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International audience; We report the case of an infant aged 8 and a half months, who had an apparent life-threatening event and died despite optimal resuscitation management. The medical history was marked by mild symptoms, mainly feeding difficulties and progressively settling skin lesions. Parents were related (first cousins) and the patient had two healthy older sisters. Autopsy showed growth delay, symmetrical erythematous and ulcerated periorificial lesions associated with punctiform erythematous lesions of the face and alopecia. Microscopic examination revealed deep bronchial inhalation with the onset of infectious pneumopathy, major inflammatory ulceration of the gastrointestinal tract, hepatic steatosis, brain stem and pancreas abnormalities. We conclude that the cause of death was a multi-visceral failure with inhalation pneumopathy, in a context of very early onset inflammatory bowel disease (VEO-IBD). Genetic consultation, into a rare disease reference center, allowed to orient the analysis, to identify a homozygous pathogenic variant in the IL10RA gene, confirming the diagnostic of an autosomal recessive very early onset inflammatory bowel disease (inflammatory bowel disease 28, early-onset, autosomal recessive, #613148).; Nous rapportons le cas d’un nourrisson âgé de 8 mois et demi, ayant fait un malaise grave du nourrisson et décédé malgré une prise en charge optimale en réanimation. L’histoire de la maladie est marquée par des symptômes frustes, principalement des difficultés alimentaires et des lésions cutanées d’installation progressive. Parmi les antécédents, on note que les parents étaient apparentés et qu’il y avait deux sœurs aînées en bonne santé. L’autopsie a montré, outre un retard staturo-pondéral, des lésions péri-orificielles érythémateuses et ulcérées, symétriques, associées à des lésions érythémateuses punctiformes du visage et à une alopécie. L’examen microscopique a mis en évidence une inhalation bronchique profonde avec début de pneumopathie infectieuse, des ulcérations inflammatoires majeures du tube digestif, une stéatose hépatique et des anomalies du tronc cérébral et du pancréas. Ce tableau clinique nous a permis d’évoquer une défaillance multi-viscérale avec pneumopathie d’inhalation, dans un contexte de maladie inflammatoire de l’intestin à début précoce. Un avis génétique, au sein d’un centre de référence maladie rare, a permis d’orienter les analyses, d’identifier un variant pathogène homozygote dans le gène IL10RA et de poser le diagnostic de maladie inflammatoire de l’intestin à début précoce, de transmission autosomique récessive (inflammatory bowel disease 28, early onset, autosomal recessive, #613148).

Objective Congenital diarrheal disorders (CDDs) are a group of rare diseases among which some present as inherited disorders of intestinal electrolyte transportation: congenital chloride diarrhea (CCD) and congenital sodium diarrhea (CSD) with prenatal manifestations, mainly polyhydramnios, leading to premature delivery. Affected neonates present with watery stools, sometimes mistaken as urine, leading to a misdiagnosis of Bartter syndrome. The aim of this study was to study the value of a prenatal biochemical pattern in the case of suspected CDD. Methods We retrospectively studied 12 amniotic fluids of CDD-affected fetuses prenatally suspected and confirmed after birth. Digestive enzymes, proteins and electrolytes were assayed and showed abnormal biochemical patterns. Results The 12 infants (8 CCD- and 4 CSD-affected) were born prematurely with a normal birth weight. Electrolytes and the Bartter index were normal for all cases. Amniotic fluid enzyme patterns were abnormal: anal leakage for 9, as expected, but vomiting of bile was observed for 3 infants, for whom an occlusive syndrome required surgery, and thereafter severe complications appeared with a poor prognosis. Conclusion Amniotic fluid biochemical patterns differentiate CDD from Bartter syndrome. If a vomiting bile pattern is observed, postnatal management should take into account the hypothesis of a most severe complication. This article is protected by copyright. All rights reserved.

Low weight in early infancy is a known risk factor for cardio-metabolic syndrome in adult life. However, little is known either about developmental programming in subjects of normal birthweight or about events between the ages which separate early programming and the occurrence of disease at late adulthood. We tested the hypothesis that circulating concentrations of leptin, adiponectin and insulin in young, healthy adults, born with a birth size within the normal range, are influenced by early life growth patterns. In an observational study of 188 healthy volunteers aged 18–25 years (97 males, 91 females) we investigated the association of metabolic function with their birth size, their growth during childhood and their body composition. High plasma leptin in early adulthood, a risk factor for cardio-metabolic syndrome, was associated with low weight at age 2 years (correlation coefficient controlled for adult weight = −0.21, P P

BackgroundVitamin D (VitD) is involved in lung development but its influence on respiratory distress syndrome of extremely preterm (EPT) infants have been little investigated. In this study, we examined the influence of low vitamin D status at birth on early respiratory outcomes of this vulnerable infant population.MethodsCord blood 25(OH)D levels ≤ 75 nmol/L were considered as Low vitamin D levels. Stepwise logistic regression and classification regression-tree analyses were used and the primary outcome was the combined outcome of death or mechanical ventilation need by the end of the first week (death or MV DoL7) as a marker od RDS severity.ResultsThe mean (SD) GA and birth weight were 26 (1.4) weeks and 801 (212) gr, respectively; 81/109 (74%) infants had low 25(OH)D levels. Infants with low VitD levels had 25% higher initial FiO2 levels (p < 0.05) and were more likely to be mechanically ventilated on DoL7 (36 vs. 7%, p < 0.05). Adjusted for gestational age, they had 10-fold higher odds of death or MV DoL7 (p < 0.01). By regression tree analysis, the rate of death or MV DoL7 increased from 18 to 71% in infants with GA < 26 weeks and with cord blood 25(OH)D levels higher and lower than 74 nmol/L, respectively (p < 0.05).ConclusionLow vitamin D levels at birth are associated with early adverse respiratory outcomes in infants with GA less 29 weeks. Further largest studies are needed to confirm this association.

