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This study explored Black and Latinx youth organizers' experiences of racism within national gun violence prevention organizing spaces. Interview data were analyzed from 17 Black and/or Latinx youth (M age  = 20.17, 47% women) across the United States who organized against gun violence. The findings identified three forms of racism that Black and Latinx organizers experienced in national organizations: (1) being tokenized for their racial identities and experiences without having real decision making power; (2) feeling a burden to educate their white peers about the structural causes of gun violence and how to improve organizing spaces for other youth of color; and (3) being silenced in their racially conscious organizing efforts to address the structural causes of gun violence in their communities. This research highlights how Black and Latinx youth gun violence prevention organizers contend both with structural racism in their everyday lives and racism in organizing spaces., (© 2023 The Authors. Journal of Research on Adolescence published by Wiley Periodicals LLC on behalf of Society for Research on Adolescence.)

The tumor microenvironment is a dynamic network of stromal, cancer, and immune cells that interact and compete for resources. We have previously identified the Vanin1 pathway as a tumor suppressor of sarcoma development via vitamin B5 and coenzyme A regeneration. Using an aggressive sarcoma cell line that lacks Vnn1 expression, we showed that the administration of pantethine, a vitamin B5 precursor, attenuates tumor growth in immunocompetent but not nude mice. Pantethine boosts antitumor immunity, including the polarization of myeloid and dendritic cells towards enhanced IFNγ-driven antigen presentation pathways and improved the development of hypermetabolic effector CD8 + T cells endowed with potential antitumor activity. At later stages of treatment, the effect of pantethine was limited by the development of immune cell exhaustion. Nevertheless, its activity was comparable with that of anti-PD1 treatment in sensitive tumors. In humans, VNN1 expression correlates with improved survival and immune cell infiltration in soft-tissue sarcomas, but not in osteosarcomas. Pantethine could be a potential therapeutic immunoadjuvant for the development of antitumor immunity., (© 2023 Miallot et al.)

Coenzyme A (CoA) serves as a vital cofactor in numerous enzymatic reactions involved in energy production, lipid metabolism, and synthesis of essential molecules. Dysregulation of CoA-dependent metabolic pathways can contribute to chronic diseases, such as inflammatory diseases, obesity, diabetes, cancer, and cardiovascular disorders. Additionally, CoA influences immune cell activation by modulating the metabolism of these cells, thereby affecting their proliferation, differentiation, and effector functions. Targeting CoA metabolism presents a promising avenue for therapeutic intervention, as it can potentially restore metabolic balance, mitigate chronic inflammation, and enhance immune cell function. This might ultimately improve the management and outcomes for these diseases. This review will more specifically focus on the contribution of pathways regulating the availability of the CoA precursor Vitamin B5/pantothenate in vivo and modulating the development of Th17-mediated inflammation, CD8-dependent anti-tumor immunity but also tissue repair processes in chronic inflammatory or degenerative diseases., (© 2023 Wiley-VCH GmbH.)

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 B 5 , 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 B 5 -driven metabolism should improve mucosal healing and might increase the efficacy of anti-inflammatory therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Aggressive tumors often display mitochondrial dysfunction. Upon oxidative stress, mitochondria undergo fission through OMA1-mediated cleavage of the fusion effector OPA1. In yeast, a redox-sensing switch participates in OMA1 activation. 3D modeling of OMA1 comforted the notion that cysteine 403 might participate in a similar sensor in mammalian cells. Using prime editing, we developed a mouse sarcoma cell line in which OMA1 cysteine 403 was mutated in alanine. Mutant cells showed impaired mitochondrial responses to stress including ATP production, reduced fission, resistance to apoptosis, and enhanced mitochondrial DNA release. This mutation prevented tumor development in immunocompetent, but not nude or cDC1 dendritic cell-deficient, mice. These cells prime CD8 + lymphocytes that accumulate in mutant tumors, whereas their depletion delays tumor control. Thus, OMA1 inactivation increased the development of anti-tumor immunity. Patients with complex genomic soft tissue sarcoma showed variations in the level of OMA1 and OPA1 transcripts. High expression of OPA1 in primary tumors was associated with shorter metastasis-free survival after surgery, and low expression of OPA1, with anti-tumor immune signatures. Targeting OMA1 activity may enhance sarcoma immunogenicity., (© 2023 Miallot et al.)

In the absence of formal marketing authorisation, the manufacturers of cosmetic products are responsible for their compliance with the cosmetic regulations. To present the key features of a structured, reactive, and rigorous global cosmetovigilance system through practical examples. During clinical development, adverse reactions are collected formally and analysed by cosmetovigilance experts. After commercialisation, information on reported adverse reactions is sought directly from the consumers. The results of allergological investigations are systematically requested. Pre- and post-marketing cases are analysed along with other sources of information (e.g. monitoring of the literature) to detect safety signals per product and per ingredient. A cosmetovigilance index (CVI) is calculated for each formula, based on the number of cases, causality level and number of commercialised units. Updated periodically, it is used to detect signals and select the best tolerated formulas to help formulating new products. Examples of safety issues raised during development or after commercialisation, and corresponding corrective actions, are presented. These actions include (but are not limited to) a safety watch to closely monitor adverse reactions, the modification of the formula or a change in the packaging. Cosmetovigilance data also impact future product development, as illustrated by the work done on sunscreens. Through the rigorous collection and analysis of adverse reactions during development and after commercialisation, the safety of dermo-cosmetic products can be improved by taking the appropriate corrective actions, monitoring their effectiveness and optimising future product development by focusing on the best tolerated formulas.

