Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

Herein, we report the first identification of biallelic-inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function. ALPI mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients’ biopsies, and ALPI activity was undetectable in ALPI-deficient patient\u27s stool. Our findings highlight the crucial role of ALPI in regulating host–microbiota interactions and restraining host inflammatory responses. These results indicate that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders

Is alfa-interferon still current in the management of Kasabach-Merritt syndrome?

International audienceKasabach-Merritt syndrome (KMS), characterized by thrombocytopenia, may complicate vascular tumors such as kaposiform hemangioendothelioma and tufted angioma. We report on two infants, respectively 2 months and 15 days old at the onset of symptoms, the first of whom presented with a left cervico-occipito-scapular hemangioma with parotid extension, and the second with a vascular tumor located on the left shoulder with fast extension on the left inferior hemithorax and the left arm. Thrombocytopenia (\textless 20 G/L) was associated in both cases. Treatment comprised first high-dose corticosteroids (2mg/kg) in association with vincristine (1mg/m(2)/week). Interferon was introduced as third-line treatment at 3 MIU/m(2)/day. In the first patient, interferon was effective both on thrombocytopenia and tumor in 2 months. In the second patient, the first interferon treatment was not effective despite 6 months of therapy. However, a second treatment 8 years later was successful. After 10 and 3 years follow-up, respectively, there were no side effects and most particularly no neurologic complications. These two observations open the discussion of the role of interferon (3 MIU/m(2)/day) as well as new therapies in the control of angiogenesis in case of failure of first-line treatment of complicated KMS vascular tumors

Selective Autophagy Receptors in Antiviral Defense

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Regulation of anti-microbial autophagy by factors of the complement system

International audienceThe complement system is a major component of innate immunity that participates in the defense of the host against a myriad of pathogenic microorganisms. Activation of complement allows for both local inflammatory response and physical elimination of microbes through phagocytosis or lysis. The system is highly efficient and is therefore finely regulated. In addition to these well-established properties, recent works have revealed that components of the complement system can be involved in a variety of other functions including in autophagy, the conserved mechanism that allows for the targeting and degradation of cytosolic materials by the lysosomal pathway after confining them into specialized organelles called autophagosomes. Besides impacting cell death, development or metabolism, the complement factors-autophagy connection can greatly modulate the cell autonomous, antimicrobial activity of autophagy: xenophagy. Both surface receptorligand interactions and intracellular interactions are involved in the modulation of the autophagic response to intracellular microbes by complement factors. Here, we review works that relate to the recently discovered connections between factors of the complement system and the functioning of autophagy in the context of host-pathogen relationship

Pediatric combined liver-kidney transplantation: a single-center experience of 18 cases

Background Experience in combined liver-kidney transplantation (CLKT) in children is limited. Methods We conducted a retrospective study of all pediatric CLKTs performed at our medical institution between 1992 and 2013.L'expérience de fond dans la transplantation combinée de reins de foie (CLKT) dans des enfants est limitée. Les méthodes nous ont conduit vers une étude rétrospective de tout le CLKTS pédiatrique réalisé dans notre institution médicale entre 1992 et 2013

Unexpected Actors in Inflammatory Bowel Disease Revealed by Machine Learning from Whole-Blood Transcriptomic Data

Although big data from transcriptomic analyses have helped transform our understanding of inflammatory bowel disease (IBD), they remain underexploited. We hypothesized that the application of machine learning using lasso regression to transcriptomic data from IBD patients and controls can help identify previously overlooked genes. Transcriptomic data provided by Ostrowski et al. (ENA PRJEB28822) were subjected to a two-stage process of feature selection to discriminate between IBD and controls. First, a principal component analysis was used for dimensionality reduction. Second, the least absolute shrinkage and selection operator (lasso) regression was employed to identify genes potentially involved in the pathobiology of IBD. The study included data from 294 participants: 100 with ulcerative colitis (48 adults and 52 children), 99 with Crohn’s disease (45 adults and 54 children), and 95 controls (46 adults and 49 children). IBD patients presented a wide range of disease severity. Lasso regression preceded by principal component analysis successfully selected interesting features in the IBD transcriptomic data and yielded 12 models. The models achieved high discriminatory value (range of the area under the receiver operating characteristic curve 0.61–0.95) and identified over 100 genes as potentially associated with IBD. PURA, GALNT14, and FCGR1A were the most consistently selected, highlighting the role of the cell cycle, glycosylation, and immunoglobulin binding. Several known IBD-related genes were among the results. The results included genes involved in the TGF-beta pathway, expressed in NK cells, and they were enriched in ontology terms related to immunity. Future IBD research should emphasize the TGF-beta pathway, immunoglobulins, NK cells, and the role of glycosylation

Salivary cholesterol level does not reflect cholesterolemia in children with heterozygous familial hypercholesterolemia