International audience; Objectives: Congenital diarrhea and enteropathies linked to epithelial structural abnormalities constitute 3 different rare diseases: the tufting enteropathies (TE; EPCAM and SPINT2 mutations), microvillous inclusion disease (MVID; MYO5B and STX3 mutations), and tricho-hepato-enteric syndrome (THE; TTC37 and SKIV2L mutations). Moreover, enteroendocrine deficiencies (ED; PCSK1 and NEUROG3 mutations) share common clinical characteristics with TE, THE, and MVID in that the treatment requires, in most cases, long-term parenteral nutrition. Although numerous cases have been reported in the literature, aggregated data on morbidity and mortality are missing owing to the rarity of the diseases.Methods: We performed a systematic review of all published cases and retrieved 86 articles describing 323 patients (164 boys and 135 girls).Results: The mortality rate was 20.28%, with a median age at death of 13.5 months (range 0–228 months); the mortality risk was 30.8/1000 person-year; in half of the cases, death was caused by infections. Parenteral nutrition was required in 95.4% of patients and weaning off from parenteral nutrition was achieved in 29.35% at a median age of 23 months (range 3.3–276 months). The patients with ED linked to PCSK1 were nearly all weaned at a median age of 14 months, but most of the patients became overweight. MVID patients with MYO5B mutations were most often born preterm. ED linked to NEUROG3 mutation and THE patients usually presented with intrauterine growth retardation.Conclusions: This review presents data from 323 patients with congenital diarrhea linked to EPCAM TE, SPINT2 TE, TTC37 THE, SKIV2L THE, MYO5B MVID, STX3 MVID, NEUROG3 ED, and PCSK1 ED mutations.

Aspirin (acetyl-salicylic acid) is one of the most ancient drugs of the human pharmacopeia. Nonetheless, its action at low doses is not well understood at the molecular level. One of the applications of low-dose aspirin treatment is the prevention of preeclampsia (PE) in patients at risk. Foeto-placental overexpression of the STOX1A transcription factor in mice triggers PE symptoms. Transcriptomic analysis of the placentas, showed that aspirin massively down-regulates genes of the coagulation and complement cascade, as well as genes involved in lipid transport. The genes modified by aspirin treatment are not the ones that are modified by STOX1 overexpression, suggesting that aspirin could act downstream, symptomatically on the preeclamptic disease. Bioinformatics analysis of the promoters of the deregulated genes showed that they are strongly enriched in HNF transcription factors-binding sites, in accordance with existing literature showing their roles as regulators of coagulation. Two of these transcription factors, Hnf1β and Hnf4α are found down-regulated by aspirin treatment. In parallel, we show that in human patient placentas, aspirin-induced deregulations of genes of the coagulation cascade are also observed. Finally, the expression of Hnf1β target sequences (Kif12, F2, Hnf4α promoters and a synthetic concatemer of the Hnf1β-binding site) were investigated by transfection in trophoblast cell models, with or without aspirin treatment and with or without STOX1A overexpression. In this model we observed that STOX1A and aspirin tended to synergize in the down-regulation of Hnf1β target genes in trophoblasts.

Simple Summary Brain cancers, such as gliomas, are very difficult to detect because of their localization and late onset of symptoms. Here, we have developed a novel cancer detection method based on plasma denaturation profiles obtained by a non-conventional use of Differential Scanning Fluorimetry. Using blood samples from glioma patients and healthy controls, we show that their denaturation profiles can be automatically distinguished with the help of machine learning algorithms with 92% accuracy. This promising approach can now be extended to other types of cancers and could become a powerful pan-cancer diagnostic and monitoring tool requiring only a simple blood test. Abstract Glioblastoma is the most frequent and aggressive primary brain tumor. Its diagnosis is based on resection or biopsy that could be especially difficult and dangerous in the case of deep location or patient comorbidities. Monitoring disease evolution and progression also requires repeated biopsies that are often not feasible. Therefore, there is an urgent need to develop biomarkers to diagnose and follow glioblastoma evolution in a minimally invasive way. In the present study, we described a novel cancer detection method based on plasma denaturation profiles obtained by a non-conventional use of differential scanning fluorimetry. Using blood samples from 84 glioma patients and 63 healthy controls, we showed that their denaturation profiles can be automatically distinguished with the help of machine learning algorithms with 92% accuracy. Proposed high throughput workflow can be applied to any type of cancer and could become a powerful pan-cancer diagnostic and monitoring tool requiring only a simple blood test.

ObjectiveWe sought to determine whether the early luteal serum progesterone (P4) level predicts the success of IVF treatment with oral dydrogesterone for luteal support.MethodThis retrospective monocentric cohort study included 242 women who underwent IVF treatment with fresh embryo transfer (ET) between July 2017 and June 2018. The population was unselected, and women were treated according to our unit's usual stimulation protocols. For the luteal phase support (LPS), all women were supplemented with a 10 mg three-times-daily dose of oral dydrogesterone beginning on the day of oocyte pick-up (OPU). Blood sampling was performed on the day of ET (Day 2-3 after OPU) to determine the early luteal serum progesterone level.ResultsROC curve analysis allowed us to determine two thresholds for the prediction of live birth using the early P4 level. Women who had early luteal P4 levels greater than 252 nmol/l had a significantly higher live birth rate (27.1%) than women with early luteal P4 between 115 and 252 nmol/l (17.2%) and women with early luteal P4 below 115 nmol/l (6.0%; p = 0.011). After a multiple regression analysis, an early luteal P4 level greater than 252 nmol/l was still associated with a higher chance of a live birth than a P4 between 115 and 252 nmol/l (OR = 0.40 [0.18-0.91]; p = 0.028) or a P4 below 115 nmol/l (OR = 0.10 [0.01-0.52]; p = 0.006).ConclusionsOur study suggests a positive association between early P4 levels and reproductive outcomes in IVF using oral dydrogesterone for luteal support. The inconsistencies between our results and those of other studies suggest that extrapolation is impractical. Further larger prospective cohort studies should be conducted to determine reliable thresholds that could be used to personalize luteal phase support.