Metabolic rewiring offers novel therapeutic opportunities in cancer. Until recently, there was scant information regarding soft tissue sarcomas, due to their heterogeneous tissue origin, histological definition and underlying genetic history. Novel large-scale genomic and metabolomics approaches are now helping stratify their physiopathology. In this review, we show how various genetic alterations skew activation pathways and orient metabolic rewiring in sarcomas. We provide an update on the contribution of newly described mechanisms of metabolic regulation. We underscore mechanisms that are relevant to sarcomagenesis or shared with other cancers. We then discuss how diverse metabolic landscapes condition the tumor microenvironment, anti-sarcoma immune responses and prognosis. Finally, we review current attempts to control sarcoma growth using metabolite-targeting drugs., (© 2021. The Author(s).)

Like other tumors, aggressive soft tissue sarcomas (STS) use glycolysis rather than mitochondrial oxidative phosphorylation (OXPHOS) for growth. Given the importance of the cofactor coenzyme A (CoA) in energy metabolism, we investigated the impact of Vnn1 pantetheinase-an enzyme that degrades pantetheine into pantothenate (vitamin B5, the CoA biosynthetic precursor) and cysyteamine-on tumor growth. Using two models, we show that Vnn1 + STS remain differentiated and grow slowly, and that in patients a detectable level of VNN1 expression in STS is associated with an improved prognosis. Increasing pantetheinase activity in aggressive tumors limits their growth. Using combined approaches, we demonstrate that Vnn1 permits restoration of CoA pools, thereby maintaining OXPHOS. The simultaneous production of cysteamine limits glycolysis and release of lactate, resulting in a partial inhibition of STS growth in vitro and in vivo. We propose that the Warburg effect observed in aggressive STS is reversed by induction of Vnn1 pantetheinase and the rewiring of cellular energy metabolism by its products., Competing Interests: The authors declare that they have no conflict of interest.

Tissue pantetheinase, encoded by the VNN1 gene, regulates response to stress, and previous studies have shown that VNN genes contribute to the susceptibility to malaria. Herein, we evaluated the role of pantetheinase on erythrocyte homeostasis and on the development of malaria in patients and in a new mouse model of pantetheinase insufficiency. Patients with cerebral malaria have significantly reduced levels of serum pantetheinase activity (PA). In mouse, we show that a reduction in serum PA predisposes to severe malaria, including cerebral malaria and severe anemia. Therefore, scoring pantetheinase in serum may serve as a severity marker in malaria infection. This disease triggers an acute stress in erythrocytes, which enhances cytoadherence and hemolysis. We speculated that serum pantetheinase might contribute to erythrocyte resistance to stress under homeostatic conditions. We show that mutant mice with a reduced serum PA are anemic and prone to phenylhydrazine-induced anemia. A cytofluorometric and spectroscopic analysis documented an increased frequency of erythrocytes with an autofluorescent aging phenotype. This is associated with an enhanced oxidative stress and shear stress-induced hemolysis. Red blood cell transfer and bone marrow chimera experiments show that the aging phenotype is not cell intrinsic but conferred by the environment, leading to a shortening of red blood cell half-life. Therefore, serum pantetheinase level regulates erythrocyte life span and modulates the risk of developing complicated malaria., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Oxidant stress is implicated in the pathogenesis of bronchopulmonary dysplasia (BPD). Light induces peroxide generation in parenteral nutrition (PN) solutions, creating an oxidant stress. Shielding PN from light decreases its peroxide content, which has nutrition and biochemical benefits in animals and humans. This study aims at determining whether full light protection of PN decreases the rate of bronchopulmonary dysplasia and/or death in very low-birth-weight infants., Methods: Multicenter randomized controlled trial of photoprotection, using amber bags and tubing initiated during compounding of PN and maintained throughout infusion in the light-protected (LP) group. The control group (light exposed [LE]) received PN exposed to ambient light. Depending on centers, lipids were infused either separately or as all-in-one PN., Results: In total, 590 infants born <30 weeks gestational age were included. At randomization, LE and LP groups did not differ clinically except for maximal FiO2 before 12 hours. The rate of BPD/death was not different between groups at 28 days (77% LP vs 72% LE, P = .16) or at 36 weeks corrected age (30% LP vs 27% LE, P = .55). Multivariate analysis showed no significant effect of photoprotection on BPD and/or death. The rate of BPD/death was significantly lower (odds ratio, 0.54; 95% confidence interval, 0.32-0.93; P = .02) in infants receiving all-in-one PN vs those who received lipids separately., Conclusion: This study did not show significant beneficial effects of photoprotection. Since the decreased rate of BPD/death found with all-in-one PN relates to a center-dependent variable, this warrants further investigation., (© 2014 American Society for Parenteral and Enteral Nutrition.)