International audienceObjectivesHeterozygous familial hypercholesterolemia is a common genetic disease responsible for premature atherosclerosis. Therefore, early diagnosis and treatment are recommended to reduce cardiovascular risk. Usually, the screening is based on high plasma LDL-cholesterol. In children, blood testing is often an obstacle for screening. This study aims to evaluate the relevance of a salivary non-invasive LDL dosage in heterozygous familial hypercholesterolemia in a pediatric population.Materials and methodsProspective, case control, monocentric study comparaing the salivary cholesterol of 30 heterozygous familial hypercholesterolemia pediatric patients and 30 healthy age-matched controls with two different enzymatic kits (Amplite™ kit - AAT Bioquest® and Total Cholesterol Assay kit - CELL BIOLABS®, Inc).ResultsWhile the median serum total-cholesterol was significantly different in control and heterozygous familial hypercholesterolemia patients as expected, the median salivary cholesterol concentration was similar between the two groups and 1000 times lower than in serum. No correlation was found between salivary and serum cholesterol concentrations.ConclusionAlthough cholesterol is detectable in saliva, our study suggests that the low salivary cholesterol concentrations result mostly from variable gingival bleeding, precluding any reliable use for Heterozygous Familial Hypercholesterolemia screening in children.But/ObjectifL’hypercholestérolémie familiale est une maladie génétique fréquente responsable de lésion d’athérosclérose précoce. Ainsi, le diagnostic et le traitement précoce sont recommandés pour réduire le risque cardiovasculaire. Le dépistage actuellement recommandé est réalisé par le dosage sanguin de LDL-cholestérol. Chez l’enfant, le caractère invasif des prises de sang peut être un obstacle à la réalisation du dépistage. Cette étude a pour but d’évaluer la pertinence du dosage salivaire non invasif du LDL-cholestérol chez les enfants atteints d’hypercholestérolémie familiale.Matériels et méthodesÉtude prospective, cas-contrôle, monocentrique comparant le cholestérol salivaire chez 30 enfant témoins et chez 30 enfants hypercholestérolémiques apparié en age dosé par deux kits enzymatiques (Amplite™ kit - AAT Bioquest® et Total Cholesterol Assay kit - CELL BIOLABS®, Inc)RésultatsLe cholestérol total sérique médian est significativement différent entre les deux groupes comme attendu, néanmoins les taux médians de cholestérol salivaire sont similaires entre les deux groupes et 1000 fois inférieures au sérum. Aucune corrélation n’a été retrouvée entre la salive et le cholestérol total sérique.ConclusionLe cholestérol total est bien détectable dans la salive, notre étude suggère que le faible taux de cholestérol dans la salive résulte en majeur parti d’une contamination par micro-saignement gingival, ne permettant pas de l’envisager comme un outil fiable non invasif pour le dépistage de l’hypercholestérolémie familiale chez l’enfant

Comparison of Endoscopic Dilatation and Heller's Myotomy for Treating Esophageal Achalasia in Children: A Multicenter Study

International audienceObjective: To compare the efficacy of, and complications from, the 2 main treatments for achalasia: endoscopic dilatation and surgical cardiomyotomy (Heller's myotomy).Study design: We retrospectively collected data on children treated for achalasia over an 11-year period from 8 tertiary pediatric centers. A line of treatment was defined as performing either Heller's myotomy or 1-3 sessions of endoscopy dilatation over 3 months. Treatment success was a priori defined as clinical improvement and no need for new treatment.Results: Ninety-seven children (median age, 12 years; 57% boys) were included. The median time to diagnosis was 10.5 months, and the median follow-up period was 27 months. Thirty-seven children were treated by Heller's myotomy and 60 by endoscopy dilatation as the first-line treatment. After adjustment for potentially confounding factors, Heller's myotomy was significantly more successful than endoscopy dilatation (hazard ratio, 3.93 [1.74; 8.88]; P = .001), with a median survival without failure of 49 and 7 months, respectively, and with no significant difference in the occurrence of complications (35.2% for Heller's myotomy, 29.7% for endoscopy dilatation, P = .56). Hydrostatic dilatation was as successful as pneumatic dilatation (hazard ratio, 1.35 [0.56; 3.23]; P = .50).Conclusions: Heller's myotomy is more successful than endoscopy dilatation, with no significant difference in the occurrence of serious complications. This raises the potential role of peroral endoscopic myotomy as an alternative treatment to Heller's myotomy

Measles Virus-Imposed Remodeling of the Autophagy Machinery Determines the Outcome of Bacterial Coinfection

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Myosin-1b interacts with UNC45A and controls intestinal epithelial morphogenesis

Abstract Vesicle trafficking and the establishment of apico-basal polarity are essential processes in epithelium morphogenesis. Myosin-1b, an actin-motor able to bind membranes, regulates membrane shaping and vesicle trafficking. Here, we investigate Myosin-1b function in gut morphogenesis and congenital disorders using cell line and zebrafish larvae as well as patient biopsies. In a 3D Caco-2 cyst model, lumen formation is impaired in absence of Myosin-1b. In zebrafish, both Morpholino knock-down and genetic mutation of myo1b result in intestinal bulb epithelium folding defects associated with vesicle accumulation, reminiscent of a villous atrophy phenotype. We show that Myosin-1b interacts with the chaperone UNC45A, genetic deletion of which also results in gut folding defects in zebrafish. Loss of function mutations in UNC45A have been reported in complex hereditary syndromes, notably exhibiting intestinal disorders associated with villous atrophy. In UNC45A-depleted cells and in patient biopsies, Myosin-1b protein level is strikingly decreased. The appearance of Myosin-1b aggregates upon proteasome inhibition in cells points at a degradation mechanism of misfolded Myosin-1b in the absence of its chaperone. In conclusion, Myosin-1b plays an unexpected role in the development of the intestinal epithelium folds or villi downstream UNC45A, establishing its role in the gut defects reported in UNC45A patients. Summary statement Myosin-1b is important for intestinal epithelium folding during zebrafish development and participates in the villous atrophy clinical manifestation downstream UNC45A loss of function