The survival of preterm babies has increased over the last few decades. However, disorders associated with preterm birth, known as oxygen radical diseases of neonatology, such as retinopathy, bronchopulmonary dysplasia, periventricular leukomalacia, and necrotizing enterocolitis are severe complications related to oxidative stress, which can be defined by an imbalance between oxidative reactive species production and antioxidant defenses. Oxidative stress causes lipid, protein, and DNA damage. Preterm infants have decreased antioxidant defenses in response to oxidative challenges, because the physiologic increase of antioxidant capacity occurs at the end of gestation in preparation for the transition to extrauterine life. Therefore, preterm infants are more sensitive to neonatal oxidative stress, notably when supplemental oxygen is being delivered. Furthermore, despite recent advances in the management of neonatal respiratory distress syndrome, controversies persist concerning the oxygenation saturation targets that should be used in caring for preterm babies. Identification of adequate biomarkers of oxidative stress in preterm infants such as 8-iso-prostaglandin F2α, and adduction of malondialdehyde to hemoglobin is important to promote specific therapeutic approaches. At present, no therapeutic strategy has been validated as prevention or treatment against oxidative stress. Breastfeeding should be considered as the main measure to improve the antioxidant status of preterm infants. In the last few years, melatonin has emerged as a protective molecule against oxidative stress, with antioxidant and free-radical scavenger roles, in experimental and preliminary human studies, giving hope that it can be used in preterm infants in the near future.

Individuals born after intrauterine growth restriction (IUGR) are at increased risk of developing cardiovascular diseases in adulthood, notably hypertension (HTN). Alterations in the vascular system, particularly impaired endothelium-dependent vasodilation, may play an important role in long-term effects of IUGR. Whether such vascular dysfunction precedes HTN has not been fully established in individuals born after IUGR. Moreover, the intimate mechanisms of altered endothelium-dependent vasodilation remain incompletely elucidated. We therefore investigated, using a rat model of IUGR, whether impaired endothelium-dependent relaxation precedes the development of HTN and whether key components of the l-arginine-nitric oxide (NO) pathway are involved in its pathogenesis. Pregnant rats were fed with a control (CTRL, 23% casein) or low-protein diet (LPD, 9% casein) to induce IUGR. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography in 5- and 8-wk-old male offspring. Aortic rings were isolated to investigate relaxation to acetylcholine, NO production, endothelial NO synthase (eNOS) protein content, arginase activity, and superoxide anion production. SBP was not different at 5 wk but significantly increased in 8-wk-old offspring of maternal LPD (LP) versus CTRL offspring. In 5-wk-old LP versus CTRL males, endothelium-dependent vasorelaxation was significantly impaired but restored by preincubation with l-arginine or the arginase inhibitor S-(2-boronoethyl)-l-cysteine; NO production was significantly reduced but restored by l-arginine pretreatment; total eNOS protein, dimer-to-monomer ratio, and arginase activity were significantly increased; superoxide anion production was significantly enhanced but normalized by pretreatment with the NO synthase inhibitor Nω-nitro-l-arginine. In this model, IUGR leads to early-impaired endothelium-dependent vasorelaxation, resulting from arginase upregulation and eNOS uncoupling, which precedes the development of HTN.

Congenital chloride diarrhea (CCD) is a rare disease, manifesting with secretory diarrhea and life-threatening electrolyte imbalance during infancy. The early diagnosis of CCD is therefore necessary for the adequate treatment. The long-term prognosis of properly managed CCD is favorable. We present a case of complicated CCD with necrotizing enterocolitis. The child was born to nonconsanguineous parents of Lithuanian origin. CCD was suspected due to watery diarrhea, progressive hypochloremia, and high fecal chlorides. Despite oral electrolytes being prescribed, volvulus of small intestine developed requiring several surgical interventions. The clinical diagnosis of CCD was confirmed by molecular genetic testing of SLC26A3, which revealed two Polish founder mutations in the DNA of the patient. The prevalence of CCD in Lithuanian neighbor Poland is approximately 1 in 200,000 live births. This is the first described case of CCD in Lithuania to our knowledge, leading to the suggestion that this disease may be underdiagnosed.

To reduce the morbidity and mortality risk for the donor in living donor liver transplantation (LDLT), we previously identified 20% left portal vein (LPV) stenosis as an effective preconditioning method to induce cell proliferation in the contralateral lobe without downstream ipsilateral atrophy. In this study, we report the pathways involved in the first hours after preconditioning and investigate the changes in liver volume and function. Fourteen pigs were used this study. Five pigs were used to study the genetic, cellular and molecular mechanisms set up in the early hours following the establishment of our preconditioning. The remaining nine pigs were equally divided into three groups: sham-operated animals, 20% LPV stenosis, and 100% LPV stenosis. Volumetric scanning and 99 mTc-Mebrofenin hepatobiliary scintigraphy were performed before preconditioning and 14 days after to study morphological and functional changes in the liver. We demonstrated that liver regeneration triggered by 20% LPV stenosis in the contralateral lobe involves TNF-α, IL-6, and inducible nitric oxide synthase 2 by means of STAT3 and hepatocyte growth factor. We confirmed that our preconditioning was responsible for an increase in the total liver volume. Finally, we demonstrated that this volumetric gain was associated with an increase in hepatic functional capacity. NEW & NOTEWORTHY We describe a new preconditioning method for major hepatectomy that is applicable to hepatectomy for donation. We identified 20% left portal vein stenosis as effective preconditioning that is capable of inducing cell proliferation in the contralateral lobe without the downstream ipsilateral atrophy. In this study, we report the pathways involved in the first hours following preconditioning, and we confirm that 20% left portal vein stenosis is responsible for an increase in the functional capacity and total liver volume in a porcine model.

Congenital Sodium Diarrhea (CSD) due to SLC9A3 mutation is a rare cause of neonatal diarrhea explained by dysfunction of the Na+/H+ antiporter 3 in intestine. To date only 10 patients have been described. We report a male patient with typical antenatal symptoms (polyhydramnios and intestinal dilation) and neonatal diarrhea with fecal sodium and bicarbonates loss. Next generation sequencing revealed a missense homozygous mutation in exon 6 of the SLC9A3 gene (NM_004174.3:c.1039G > A, NP_004165.2:p.Glu347Lys). Oral electrolytes supplements (Sodium and Bicarbonates) allowed a normal growth to the child currently aged twenty months. CSD symptomatology usually begins during third trimester of pregnancy. Antenatal signs are polyhydramnios and diffuse intestinal dilation. Main differential diagnoses are intestinal obstruction and Congenital Chloride Diarrhea. Diarrhea begins from the first days of life and its severity is variable. Based on the report and on the literature we suggest that non syndromic CSD can be detected during third trimester of pregnancy. With adequate electrolytes supplementation good evolution is possible.