Unlabelled: Exposure to tobacco smoke has been not evaluated in children with bronchopulmonary dysplasia (BPD). We evaluate the association of in utero smoking (IUS) and environmental tobacco smoke (ETS) with the respiratory events of BPD and non-BPD children. Two hundred sixty-two children born before 35 weeks of gestational age (GA) and regularly followed up in our regional network for preterms were enrolled. They were paired according to their BPD status, their gestational age and birth weight (131 children with BPD and 131 without BPD, 28 mean weeks GA; mean weight 1000 g). Respiratory data were obtained prospectively during their first 2 years of life. A complementary questionnaire was completed by the parents about their child's respiratory health at the age of 2, their home environment, and tobacco status. IUS concerned 12.6 %; ETS, 48.8 % (67 % in BPD children treated with oxygen at home). No further influence on respiratory outcome could be found by exposure to intrauterine smoke or extrauterine tobacco smoke in this patient sample., Conclusion: IUS and ETS exposures are as high in preterm children as in a general pediatric population. The highest exposure occurs among BPD infants treated with oxygen at home., What Is Known: • Environmental tobacco smoke (ETS) and in utero smoking (IUS) are responsible for many morphological, functional, and clinical changes in children. • Children with bronchopulmonary dysplasia (BPD) have more respiratory events in their first years of life than preterm children without BPB, maybe triggered by ETS and IUS. What is New: • The exposition to ETS and IUS is high in preterm children with and without BDP, as high as in a general. • Pedaitric population, particularly in children with BPD and treated with oxygen at home. • No further influence on respiratory outcome could be found by exposure to ETS or IUS in our studied population.

Liver is a major regulator of lipid metabolism and adaptation to fasting, a process involving PPARalpha activation. We recently showed that the Vnn1 gene is a PPARalpha target gene in liver and that release of the Vanin-1 pantetheinase in serum is a biomarker of PPARalpha activation. Here we set up a screen to identify new regulators of adaptation to fasting using the serum Vanin-1 as a marker of PPARalpha activation. Mutagenized mice were screened for low serum Vanin-1 expression. Functional interactions with PPARalpha were investigated by combining transcriptomic, biochemical and metabolic approaches. We characterized a new mutant mouse in which hepatic and serum expression of Vanin-1 is depressed. This mouse carries a mutation in the HMG domain of the Sox17 transcription factor. Mutant mice display a metabolic phenotype featuring lipid abnormalities and inefficient adaptation to fasting. Upon fasting, a fraction of the PPARα-driven transcriptional program is no longer induced and associated with impaired fatty acid oxidation. The transcriptional phenotype is partially observed in heterozygous Sox17+/- mice. In mutant mice, the fasting phenotype but not all transcriptomic signature is rescued by the administration of the PPARalpha agonist fenofibrate. These results identify a novel role for Sox17 in adult liver as a modulator of the metabolic adaptation to fasting.

The membrane-bound Vanin-1 pantetheinase regulates tissue adaptation to stress. We investigated Vnn1 expression and its regulation in liver. Vnn1 is expressed by centrolobular hepatocytes. Using novel tools, we identify a soluble form of Vnn1 in mouse and human serum and show the contribution of a cysteine to its catalytic activity. We show that liver contributes to Vanin-1 secretion in serum and that PPARalpha is a limiting factor in serum Vnn1 production. Functional PPRE sites are identified in the Vnn1 promoter. These results indicate that serum Vnn1 might be a reliable reporter of PPARalpha activity in liver., (Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Background: Vanin-1 is an epithelial pantetheinase, which regulates intestinal inflammation in mouse. We investigated whether human VNN1 levels could be associated to the susceptibility to inflammatory bowel diseases (IBD) and explored the participation of PPARg to these processes., Methods: We studied VNN1 expression in colon biopsies from IBD patients. We investigated polymorphisms in the regulatory regions of the VNN1 gene and examined their genetic association with the disease. Functional relevance of these single-nucleotide polymorphisms (SNPs) was assayed, and we tested PPARg in nuclear complexes associated with specific VNN1 polymorphic sequences. In mouse, we examined Vanin-1 expression in gut and feces during dextran sulfate sodium-induced colitis and assayed the effect of PPARg on Vanin-1 regulation., Results: VNN1 is expressed by enterocytes and is upregulated in IBD. Three SNPs are statistically associated to IBD. The regions containing these SNPs specifically bind nuclear complexes and are correlated with the VNN1 transcript abundance in colon in an allele-dependent manner. One rare SNP is associated to severe ulcerative colitis with strong VNN1 and dropped PPARg levels. PPARg is involved in nuclear complexes that bound to VNN1 regulatory sites. Similarly, Vanin-1 is tightly regulated in the mouse gut in normal and colitis conditions and PPARg regulates its expression., Conclusions: VNN1 is a marker for IBD. Polymorphic positions in the VNN1 locus are direct targets for nuclear factors that might regulate the level of VNN1 in colon, and this could be linked to IBD susceptibility. It is hoped that modulating locally VNN1 expression or activity can be exploited to develop future therapeutic strategies against IBD.

