assess how frequently endoscopic sphincterotomy was performed to treat SOD in a group of patients with a 1-year history of medical management. METHODS: A total of 59 patients, who had been cholecystectomized 9.3 years previously on average, were included in this study and they all underwent biliary scintigraphy. Medical treatment was prescribed for 1 year. Endoscopic sphincterotomy was proposed for patients whose medical treatment had been unsuccessful. RESULTS: Eleven patients were rated group 1 on the Milwaukee classification scale, 34 group 2 and 14 group 3. The hile-duodenum transit time (HDTT) was lengthened in 32 patients. The medical treatment was efficient or fairly efficient in 45% of the group 1 patients, 67% of the group 2 patients, and 71.4% of the group 3 patients (P=0.29). Only 14 patients out of the 21 whose medical treatment was unsuccessful agreed to undergo endoscopic sphincterotomy. HDTT was lengthened in 11 of the 14 patients undergoing endoscopic sphincterotomy and in 21 of the 45 non-endoscopic sphincterotomy patients (P=0.03). Twelve of the 14 patients who underwent endoscopic sphincterotomy were cured. CONCLUSION: In this prospective series of patients with a 1-year history of medical management, only 23% of the patients with suspected SOD underwent endoscopic sphincterotomy although 54% had an abnormally long HDTT.

Oropharyngeal and nasopharyngeal decontamination with chlorhexidine gluconate in lung cancer surgery: a randomized clinical trial.

PURPOSE: Respiratory complications are the leading causes of morbidity and mortality after lung cancer surgery. We hypothesized that oropharyngeal and nasopharyngeal decontamination with chlorhexidine gluconate (CHG) would be an effective method to reduce these complications as reported in cardiac surgery. METHODS: In this multicenter parallel-group randomized double-blind placebo-controlled trial, we enrolled consecutive adults scheduled for anatomical pulmonary resection for lung cancer. Perioperative decontamination consisted in oropharyngeal rinse solution (0.12% CHG) and nasopharyngeal soap (4% CHG) or a placebo. The primary outcome measure was the proportion of patients requiring postoperative invasive and/or noninvasive mechanical ventilation (MV). Secondary outcome measures included occurrence of respiratory and non-respiratory healthcare-associated infections (HAIs) and outcomes within 90 days. RESULTS: Between July 2012 and April 2015, 474 patients were randomized. Of them, 24 had their surgical procedure cancelled or withdrew consent. The remaining 450 patients were included in a modified intention-to-treat analysis: 226 were allocated to CHG and 224 to the placebo. Proportions of patients requiring postoperative MV were not significantly different [CHG 14.2%; placebo 15.2%; relative risks (RRs) 0.93; 95% confidence interval (CI) 0.59-1.45; P = 0.76]. Neither of the proportions of patients with respiratory HAIs were different (CHG 13.7%; placebo 12.9%; RRs 1.06; 95% CI 0.66-1.69; P = 0.81). The CHG group had significantly decreased incidence of bacteremia, surgical-site infection and overall Staphylococcus aureus infections. However, there were no significant between-group differences for hospital stay length, change in tracheal microbiota, postoperative antibiotic utilization and outcomes by day 90. CONCLUSIONS: CHG decontamination decreased neither MV requirements nor respiratory infections after lung cancer surgery. Additionally, CHG did not change tracheal microbiota or postoperative antibiotic utilization. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov, number NCT01613365.

Upper airway modifications in head extension during development.

BACKGROUND: One of the requirements of laryngoscopy is to determine which head position will result in optimal visualization. Our hypothesis was that parameters derived from magnetic resonance imaging (MRI) can help quantify the effect of age on airway modifications due to head extension during development. METHOD: In children undergoing planned MRI, additional sequences on the upper airways were performed: one in a near-neutral position, the other with the head extended at 35°. The axis of the face, the pharynx, the larynx, the trachea, and the line of glottic visualization were determined. The following angles were calculated: the Visu-Lar angle, formed by the line of glottic visualization and the laryngeal axis, and the Phar-Lar angle, formed by the pharyngeal and laryngeal axes. RESULTS: One hundred and fifty-five patients (1 to 222 months of age [25-145] months) were included and 54% were under general anaesthesia. Age had no effect on the variation in the Visu-Lar angle, which diminished as a function of head extension, nor on the variation in the Phar-Lar angle, which was minimal in the neutral position. During extension, anatomical axes rotated similarly, and the visualization axis rotated the most, followed by the pharyngeal and laryngeal axes. These results were not correlated with general anaesthesia. CONCLUSION: Regardless of age, head extension diminished the Visu-Lar angle, and increased the Phar-Lar angle. This study supports that, as in adults, head extension is probably the key factor for good visualization conditions during laryngoscopy on children, but clinical data is needed to confirm this result.

Increased serum levels of fractalkine and mobilisation of CD34+CD45- endothelial progenitor cells in systemic sclerosis.