International audience; BACKGROUND: Intrauterine growth restriction (IUGR) and postnatal nutrition are risk factors for cardiovascular and renal diseases in both humans and animals. The long-term renal effects of protein intake early in life remain unknown. The objective was to evaluate the effects of a neonatal feeding with high protein (HP) milk on renal functions and structure in IUGR male rats. METHODS: Maternal gestational low protein diet was used to produce IUGR. At day 5, IUGR pups were gastrostomized in the "pup-in-the cup" model and received either normal protein (NP) milk or HP (+50% protein content) milk until day 21. After weaning, the animals were fed the same standard diet. Renal functions and structure were assessed at postnatal day 18 (D18) and in adult offspring. RESULTS: During the preweaning period, the postnatal weight gain between the two groups was unaffected. On D18, kidneys from HP offspring were heavier with significant glomerular hypertrophy (+40%, P < 0.05). HP diet was associated with significant proteinuria and glomerulosclerosis (+49%, P < 0.05). Glomerular number was unaltered. CONCLUSION: Neonatal HP feeding. following IUGR affects renal functions and structure at adulthood. These alterations may result from a single nephron glomerular hyperfiltration.

Intrauterine growth restriction (IUGR) is a frequent complication of pregnancy defined as a restriction of fetal growth. The objective of this work was to improve the knowledge on the pathophysiology of IUGR using a genome-wide method of expression analysis. We analyzed differentially expressed genes in pooled placental tissues from vascular IUGR (four pools of three placentas) and normal pregnancies (four pools of three placentas) using a long nucleotide microarray platform (Nimblegen). We first did a global bioinformatics analysis based only on P value without any a priori. We secondly focused on “target” genes among the most modified ones. Finally, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed on an extended panel of tissue samples (n = 62) on selected “target”. We identified 636 modified genes among which 206 were upregulated (1.5 and higher; P < 0.05). Groups of patients were classified unambiguously. Genes involved in mitochondrial function and oxidative phosphorylation were decreased affecting three out of five complexes of the respiratory chain of the mitochondria, and thus energy production and metabolism. Among the most induced genes, we identified LEP, IGFBP1, and RBP4. Complementary studies on the role and function of LEP, IGFBP1, and RBP4 in IUGR pathophysiology and also in fetal programming remain necessary.

International audience; Objective: Preterm birth is associated with altered angiogenesis and with increased risk of cardiovascular dysfunction and hypertension at adulthood. We previously demonstrated that in preterm newborns circulating cord blood endothelial progenitor cells (ECFC), responsible for angio/vasculogenesis, are reduced in number and display altered angiogenic properties. Altered angiogenic function was associated with a decreased expression of pro-angiogenic genes, among which the AMOT gene which is a strong positive regulator of angiogenesis. Such dysregulation may be related to epigenetic factors. In this study we analyse the methylation profiling of the AMOT gene during development, through a comparative analysis of the cord blood ECFC of preterm newborns and their term counterpart.Methods: We used both cloning-sequencing and pyrosequencing experiments to perform a comparative analysis of the DNA methylation profile of the promoter CpG island of AMOT gene in the cord blood ECFC of 16 preterm newborns (28–35 weeks gestational age-GA) and 15 term newborns (>37 weeks GA).Results: Twenty nine clones (obtained from 2 term newborns) and forty clones (obtained from 3 preterm newborns) were sequenced. The AMOT gene methylation rate was significantly higher in preterm compared to term newborns (4.5% versus 2.5% respectively: χ2 = 3.84; P = 1.8 10−02). Bisulfite pyrosequencing identified four CpG dinucleotides with significantly higher methylation levels in preterm newborns. This CpG-targeted methylation significantly decreased with increasing gestational age.Conclusions: These findings highlight importance of pro-angiogenic AMOT gene methylation in ECFC, suggesting that epigenetic mechanisms may control the regulation of angiogenesis during development. Therefore they pave the way to specific short term and long term complications of preterm birth by altered angiogenesis.

Background & Aims The main hindrance in promoting living donor liver transplantation remains the morbi-mortality risk for the donor. Considering the opposed remodeling influence of portal and hepatic artery flows, our working hypothesis was to identify a lobar portal vein stenosis capable of inducing a contralateral liver mass compensatory enlargement, without the downstream ipsilateral atrophic response. Methods Twenty-four pigs entered this study. Six of them were used to establish hemodynamic changes following a progressive left portal vein (LPV) stenosis, in blood flow, pressure and vessel diameter of the LPV, main portal vein and hepatic artery. Sixteen pigs were divided into 4 groups: sham operated animals, 20% LPV stenosis, 50% LPV stenosis, and 100% LPV stenosis. Daily liver biopsies were collected until post-operative day 5 to investigate liver regeneration and atrophy (Ki67, STAT3, LC3, and activated caspase 3) according to the degree of LPV stenosis. Finally, changes in liver volumetry after 20% LPVS were investigated. Results A 20% LPV stenosis led to dilatation of the hepatic artery and a subsequent four-fold increase in hepatic arterial flow. Concomitantly, liver regeneration was triggered in the non-ligated lobe and the cell proliferation peak, 5days after surgery, was comparable to that obtained after total LPV ligation. Moreover, 20% LPV stenosis preconditioning did not induce left liver atrophy contrary to 50 and 100% LPV stenosis. Conclusions A 20% LPV stenosis seems to be the adequate preconditioning to get the remnant liver of living donor ready to take on graft harvesting without atrophy of the future graft.