We investigated the consequences of premature birth on the functional neuroanatomy of the dorsal stream of visual processing. fMRI was recorded while sixteen healthy participants, 8 (two men) adults (19 years 6 months old, SD 10 months) born premature (mean gestational age 30 weeks), referred to as Premas, and 8 (two men) matched controls (20 years 1 month old, SD 13 months), performed a 1-back memory task of Object or Grip information using a hand grasping a drinking vessel as stimulus. While history of prematurity did not significantly affect task performance, Group by Task analysis of variance in regions of interest spanning the occipital, temporal and parietal lobes revealed main effects of Task and interactions between the two factors. Object processing activated the left inferior occipital cortex and bilateral ventral temporal regions, belonging to the ventral stream, with no effect of Group. Grip processing across groups activated the early visual cortex and the left supramarginal gyrus belonging to the dorsal stream. Group effect on the brain activity during Grip suggested that Controls represented the actions' goal while Premas relied more on low-level visual information. This shift from higher- to lower-order visual processing between Controls and Premas may reflect a more general trend, in which Premas inadequately recruit higher-order visual functions for dorsal stream task performance, and rely more on lower-level functions., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The patency of the ductus arteriosus has ever been considered as a pathological situation in preterm infants and one likely cause of mortality and morbidity, including broncho-pulmonary dysplasia, necrotizing enterocolitis, intraventricular haemorrhage, retinopathy of prematurity. The incidence of patent ductus arteriosus is inversely proportional to gestational age and infants with the lowest gestational ages are the most exposed to the complications of prematurity. So, associations between patent ductus arteriosus and the other morbidities may not be causative and patent ductus arteriosus could be more a sign of immaturity and severity of disease than the cause of these problems. Non-steroidal anti-inflammatory agents, such as indomethacin or ibuprofen, have been shown to be effective in closing or preventing patent ductus arteriosus, with differences in side effects. However nearly all randomized controlled trials have been designed with the closure of the ductus arteriosus, not mortality or morbidity, as the main endpoint. Thus, evidence is still lacking on the eventual benefits for the patient of pharmacological or surgical intervention on PDA. Moreover, both ibuprofen and indomethacin efficacy seems markedly reduced in extremely low gestational age infants, who are the most likely to benefit from such intervention. The explanation of the reduced pharmacodymanic effect in such population is unclear; so far, studies using increased dosing of ibuprofen have failed to show a clear benefit. Prophylaxis with indomethacin or ibuprofen has failed to show sustained benefits on neurodevelopment at 2 years of age in low gestational age infants. New curative trials may aim at investigating the effects of early curative administration of ibuprofen, which has reduced side effects compared to indomethacin, on immature kidney function, on mortality and morbidity in very low gestational age infants, ideally with a combined endpoint such as survival in the absence of severe neurodevelopmental alteration at 2 years age. Despite an understandable reluctance given the historical background of systematic, therapeutic closure of ductus arteriosus in preterm infants, there are no definite ethical obstacles to a placebo-controlled design.

Introduction: Between 5 and 7% of babies are born prematurely. In the paediatric age group, the respiratory morbidity of these patients is well known, particularly in cases of bronchopulmonary dysplasia (BPD). On the other hand, very few data are available concerning their adult respiratory status., Background: There are currently three different groups of ex-premature babies: (1) those with no BPD who are usually not considered as respiratory high-risk adults but have not been well studied; (2) ex-premature babies with BPD who have an increased risk of asthma, respiratory infections, bronchial obstruction aggravated by smoking, and non-atopic bronchial hyperreactivity; this group has been well studied but not beyond 30 years of age; (3) the babies born very prematurely and affected with a new form of BPD due to neonatal intensive care at a very immature stage of pulmonary development, and for whom the future in adult life is unknown but worrying because of reduced lung volumes since birth., Viewpoints and Conclusions: The respiratory physician must be aware of these groups of adults who he may encounter and who may develop, sooner or later, a certain type of chronic obstructive pulmonary disease., (Copyright © 2011 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Objective: The purpose of this study is to determine the inter-rater reliability of commonly used musculoskeletal screening components in a population of contemporary professional dancers., Participants: Study participants were 30 women from six contemporary dance companies between the ages of 18 and 32, with a mean age of 24, and Body Mass Index of 22.4., Methods: 101 items were assessed in the categories of Static Posture, the Beighton 9-Point Hypermobility Test, Flexibility, Strength, and Dynamic Posture, based upon the Pilot 2006 Dance USA Annual Post-Hire Health Screen for Professional Dancers. Testing was non-ordered, using 2 of the 4 available testers, with variable assignment of the lead tester., Results: High percent agreement was found for the subcategories of hallux valgus, pelvic tilt, and forefoot alignment, flexor hallucis, iliopsoas, hip internal rotation flexed, external rotation extended, and soleus extensibility, composite Beighton, and for most measures within the dynamic posture category. Low to moderate percent agreement was found in the strength tests., Conclusion: Although this study demonstrated moderate to high percent agreement between raters, further test refinement is needed to improve the reliability of the measurement components.

Objectives: To assess the impact of continuous incident reporting and subsequent prevention strategies on the incidence of severe iatrogenic events and targeted priorities in admitted neonates., Methods: We performed preintervention (January 1 to September 1, 2005) and postintervention (January 1, 2008, to January 1, 2009) prospective investigations based on continuous incident reporting. Patient-safety initiatives were implemented for a period of 2 years. The main outcome was a reduction in the incidence of severe iatrogenic events. Secondary outcomes were improvements in 5 targeted priorities: catheter-related infections; invasive procedures; unplanned extubations; 10-fold drug infusion-rate errors; and severe cutaneous injuries., Results: The first and second study periods included totals of 388 and 645 patients (median gestational ages: 34 and 35 weeks, respectively; P = .015). In the second period the incidence of severe iatrogenic events was significantly reduced from 7.6 to 4.8 per 1000 patient-days (P = .005). Infections related to central catheters decreased significantly from 13.9 to 8.2 per 1000 catheter-days (P < .0001), as did exposure to central catheters, which decreased from 359 to 239 days per 1000 patient-days (P < .0001). Tenfold drug-dosing errors were reduced significantly (P = .022). However, the number of unplanned extubations increased significantly from 5.6 to 15.5 per 1000 ventilation-days (P = .03)., Conclusions: Prospective, continuous incident reporting followed by the implementation of prevention strategies are complementary procedures that constitute an effective system to improve the quality of care and patient safety.