BACKGROUND: The disruption of endothelial homeostasis is a major determinant in the pathogenesis of systemic sclerosis (SSc) and is reflected by soluble and cellular markers of activation, injury and repair. We aimed to provide a combined assessment of endothelial markers to delineate specific profiles associated with SSc disease and its severity. METHODS: We conducted an observational, single-centre study comprising 45 patients with SSc and 41 healthy control subjects. Flow cytometry was used to quantify circulating endothelial microparticles (EMPs) and CD34+ progenitor cell subsets. Colony-forming unit-endothelial cells (CFU-ECs) were counted by culture assay. Circulating endothelial cells were enumerated using anti-CD146-based immunomagnetic separation. Blood levels of endothelin-1, vascular endothelial growth factor (VEGF) and soluble fractalkine (s-Fractalkine) were evaluated by enzyme-linked immunosorbent assay. Disease-associated markers were identified using univariate, correlation and multivariate analyses. RESULTS: Enhanced numbers of EMPs, CFU-ECs and non-haematopoietic CD34+CD45- endothelial progenitor cells (EPCs) were observed in patients with SSc. Patients with SSc also displayed higher serum levels of VEGF, endothelin-1 and s-Fractalkine. s-Fractalkine levels positively correlated with CD34+CD45- EPC numbers. EMPs, s-Fractalkine and endothelin-1 were independent factors associated with SSc. Patients with high CD34+CD45- EPC numbers had lower forced vital capacity values. Elevated s-Fractalkine levels were associated with disease severity, a higher frequency of pulmonary fibrosis and altered carbon monoxide diffusion. CONCLUSIONS: This study identifies the mobilisation of CD34+CD45- EPCs and high levels of s-Fractalkine as specific features of SSc-associated vascular activation and disease severity. This signature may provide novel insights linking endothelial inflammation and defective repair processes in the pathogenesis of SSc.

CON-COUR study: Interferential therapy in the treatment of chronic constipation in adults: study protocol for a randomized controlled trial.

BACKGROUND: The prevalence of chronic constipation is about 15 % in Western countries with a significant impact on quality of life and health care costs. The first-line therapy, based on medical treatment combined with laxatives and dietary rules, is often disappointing. Interferential therapy is a new treatment that has demonstrated its efficiency in the treatment of chronic constipation in children and encouraging results in adults. The primary objective of this study is to assess the efficacy of interferential therapy during 8 weeks in adult patients. The secondary objectives are to assess this new and noninvasive therapy in terms of persistence of the clinical efficacy, colonic transit time, ano-rectal manometry, patient satisfaction and quality of life (QoL), and tolerance. DESIGN: multicenter, prospective, randomized, placebo-controlled, double blind, two-parallel groups study. SETTING: nine French adult gastroenterology centers. INCLUSION CRITERIA: adult patients with a history of chronic constipation refractory to medical treatment for at least 3 months. Treatment groups: (1) interferential-experimental group (effective stimulation); (2) placebo-control group (sham stimulation). RANDOMIZATION: 1:1 allocation ratio. Evaluation times: inclusion (T0, randomization), baseline assessment (T1), start of stimulation (T2), intermediary assessment (T3, 4 weeks), end of stimulation (T4, 8 weeks), follow-up (T5 and T6, 1- and 6-month). ENDPOINTS: (1) primary: short-term efficacy at T4 (treatment response defined as three or more spontaneous, complete bowel movements per week); (2) secondary: efficacy at T5 and T6, symptoms (Patient Assessment of Constipation Symptoms questionnaire), colonic transit time, anorectal manometry, patient satisfaction (analogical visual scale), patient QoL (Patient Assessment of Constipation Quality of Life Questionnaire), side/unexpected effects. SAMPLE SIZE: 200 individuals to obtain 80 % power to detect a 20 % difference in treatment response at T4 between the two groups (15 % of lost to follow-up patients expected). DISCUSSION: The randomized, double-blind, placebo-controlled design is the most appropriate to demonstrate the efficacy of a new experimental therapeutic (Evidence-Based Medicine Working Group classification). National and international recommendations could be updated based on the findings of this study. TRIAL REGISTRATION: Current controlled trials NCT02381665 (registration date: February 13, 2015).

p8 inhibits the growth of human pancreatic cancer cells and its expression is induced through pathways involved in growth inhibition and repressed by factors promoting cell growth.

BACKGROUND: p8 is a stress-induced protein with multiple functions and biochemically related to the architectural factor HMG-I/Y. We analyzed the expression and function of p8 in pancreatic cancer-derived cells. METHODS: Expression of p8 was silenced in the human pancreatic cancer cell lines Panc-1 and BxPc-3 by infection with a retrovirus expressing p8 RNA in the antisense orientation. Cell growth was measured in control and p8-silenced cells. Influence on p8 expression of the induction of intracellular pathways promoting cellular growth or growth arrest was monitored. RESULTS: p8-silenced cells grew more rapidly than control cells transfected with the empty retrovirus. Activation of the Ras-->Raf-->MEK-->ERK and JNK intracellular pathways down-regulated p8 expression. In addition, the MEK1/2 inhibitor U0126 and the JNK inhibitor SP600125 up-regulates expression of p8. Conversely, p38 or TGFbeta-1 induced p8 expression whereas the specific p38 inhibitor SB203580 down-regulated p8 expression. Finally, TGFbeta-1 induction was in part mediated through p38. CONCLUSIONS: p8 inhibits the growth of human pancreatic cancer cells. p8 expression is induced through pathways involved in growth inhibition and repressed by factors that promote cell growth. These results suggest that p8 belongs to a pathway regulating the growth of pancreatic cancer cells.