Background: Intrauterine growth restriction (IUGR) is a risk factor for hypertension (HT) and chronic renal disease (CRD). A reduction in the nephron number is proposed to be the underlying mechanism; however, the mechanism is debated. The aim of this study was to demonstrate that IUGR-induced HT and CRD are linked to the magnitude of nephron number reduction, independently on its cause. Methods: Systolic blood pressure (SBP), glomerular filtration rate (GFR), proteinuria, nephron number, and glomerular sclerosis were compared between IUGR offspring prenatally exposed to a maternal low-protein diet (9% casein; LPD offspring) or maternal administration of betamethasone (from E17 to E19; BET offspring) and offspring with a normal birth weight (NBW offspring). Results: Both prenatal interventions led to IUGR and a similar reduction in birth weight. In comparison to NBW offspring, BET offspring had a severe nephron deficit (-50% in males and -40% in females, p < 0.01), an impaired GFR (-33%, p < 0.05), and HT (SBP+ 17 mmHg, p < 0.05). Glomerular sclerosis was more than twofold higher in BET offspring than in NBW offspring (p < 0.05). Long-term SBP, GFR, and glomerular sclerosis were unchanged in LPD offspring while the nephron number was moderately reduced only in males (-28% vs. NBW offspring, p < 0.05). Conclusion: In this study, the magnitude of nephron number reduction influences long term renal disease in IUGR offspring: a moderate nephron number is an insufficient factor. Extremely long-term follow-up of adults prenatally exposed to glucocorticoids are required.

Introduction Les micropuces mesurant les reponses IgE et IgG specifiques vis-a-vis de > 100 allergenes sont de plus en plus utilisees a des fins diagnostiques et epidemiologiques. La miniaturisation necessite des quantites tres faibles de chaque allergene, exposant aux interferences par competition entre les IgE et les IgG. L’effet de ces interferences sur la reactivite IgE des patients est inconnu. Methodes Nous avons utilise du serum de neuf patients allergiques pour comparer la reactivite IgE observee sur micropuce ISAC (ThermoFisher, Uppsala, Suede) avec le serum natif et apres depletion des IgG (proteine G). La concentration des IgE totales (tIgE) et d’un analyte neutre ont ete mesurees dans chaque echantillon, natif et deplete. L’analyse des resultats a ete qualitative (changement de classe d’intensite, definition des classes DOI 10.1111/all.13548) et quantitative (calcul du ratio d’intensite ISU-E apres/avant depletion). L’analyse a pris en compte l’incertitude de mesure de 25 % de la micropuce. Resultats La depletion en IgG de chaque serum a conduit a une diminution du niveau de tIgE (mediane 65 % de la concentration de chaque serum natif, extremes 50 et 73 %). Un total de 225 reactivites IgE > 0,3 ISU-E etaient observees dans les sera depletes en IgG, apres correction du niveau de tIgE. Un deplacement vers des classes d’intensite superieures etait observe dans 90 cas (40 %), dont 11 reactivites IgE demasquees apres la depletion des IgG. En analyse quantitative, l’augmentation moyenne de l’intensite de reactivite chez un sujet donne variait de 1,7 a 6,9. Nous n’avons pas observe d’association privilegiee entre une forte progression de la reactivite IgE apres depletion des IgG et les proprietes des allergenes concernes. Discussion La fixation des IgG avec competition IgG-IgE etait presente chez les neuf patients de notre etude, avec comme corollaire une sous-estimation, voire l’absence de detection, de la reactivite IgE. Conclusion Nos resultats suggerent (1) les resultats de la mesure des reactivites IgE sur micropuce devraient etre interpretes avec prudence et (2) une etape de depletion des IgG prealablement a la mesure des reactivites IgE permettrait d’obtenir des resultats plus justes.

Preeclampsia is a pregnancy disorder being a leading cause of maternal and fetal mortality and morbidity. It is a complex multisystem disease characterized by hypertension and proteinuria. In preeclampsia the placenta releases factors into the maternal circulation which cause a systemic endothelial dysfunction. Here, we review data demonstrating the central role played by the endothelium in the development of the maternal syndrome of preeclampsia. We present also original data showing how circulating factors present in the plasma of preeclamptic women can alter the transcriptome of endothelial cells. The expression of genes involved in essential functions such as vasoregulation, oxidative stress, apoptosis and cell proliferation show differential expression when endothelial cells are exposed to preeclamptic or normal pregnancy plasma. We conclude by discussing the growing evidences that the alterations of the endothelium during preeclampsia are linked to an increased risk of cardiovascular diseases latter on life. Therefore, a better understanding of the modifications undergone by the endothelial cells during preeclampsia is essential to develop new therapeutic approaches to both, manage preeclampsia and to prevent the long-term sequelae of the disease on women cardiovascular system.

Preeclampsia (PE) is a common human-specific pregnancy disorder defined by hypertension and proteinuria during gestation and responsible for maternal and fetal morbimortality. STOX1 , encoding a transcription factor, was the first gene associated with PE as identified by positional cloning approaches. Its overexpression in choriocarcinoma cells mimics the transcriptional consequences of PE in the human placenta. Here, we created transgenic mouse strains overexpressing human STOX1 . Wild-type female mice crossed with transgenic male mice reproduce accurately the symptoms of severe PE: gestational hypertension, proteinuria, and elevated plasma levels of soluble fms-like tyrosine kinase 1 and soluble endoglin. Placental and kidney histology were altered. Symptoms were prevented or alleviated by aspirin treatment. STOX1-overexpressing mice constitute a unique model for studying PE, allow testing therapeutic approaches, and assessing the long-term effects of the preeclamptic syndrome.

Preeclampsia is a disease of pregnancy involving systemic endothelial dysfunction. However, cardiovascular consequences of preeclampsia are difficult to analyze in humans. The objective of the present study is to evaluate the cardiovascular dysfunction induced by preeclampsia by examining the endothelium of mice suffering of severe preeclampsia induced by STOX1 overexpression. Using Next Generation Sequencing on endothelial cells of mice carrying either transgenic or control embryos, we discovered significant alterations of gene networks involved in inflammation, cell cycle and cardiac hypertrophy. In addition, the heart of the preeclamptic mice revealed cardiac hypertrophy associated with histological anomalies. Bioinformatics comparison of the networks of modified genes in the endothelial cells of the preeclamptic mice and HUVECs exposed to plasma from preeclamptic women identified striking similarities. The cardiovascular alterations in the pregnant mice are comparable to those endured by the cardiovascular system of preeclamptic women. The STOX1 mice could help to better understand the endothelial dysfunction in the context of preeclampsia and guide the search for efficient therapies able to protect the maternal endothelium during the disease and its aftermath.