We report a case of placental metastasis of melanoma in a 30-year-old woman, without fetal involving, the child being healthy after 5 months of follow-up. Placental or fetal metastasis of maternal cancer are rare, but melanoma is remarkable by its metastatic potential among the cancers of the woman in age to procreate. Thirty cases of placental or foetal metastasis of melanoma have been reported. The fetal involvement seems to be always associated with at least a microscopic invasion of the placenta, that is why systematic microscopic examination of the placenta in case of maternal cancer needs to be encouraged. The other predictive factors of fetal involvement seem multiple and complex. The follow-up of the children arisen from a mother affected by a cancer must be close even if, in case of metastasis in children, the prognosis is very poor., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

Background: Vanin-1 is an epithelial pantetheinase that provides cysteamine to tissue and regulates response to stress. Vanin-1 is expressed by enterocytes, and its absence limits intestinal epithelial cell production of proinflammatory signals. A link between chronic active inflammation and cancer is illustrated in patients with ulcerative colitis, who have an augmented risk of developing colorectal cancer. Indeed, sustained inflammation provides advantageous growth conditions to tumors. We examined whether epithelial cells affect tumorigenesis through vanin-1-dependent modulation of colonic inflammation., Methods: To vanin-1(-/-) mice, we applied the colitis-associated cancer (CAC) protocol, which combines injection of azoxymethane (AOM) with repeated administrations of dextran sodium sulfate (DSS). We numbered tumors and quantified macrophage infiltration and molecular markers of cell death and proliferation. We also tested DSS-induced colitis. We scored survival, tissue damages, proinflammatory cytokine production, and tissue regeneration. Finally, we explored activation pathways by biochemical analysis on purified colonic epithelial cells (CECs) and in situ immunofluorescence., Results: Vanin-1(-/-) mice displayed a drastically reduced incidence of colorectal cancer in the CAC protocol and manifested mild clinical signs of DSS-induced colitis. The early impact of vanin-1 deficiency on tumor induction was directly correlated to the amount of inflammation and subsequent epithelial proliferation rather than cell death rate; all this was linked to the modulation of NF-kappaB pathway activation in CECs., Conclusions: These results emphasize the importance of the intestinal epithelium in the control of mucosal inflammation acting as a cofactor in carcinogenesis. This might lead to novel anti-inflammatory strategies useful in cancer therapy.

Thymic dendritic cells (DC) and epithelial cells play a major role in central tolerance but their respective roles are still controversial. Epithelial cells have the unique ability to ectopically express peripheral tissue-restricted antigens conferring self-tolerance to tissues. Paradoxically, while negative selection seems to occur for some of these antigens, epithelial cells, contrary to DC, are poor negative selectors. Using a thymic epithelial cell line, we show the functional intercellular transfer of membrane material, including MHC molecules, occurring between epithelial cells. Using somatic and bone marrow chimeras, we show that this transfer occurs efficiently in vivo between epithelial cells and, in a polarized fashion, from epithelial to DC. This novel mode of transfer of MHC-associated, epithelial cell-derived self-antigens onto DC might participate to the process of negative selection in the thymic medulla.

Intragastric fat digestion was investigated by analyzing the products of lipolysis and the gastric lipase (HGL) levels of premature infants fed with a formula enriched with medium chain triglycerides (MCT) and those of infants fed with human milk. Infants were fed using a gastric tube and the gastric contents were aspirated twice a day for 5 d, before and at various times after gavage feeding. HGL levels were measured using the pHstat technique. After extraction, lipids were separated and quantified using thin-layer chromatography coupled to a flame ionization detector. Fatty acid methyl esters were analyzed by gas chromatography. HGL concentration increased during digestion, reaching 77.4 +/- 43.1 microg/mL (around 75% of those recorded in adults). Mean HGL output was 115 +/- 43 microg for 3 h and the overall intragastric lipolysis was 6.1 +/- 2.6%. Although the formula was enriched with octanoic and decanoic acid, the main fatty acids released in the stomach were palmitic (C16:0, 17.03 +/- 0.23% wt/wt) and oleic (C18:1 n-9, 28.23 +/- 1.26% wt/wt) acid. Similar results were obtained with infants fed with human milk. MCT supplementation has no quantitative or qualitative effects on the intragastric lipolysis, which is not higher in premature infant than in adults.

Colitis involves immune cell-mediated tissue injuries, but the contribution of epithelial cells remains largely unclear. Vanin-1 is an epithelial ectoenzyme with a pantetheinase activity that provides cysteamine/cystamine to tissue. Using the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-colitis model we show here that Vanin-1 deficiency protects from colitis. This protection is reversible by administration of cystamine or bisphenol A diglycidyl ether, a peroxisome proliferator-activated receptor (PPAR)gamma antagonist. We further demonstrate that Vanin-1, by antagonizing PPARgamma, licenses the production of inflammatory mediators by intestinal epithelial cells. We propose that Vanin-1 is an epithelial sensor of stress that exerts a dominant control over innate immune responses in tissue. Thus, the Vanin-1/pantetheinase activity might be a new target for therapeutic intervention in inflammatory bowel disease.