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.

Objective To test plasma levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) in patients with high-grade carotid stenosis according to plaque histology. Methods This cross-sectional single-centre study included patients with ≥70% North American Symptomatic Carotid Endarterectomy Trial (NASCET) carotid stenosis, who were treated surgically. Serum Lp-PLA2 and high-sensitivity C-reactive protein (hs-CRP) were determined on the day of surgery. Histopathological analysis classified carotid plaque as stable or unstable, according to AHA classification. Results Of the 42 patients (mean age 70.4 ± 10.5 years; 67% men), neurological symptoms were present in 16 (38%). Unstable plaques were found in 23 (55%). Median plasma level of Lp-PLA2 was significantly higher in patients with unstable plaque compared to those with stable plaque (222.4 (174.9–437.5) interquartile range (IQR) 63.5 vs. 211.1 (174.9–270.6) IQR 37.2 ng ml−1; p = 0.02). Moreover, median Lp-PLA2 level were higher in asymptomatic patients with unstable plaque (226.8 ng ml−1 (174.9–437.5) IQR 76.8) vs. stable plaque (206.9 ng ml−1 (174.9–270.6) IQR 33.7; p = 0.16). Logistic regression showed that only the neurological symptoms (OR = 30.9 (3.7–244.6); p

Background: Mast cells participate in immune defense and allergic disease. At baseline, serum tryptase levels primarily reflect mast cell burden, while mast cell degranulation leads to granule tryptase release, which may be detectable as a transitory elevation of serum tryptase levels. Thus, mast cell burden and mast cell activity are reflected by serum tryptase levels, but reports are scarce in infants under 1 yr. We aimed at defining levels of total serum tryptase levels in this population. Methods: Total serum tryptase levels (ImmunoCAP; Phadia) were measured in 372 sera from infants younger than 1 yr. Two hundred and forty-two sera came from non-atopic, non-allergic infants in good condition, who had blood drawn for routine follow-up or diagnosis of illnesses that are not known to induce changes in serum tryptase levels. Seventy-two sera were from atopic and/or allergic infants, and

Les retards de croissance intra-uterins constituent des complications frequentes de la grossesse (3-5 %), caracterisees par une rupture de la courbe de croissance des foetus in utero. Dans les cas les plus graves le RCIU entraine une souffrance fœtale chronique, qui en fait la troisieme cause de letalite apres la prematurite et les malformations. Dans de rares cas, le retard de croissance a ete associe a des maladies impliquant l'empreinte genetique. De nombreux travaux se sont focalises sur ce point probablement a la suite de l'identification des effets de l'invalidation du gene soumis a empreinte IGF2 au debut des annees 1990. Independamment de l'empreinte, le lien de cause a effet entre mutation d'un gene particulier et RCIU n'a ete demontre que dans de tres rares cas et en general dans le contexte de syndromes complexes. C'est le cas des mutations de la culline 7 dans le syndrome dit «3M». L'heterogeneite evidente du RCIUprovient de sa definition clinique extremement vague, et necessitant des subdivisions. On peut par exemple distinguer des causes «endogenes » liees a des defauts de genes impliques dans le developpement foeto-placentaire, et des causes vasculaires induites par un dysfonctionnement placentaire, comme dans le defaut trophique induit par la preeclampsie. Cette derniere categorie de «RCIU vasculaires » est elle-meme caracterisee par une tres grande heterogeneite. Un axe de recherche important part neanmoins de l'hypothese que les consequences physiologiques du RCIU pourraient presenter des tendances generales. Ces tendances peuvent etre analysees sur le placenta, mais aussi sur des organes perennes de l'individu, comme les reins, le foie, le cerveau, etc. La perennisation des alterations nutritionnelles de la grossesse pourrait passer par des modifications « memorisables» par les cellules, en particulier par exemple par l'intermediaire d'un tissu commun a tous les organes: l'endothelium vasculaire. Les mecanismes qui permettent la transmission de l'information, la memorisation d'un stress precoce sont materialises dans la chromatine par des mecanismes dits « epigenetiques ». Les modifications epigenetiques sont heritables mais ne modifient pas la sequence de l'ADN. On ne parle pas de mutations, mais d'epimutations. Elles sont realisees par trois mecanismes complementaires: des modifications chimiques de la molecule d'ADN (methylation des cytosines dans les sequences CG), des modifications chimiques des histones (influant sur la structure de la chromatine, son etat « ouvert », transcriptionnellement actif, ou « ferme », et des ARNs non codants capables de bloquer l'expression de genes de facon ciblee). Le RCIU peut etre induit experimentalement par le regime alimentaire dans des modeles animaux (revue exhaustive dans Mc MILLEN et ROBINSON, Physiol Reviews, 2005). C'est ce que nous avons realise chez le rat par restriction protidique pendant la grossesse. Nous avons ensuite analyse les alterations trasncriptomiques dans cinq organes cibles: le placenta, le rein, le cœur, le foie et le poumon. L'analyse approfondie des alterations placentaires a suggere l'implication du gene Pdx1 comme coordinateur majeur des alterations expressionnelles placentaires, en parallele avec celles de nombreuses proteines a doigt de zinc. L'analyse comparee avec l'humain a revele qu'une proportion elevee de facteurs coordonnant les alterations transcriptomiques est modifiee comme chez le rat, renforcant l'idee d'une unite dans les alterations placentaires (BUFFAT et al., 2007a). L'analyse des effets de PDX1 se poursuit dans un modele cellulaire (GASCOIN-LACHAMBRE et al., en preparation). Parmi les acteurs reveles par des approches globales ou ciblees independantes, on retrouve une famille de 7 proteines appelees cullines. En particulier, la culline 4B et la culline 7 semblent alterees au niveau transcriptionnel par le RCIU, chez l'homme comme chez les rongeurs. Nous avons recemment montre que le RCIU induit des modifications subtiles de l'epissage de ces genes, tout en alterant leur regulation expressionnelle, et leur marquage epigenetique au niveau de sequences CG specifiques. Les cullines sont impliquees dans l'echafaudage de proteines cytoplasmiques structurant la cellule, ainsi que dans l'acheminement de proteines specifiques vers le proteasome. Ce sont donc des acteurs importants de la physiologie et de l'homeostasie cellulaire, qui pourraient donc temporiser les effets du RCIU, et donc etre systematiquement activees dans cette pathologie. En ce qui concerne les alterations des organes induites chez les fœtus par le RCIU, nous les avons analysees en detail dans le cas du rein. Nous avons pu montrer une augmentation massive de genes impliques dans la coagulation et l'activation du complement dans cet organe, ce qui est correle a la diminution du nombre de glomerules et donc globalement a un fonctionnement probablement moins efficace (BUFFAT et al., 2007b). L'analyse transcriptomique globale des cinq organes analyses dans le modele rat conduit a l'idee que le placenta et le rein servent de « filtres » a deux niveaux entre la mere et le fœtus, car ces deux organes ont des alterations expressionnelles correlees tandis que les trois autres organes fœtaux analyses (cœur,foie,poumon) sont correles entre eux. L'etude des effets a long terme sur les organes perennes suite au RCIU est un sujet encore neuf, qui pose de tres nombreuses questions en termes de regulation, d'adaptation des organes a un environnement agressif. La meilleure comprehension des effets du RCIU pourrait permettre par des apports nutritionnels cibles, d'ameliorer le pronostic a court et a long terme.