The number of pregnant women and women of childbearing age who are receiving drugs is increasing. A variety of drugs are prescribed for either complications of pregnancy or maternal diseases that existed prior to the pregnancy. Such drugs cross the placental barrier, enter the fetal circulation and potentially alter fetal development, particularly the development of the kidneys. Increased incidences of intrauterine growth retardation and adverse renal effects have been reported. The fetus and the newborn infant may thus experience renal failure, varying from transient oligohydramnios to severe neonatal renal insufficiency leading to death. Such adverse effects may particularly occur when fetuses are exposed to NSAIDs, ACE inhibitors and specific angiotensin II receptor type 1 antagonists. In addition to functional adverse effects, in utero exposure to drugs may affect renal structure itself and produce renal congenital abnormalities, including cystic dysplasia, tubular dysgenesis, ischaemic damage and a reduced nephron number. Experimental studies raise the question of potential long-term adverse effects, including renal dysfunction and arterial hypertension in adulthood. Although neonatal data for many drugs are reassuring, such findings stress the importance of long-term follow-up of infants exposed in utero to certain drugs that have been administered to the mother.

Some guidelines and expert consensus consider the way of care management practices for the recurrent depressive disorder, particularly according to different identified risk factors for recurrence. But, few data are available about the way that these risk factors influence the care management of depressive recurrent patients during the partial or complete remission phase. Eclair study is a longitudinal observatory multicentric and national study, which describes the different risk factors that influence the psychiatrist decision about the following of patients suffering form Major Depressive Disorder (at least 3 Major Depressive Episode (MDE) according to DSM IV). This article presents the inclusion data (V0) of patients, with a focus on their demography characteristics and history of trouble, diagnosis, symptomatology evaluation (with CGI-S, HAM-D, Carroll scale and Sheehan scale) and Cloninger's personality questionnaire (TCI). A total of 596 patients with a recurrent depression either on partial remission (PaR) or complete remission (ToR) to their last episode at the selection, have been included. Complete remission was defined by the presence of a maximum of two criteria of MDE (according to DSM IV) excepted depressed mood and diminished interest or pleasure during at least two months with a HAM-D (17 items) score < 7 and partial remission was defined by the persistence of depressed symptoms but not sufficient to complete a diagnosis of MDE (according to DSM IV) associated with a HAM-D (17 items) score between 8 and 13 included. Mean HAM-D scores at V0 were 10.3 +/- 1.6 for PaR group and 4.0 +/- 1.9 for the ToR group. Free time since last episode was 6.5 +/- 10.5 months in ToR group and 11.2 +/- 16.9 months in PaR group (n = 385). Residual symptomatology between prior episodes was systematically present for 47.6% patients in PaR group, and for 26.7% patients ToR group. The feel to have a stressful daily life persisted for 62.5% of patient in PaR group and 34.3% in ToR group; 70.3% patients in PaR group and 57.9% patients in ToR group reported persistence of causal factor. The main collected risk factors for recurrence were the number of prior depressive episodes (64.9%), familial conflict existence (52.9%) and recent events of life (45.1%). In the TCI, a significant difference in comparison with the French normative data has been found for 3 dimensions: Harm Avoidance, Cooperativeness and Self-Directedness. Some differences were obtained for Novelty Seeking, Reward Dependence, and Self-Transcendence, but without sufficient clinical significance.This study confirms various characteristics about the unipolar depressive disorder, particularly the high risk of recurrence in patients with high number of previous episodes. In the research of predictive depressive recurrence signs, it would be interesting to focus on discriminating elements between complete remitted patients and partial remitted patients.

Cushing's syndrome is rare in pregnancy but can cause spontaneous abortion, stillbirth or premature birth. We report a case of transient hypertrophic obstructive cardiomyopathy in a newborn whose mother had hypercortisolism due to a primary adrenal lesion. There was no family history of hypertrophic obstructive cardiomyopathy. Follow-up revealed complete resolution of the cardiac abnormalities in the infant. Cushing's syndrome in the mother resolved after delivery. Although maternal hypercortisolism seldom results in symptomatic hypercortisolism in the newborn, hypertrophic obstructive cardiomyopathy can occur.

Vanin-1 is an epithelial ectoenzyme with pantetheinase activity and generating the amino-thiol cysteamine through the metabolism of pantothenic acid (vitamin B(5)). Here we show that Vanin-1(-/-) mice, which lack cysteamine in tissues, exhibit resistance to oxidative injury induced by whole-body gamma-irradiation or paraquat. This protection is correlated with reduced apoptosis and inflammation and is reversed by treating mutant animals with cystamine. The better tolerance of the Vanin-1(-/-) mice is associated with an enhanced gamma-glutamylcysteine synthetase activity in liver, probably due to the absence of cysteamine and leading to elevated stores of glutathione (GSH), the most potent cellular antioxidant. Consequently, Vanin-1(-/-) mice maintain a more reducing environment in tissue after exposure to irradiation. In normal mice, we found a stress-induced biphasic expression of Vanin-1 regulated via antioxidant response elements in its promoter region. This process should finely tune the redox environment and thus change an early inflammatory process into a late tissue repair process. We propose Vanin-1 as a key molecule to regulate the GSH-dependent response to oxidative injury in tissue at the epithelial level. Therefore, Vanin/pantetheinase inhibitors could be useful for treatment of damage due to irradiation and pro-oxidant inducers.