Various antenatal events impair nephrogenesis in humans as well as in several animal models. The consecutive low nephron endowment may contribute to an increased risk for cardiovascular and renal diseases in adulthood. However, little knowledge is available on the influence of the postnatal environment, especially nutrition, on nephrogenesis. Moreover, the consequences of early postnatal nutrition in late adulthood are not clear. We used a model of early postnatal overfeeding (OF) induced by reduction of litter size (3 pups/litter) in rats. Systolic blood pressure (SBP; plethysmography), glomerular filtration rate (clearance of creatinine), glomerular number and volume, and glomerulosclerosis were evaluated in 22-mo-old aging offspring. Early postnatal OF was associated with increased weight gain during the suckling period (+40%, P < 0.01) and a 20% increase in glomerular number ( P < 0.05). However, an increase in SBP at 12 mo by an average of 18 mmHg and an increase in proteinuria (2.6-fold) and glomerulosclerosis at 22 mo of age were observed in OF male offspring compared with controls. In conclusion, early postnatal OF in the rat enhances postnatal nephrogenesis, but elevated blood pressure and glomerulosclerosis are still observed in male adults. Factors other than glomerular number reduction are likely to contribute to the arterial hypertension induced by early postnatal OF.

In this study, low birth weight was induced in rats by feeding the dams with a low-protein diet during pregnancy. Kidneys from the fetuses at the end of gestation were collected and showed a reduction in overall and relative weight, in parallel with other tissues (heart and liver). This reduction was associated with a reduction in nephrons number. To better understand the molecular basis of this observation, a transcriptome analysis contrasting kidneys from control and protein-deprived rats was performed, using a platform based upon long isothermic oligonucleotides, strengthening the robustness of the results. We could identify over 1800 transcripts modified more than twice (772 induced and 1040 repressed). Genes of either category were automatically classified according to functional criteria, making it possible to bring to light a large cluster of genes involved in coagulation and complement cascades. The promoters of the most induced and most repressed genes were contrasted for their composition in putative transcription factor binding sites, suggesting an overrepresentation of the AP1R binding site, together with the transcription induction of factors actually binding to this site in the set of induced genes. The induction of coagulation cascades in the kidney of low-birth-weight rats provides a putative rationale for explaining thrombo-endothelial disorders also observed in intrauterine growth-restricted human newborns. These alterations in the kidneys have been reported as a probable cause for cardiovascular diseases in the adult.

Gs alpha, the alpha-subunit of the heterotrimeric GTP-binding protein, is coded from the GNAS gene, which is imprinted in a tissue-specific manner. Gs alpha is paternally silenced in normal pituitary, but Gs alpha imprinting relaxation is found in some tumoral tissue. In addition, Gs alpha mRNA levels are high in some somatotroph adenomas not bearing the active Gs alpha mutant, the gsp oncogene. In this study, the impact of loss of imprinting on Gs alpha expression level and on tumoral phenotype has been investigated. We compared the expression and imprinting of 4 transcripts of GNAS locus (NESP55, XL alpha s, exon 1A, Gs alpha) of 60 somatotroph adenomas with those of 23 lactotroph adenomas. The paternal and maternal transcripts were quantified using allele-specific real-time PCR and FokI polymorphism. Moreover, the methylation of exon 1A DMR was analyzed. As is the case for the gsp oncogene, high Gs alpha expression in gsp- tumors was associated with smaller tumor size and better octreotide sensitivity. A strong imprinting relaxation (percentage of paternal Gs alpha expressionor=7.5%) was found only in gsp- tumors. The loss of Gs alpha imprinting was associated with a decrease in exon 1A mRNA expression. Unexpectedly, the methylation status of exon 1A DMR was not modified in relaxed tumors. Maternal Gs alpha mRNA level decreased with exon 1A level, and consequently the loss of Gs alpha imprinting did not induce the expected Gs alpha overexpression. Finally, XL alpha s mRNA level correlated with that of paternal Gs alpha and of NESP55 showing the complexity of gene regulation in the GNAS locus.