To identify the efficacy of early cerebral MR, performed in the first month of birth, in the detection of brain lesions in high risk preterm infants, compared with conventional US, we recruited into the study a group of 30 preterm infants born at or below a gestational age of 30 weeks, who had a pathologic scan. The findings on US were compared with those of the early MR scan, performed in the same days, the results of which were considered as the final diagnosis. The value of cranial US as a predictor of MR signal intensity was assessed by calculating sensitivity, specificity, positive and negative predictive values. Agreement between two investigations was evaluated by calculating the K coefficient. US showed 33 haemorrhagic lesions in 25 preterms; MR showed 27 haemorrhagic lesions in 22 infants: in 16 cases MR gave the same results of US. Cranial US was reliable in detecting lesions such as GLH and IVH, but less sensitive in the definition of their size and distribution. Sensitivity of US for haemorrhagic lesions was 96.3%, PPV 78.8%, K coefficient 0.55 (p < 0.001). About the White Matter, cranial US demonstrated 20 lesions in 20 preterms; MR showed 16 lesions in 16 infants: in 3 cases MR was agree to US. US showed high reliability in the detection of cystic lesions, but significant limitations in the demonstration of non-cystic injury. We founded that normal WM echogenicity on US is not a good predictor of normal WM signal intensity on MR (30%). Sensitivity of US for WM lesions was 81.3%, PPV 65%, K coefficient 0.23 (p = 0.04). Finally US showed 4 lesions in other brain locations, MR confirmed 3 of them and discovered other 10. Sensitivity of US for these lesions was 23.1%, PPV 75%, K coefficient 0.21 (p = 0.11). We founded that cranial US is a good method for detecting GLH, IVH, HPI and severe WM lesions (cystic PVL), but it can miss non-cystic PVL, punctate haemorrhages, WMD and lesions in other brain locations, that, on the other hand, MR detects clearly.

Purpose: To describe the surveillance, results of screening, and treatment of retinopathy of prematurity (ROP) in a university hospital setting in southeast France., Patients and Methods: Five hundred two premature infants were included in the screening protocol between January 1997 and December 1999. Criteria for inclusion in the study were a gestational age of 32 weeks or younger, a birth weight of less than 1,501 g, or both. The first fundus examination was performed between 4 and 6 weeks of life. Thereafter, fundus examination was performed in the absence of ROP every 2 weeks until complete retinal vasculature developed, gestational age of 50 weeks, or death. Examination was weekly in cases of retinopathy, biweekly if progression was ascertained, and less frequent only if regression was evident. Hospital records were reviewed to assess the presence or absence and eventual degree of ROP., Results: Stage 1 was observed in 32 infants, and stage 2 in 11 infants; all of these cases regressed. Three cases of bilateral stage 3 (two threshold and one prethreshold) disease underwent diode laser peripheral retinal ablation and regressed. One infant with bilateral stage 3 disease who underwent peripheral cryoablative surgery progressed to stage 4A in one eye and 4B in the other eye and then underwent scleral buckling surgery in the second eye., Conclusions: Despite survival increasing with improved neonatal intensive care, the incidence of ROP does not appear to be increasing. In our center, the incidence appears to be lower than previously reported.

Currently available murine models to evaluate mesenchymal stem cell (MSC) differentiation are based on cell injection at ectopic sites such as muscle or skin. Due to the importance of environmental factors on the differentiation capacities of stem cells in vivo, we investigated whether the peculiar synovial/cartilaginous environment may influence the lineage specificity of bone morphogenetic protein (BMP)-2-engineered MSCs. To this aim, we used the C3H10T1/2-derived C9 MSCs that express BMP-2 under control of the doxycycline (Dox)-repressible promoter, Tet-Off, and showed in vitro, using the micropellet culture system that C9 MSCs kept their potential to differentiate toward chondrocytes. Implantation of C9 cells, either into the tibialis anterior muscles or into the joints of CB17-severe combined immunodeficient bg mice led to the formation of cartilage and bone filled with bone marrow as soon as day 10. However, no differentiation was observed after injection of naïve MSCs or C9 cells that were repressed to secrete BMP-2 by Dox addition. The BMP-2-induced differentiation of adult MSCs is thus independent of soluble factors present in the local environment of the synovial/cartilaginous tissues. Importantly, we demonstrated that a short-term expression of the BMP-2 growth factor is necessary and sufficient to irreversibly induce bone formation, suggesting that a stable genetic modification of MSCs is not required for stem cell-based bone/cartilage engineering.

Ventriculomegaly constitutes the major indication of fetal brain MRI. MRI is therefore of utmost importance to look for a cause through the depiction of criteria of malformations and through the definition of criteria of destructive lesions. Malformations and destructive lesions are the most common causes of ventricular dilatation. Some challenging points are worth mentioning in term of mechanism with the challenge of hydrocephalus (in term of increased in intracranial pressure) and of isolated ventriculomegaly. The image itself is also challenging since a similar image may be of different origin. In term of natural history of fetal brain injury an irregular, nodular aspect of the ventricular wall and/or the germinal matrix is often the only pathologic MRI finding that is known to be of clastic origin. In term of prognosis the challenge is represented by the isolated mild ventriculomegaly, the literature being quite confusing. The purpose of this review paper is to highlight the underlying mechanisms and pathophysiology of ventricular dilatation based on results from the literature as well as from personal experience.

Neonatal brain disorders consist of a wide chapter including brain malformations, hypoxic-ischemic encephalopathy, intracranial infections, perinatal trauma and metabolic encephalopathies. The aim of this review paper is to describe the main imaging modalities (ultrasonography, CT, MRI) that are used extensively for the diagnosis of neonatal brain disorders, with their respective advantages and limitations, to illustrate and describe the main brain lesions encountered in the neonatal period, particularly with MRI since its role has increased over the recent years. We will focus on hypoxic-ischemic encephalopathy, materno-fetal infections, metabolic encephalopathies and stroke, those four conditions being the most frequent so far. Imaging modalities, especially MRI, by showing the extent of brain damage, are part of the prognostic factors in cases of infective causes and of hypoxic-ischemic origin. MRI is also very efficient in showing brain damage as atrophy and white matter abnormalities suggestive of an underlying abnormal brain of metabolic origin.

The doxycycline (Dox)-inducible reverse tetracycline transactivator (rtTA) is often used to control gene expression. However, the Tet-on system displays a high background activity. To overcome this unregulated expression we used the tetracycline-dependent transcriptional silencer (tTS), which binds the tetO inducible promoter in the absence of Dox. Controlled gene expression was analyzed in vivo by delivering combinations of Dox-regulated luciferase reporter construct, rtTA, and tTS expression plasmids into mouse muscle, using electrotransfer. Elevated luciferase expression levels were observed in the absence of doxycycline, and a 10-fold induction was obtained after drug administration. In contrast, when tTS was added, background expression was dramatically lowered by three to four orders of magnitude, and induction was maintained. The tTS system was then used to control expression of a therapeutic gene in experimental arthritis. DBA/1 mice were coinjected with plasmids encoding the antiinflammatory interleukin-10 cytokine under the control of the tetO promoter, the rtTA, and the tTS. Electrotransfer resulted in a dose-dependent increase in IL-10 expression, maintained over a 3-month period, and significant inhibitory effects on collagen-induced arthritis. We conclude that the use of tTS significantly improves the utility of the rtTA system for somatic gene transfer by reducing background activity.

The adeno-associated viruses (AAV) offer new perspectives for cytokine gene transfer in rheumatoid arthritis (RA) because they are nonpathogenic and allow long-term transgene expression in vivo. Moreover, the use of a tetracycline-inducible promoter allows regulation of therapeutic gene expression. This study assessed the potential long-term gene regulation of a recombinant AAV vector expressing viral interleukin-10 (vIL-10) in human rheumatoid synovium and the therapeutic efficiency in a mouse model of RA. We constructed a recombinant AAV vector in which the transcription of vIL-10 cDNA is controlled by the TetON system. Transduction of human primary RA synovial cells with AAV-tetON-vIL10 conferred in vitro controlled vIL-10 expression. After intramuscular injection, both incidence and severity of collagen-induced arthritis were significantly reduced at macroscopic, radiological, and histological levels in the group of DBA1 mice treated with AAV-TetON-vIL10 vector plus doxycycline after immunization and boosting compared to control groups. When coinjecting two separate AAV vectors, one encoding the inducible vIL-10 and the other the transcriptional activator, a 10 times excess of the transactivator vector dose allowed efficient control of vIL-10 secretion by doxycycline administration or withdrawal, over an 8-week period. Our results supported, for the first time, the utility of AAV-tetON-vIL10 as a therapeutic tool for gene therapy in RA.

Plasmin is essential for metalloproteases activation, endothelial cell migration and degradation of the extracellular matrix. The process is common to neoangiogenesis pannus formation and cartilage degradation within arthritic joints. Since 80% of synovial cells express urokinase plasminogen activator receptor (uPAR), we investigated the inhibition of plasmin activation in a collagen-induced arthritis (CIA) mice model, by expressing a uPA/uPAR antagonist molecule (ATF) fused to human serum albumin (HSA) to extend its serum half-life. Overexpression was obtained with an adenoviral vector expressing the chimeric murine ATF-HSA. We showed that the genetic coupling did not significantly reduce the ability of the ATF moiety to interact with its receptor uPAR. The chimeric protein was detectable in the sera of injected mice 7 days following Ad-mATF-HSA injection, then decreased in parallel with the anti-HSA titer increase. Systemic Ad-mATF-HSA injection performed on day 25 following CIA induction decreased the incidence of arthritis and the severity of the disease. Moreover, synovial angiogenesis in arthritic paws was decreased after Ad-mATF-HSA gene transfer, as assessed by smooth muscle actin immunostaining. The preventive effect observed on arthritis was related to the decrease in angiogenesis, rather than inhibition of extracellular matrix degradation.

How far providing neonatal intensive care to extremely low birth weight infants is appropriate is still a highly controversial issue. Decision making when a poor prognosis has been established may be facilitated by consensus based recommendations and rigorous procedures. In the very majority of situations, the provision of intensive care is advocated at birth a priori. A decision of treatment withholding or withdrawal may eventually be made secondarily, in the case major neurological complications, likely to induce severe long term deficits, are evidenced. In any case, an ethical policy focused on each infant's best interest is justified, while the adoption of a systematic, gestational age or birth weight based restriction of access to intensive care may not be acceptable in most countries. Rigorous criteria must be fulfilled for end of life decision making and procedures. Continuous assistance to the patient and to the parents is key determinant.