The virulence of Salmonella relies on the expression of effector proteins that the bacterium injects inside infected cells. Salmonella enters eukaryotic cells and resides in a vacuolar compartment on which a number of effector proteins such as SifA are found. SifA plays an essential role in Salmonella virulence. It is made of two distinct domains. The N-terminal domain of SifA interacts with the host protein SKIP. This interaction regulates vacuolar membrane dynamics. The C-terminal has a fold similar to other bacterial effector domains having a guanine nucleotide exchange factor activity. Although SifA interacts with RhoA, it does not stimulate the dissociation of GDP and the activation of this GTPase. Hence it remains unknown whether the C-terminal domain contributes to the function of SifA in virulence. We used a model of SKIP knockout mice to show that this protein mediates the host susceptibility to salmonellosis and to establish that SifA also contributes to Salmonella virulence independently of its interaction with SKIP. We establish that the C-terminal domain of SifA mediates this SKIP-independent contribution. Moreover, we show that the two domains of SifA are functionally linked and participate to the same signalling cascade that supports Salmonella virulence.

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.

Pregnancy is dependent on maternal–fetal tolerance that may be compromised because of infections or inflammation of the placenta. In this study, we examined whether the context of placental immune tolerance affected the functions of resident macrophages and if their functions were altered during chorioamnionitis, an infectious pathology of the placenta. Macrophages from at-term placentas expressed CD14, exhibited macrophage microbicidal functions, but were less inflammatory than monocyte-derived macrophages. Moreover, placental macrophages spontaneously matured into multinucleated giant cells (MGCs), a property not exhibited by monocyte-derived macrophages, and we detected MGCs of myeloid origin in placental tissue. Compared with placental macrophages, MGCs exhibited a specific phenotype and gene expression signature, consisting of increased cytoskeleton-associated gene expression along with depressed expression of inflammatory response genes. Furthermore, placental macrophages from patients with chorioamnionitis were unable to form MGCs, but this defect was partially corrected by incubating these placental macrophages with control trophoblast supernatants. MGCs formation likely serves to regulate their inflammatory and cytocidal activities in a context that imposes semiallograft acceptance and defense against pathogens.

Background About 1% of patients admitted to the Emergency Department (ED) have hypernatremia, a condition associated with a mortality rate of 20 to 60%. Management recommendations originate from intensive care unit studies, in which patients and medical diseases differ from those in ED. Methods We retrospectively studied clinical characteristics, treatments, and outcomes of severely hypernatremic patients in the ED and risk factors associated with death occurrence during hospitalization. Results During 2010, 85 cases of severe hypernatremia ≥150 mmol/l were admitted to ED. Hypernatremia occurred in frail patients: mean age 79.7 years, 55% institutionalized, 28% with dementia. Twenty four percent of patients died during hospitalization. Male gender and low mean blood pressure (MBP) were independently associated with death, as well as slow natremia correction speed, but not the severity of hyperosmolarity at admission. Infusion solute was inappropriate for 45% of patients with MBP

International audience; Objective: Low birth weight (LBW) is a risk factor for hypertension at adulthood. Endothelial progenitor cells (EPCs) dysfunction has been characterized in LBW neonates. We hypothesized that changes in soluble, plasma pro-or anti-angiogenic factors are associated with EPCs dysfunction and impaired angiogenesis in LBW neonates. Method: Venous umbilical cord blood was collected from 42 normal, term neonates and 75 LBW neonates. Cord blood endothelial colony forming cells (ECFC) from control patients were cultured in the presence of 10% of serum obtained from both groups. Results: The proliferation and the migration of ECFC were significantly reduced when cultured with 10% of serum of LBW neonates compared to serum of control neonates. Matrigel invasion assay was not significantly altered. Umbilical vein plasma VEGF concentration was significantly reduced in LBW neonates while that of sVEGFR and PF4 were significantly higher. Addition of VEGF corrected the inhibitory effect of LBW serum on normal ECFC proliferation. Conclusions: Serum obtained from LBW babies contains factors that exhibit an antiangiogenic effect on ECFC proliferation and migration. VEGF/sVEGF/PF4 pathway seems to be involved in the EPCs dysfunction in LBW neonates.

Preeclampsia is a pregnancy disorder characterized by hypertension and proteinuria. In preeclampsia, the placenta releases factors into the maternal circulation that cause a systemic endothelial dysfunction. Herein, we investigated the effects of plasma from women with preeclamptic and normal pregnancies on the transcriptome of an immortalized human umbilical vein endothelial cell line. The cells were exposed for 24 hours to preeclamptic or normal pregnancy plasma and their transcriptome was analyzed using Agilent microarrays. A total of 116 genes were found differentially expressed: 71 were up-regulated and 45 were down-regulated. In silico analysis revealed significant consistency and identified four functional categories of genes: mitosis and cell cycle progression, anti-apoptotic, fatty acid biosynthesis, and endoplasmic reticulum stress effectors. Moreover, several genes involved in vasoregulation and endothelial homeostasis showed modified expression, including EDN1, APLN, NOX4, and CBS. Promoter analysis detected, among the up-regulated genes, a significant overrepresentation of genes containing activation protein-1 regulatory sites. This correlated with down-regulation of JDP2, a gene encoding a repressor of activation protein-1. The role of JDP2 in the regulation of a subset of genes in the human umbilical vein endothelial cells was confirmed by siRNA inhibition. We characterized transcriptional changes induced by preeclamptic plasma on human umbilical vein endothelial cells, and identified, for the first time to our knowledge, JDP2 as a regulator of a subset of genes modified by preeclamptic plasma.

Cardiovascular diseases are one of the leading causes of mortality. Hypertension (HT) is one of the principal risk factors associated with death. Chronic kidney disease (CKD), which is probably underestimated, increases the risk and the severity of adverse cardiovascular events. It is now recognized that low birth weight is a risk factor for these diseases, and this relationship is amplified by a rapid catch-up growth or overfeeding during infancy or childhood. The pathophysiological and molecular mechanisms involved in the “early programming” of CKD are multiple and partially understood. It has been proposed that the developmental programming of arterial hypertension and chronic kidney disease is related to a reduced nephron endowment. However, this mechanism is still discussed. This review discusses the complex relationship between birth weight and nephron endowment and how early growth and nutrition influence long term HT and CKD. We hypothesize that fetal environment reduces moderately the nephron number which appears insufficient by itself to induce long term diseases. Reduced nephron number constitutes a “factor of vulnerability” when additional factors, in particular a rapid postnatal growth or overfeeding, promote the early onset of diseases through a complex combination of various pathophysiological pathways.