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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)., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Vitamin 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., Methods: Cord 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., Results: The 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 FiO 2 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)., Conclusion: Low 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Papalia, Samonini, Buffat, Gras, des Robert, Landrier, Pauly and Boubred.)

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

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.

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 (eight CCD- and four 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 nine, as expected, but vomiting of bile was observed for three 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., (© 2020 John Wiley & Sons Ltd.)

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 < 0.01). It was also positively associated with pre-prandial insulin and with HOMA (Homeostasis Model Assessment) insulin resistance. Leptin, leptin-adiponectin ratio and insulin correlated with lean mass, fat mass and percent fat (P < 0.0001). In conclusion, high leptin in early adulthood was associated with both low weight at age 2 years and insulin resistance. We speculate that high leptin is developmentally programmed and can contribute to the association between low weight in early infancy and increased cardio-metabolic risk in adulthood in healthy subjects.

The intracellular bacterium Coxiella burnetii is responsible for Q fever, an infectious disease that increases the risk of abortion, preterm labor, and stillbirth in pregnant women. It has been shown that C. burnetii replicates in BeWo trophoblast cell line and inhibits the activation and maturation of decidual dendritic cells. Although tissue macrophages are known to be targeted by C. burnetii , no studies have investigated the interplay between placental macrophages and C. burnetii . Here, CD14 + macrophages from 46 full-term placentas were isolated by positive selection. They consisted of a mixed population of maternal and fetal origin as shown by genotype analysis. We showed that C. burnetii organisms infected placental macrophages after 4 h. When these infected macrophages were incubated for an additional 9-day culture, they completely eliminated organisms as shown by quantitative PCR. The ability of placental macrophages to form multinucleated giant cells was not affected by C. burnetii infection. The transcriptional immune response of placental macrophages to C. burnetii was investigated using quantitative real-time RT-PCR on 8 inflammatory and 10 immunoregulatory genes. C. burnetii clearly induced an inflammatory profile. Interestingly, the production by placental macrophages of interferon-γ, a cytokine known to be involved in efficient immune responses, was dramatically increased in response to C. burnetii . In addition, a clear correlation between interferon-γ production and C. burnetii elimination was found, suggesting that macrophages from full-term placentas eliminate C. burnetii under the control of an autocrine production of interferon-γ., (Copyright © 2019 Mezouar, Benammar, Boumaza, Diallo, Chartier, Buffat, Boudjarane, Halfon, Katsogiannou and Mege.)

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&#95;004174.3:c.1039G > A, NP&#95;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., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objective: We sought to determine whether the early luteal serum progesterone (P4) level predicts the success of IVF treatment with oral dydrogesterone for luteal support., Method: This 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., Results: ROC 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)., Conclusions: Our 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., Competing Interests: The authors have declared that no competing interests exist.

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., Competing Interests: The authors declare that they have no conflict of interest.

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 N ω -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.

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.

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: There are several possible malaria prevention strategies for travellers. In Switzerland, chemoprophylaxis (CP) is recommended for persons visiting areas highly endemic for malaria and stand-by emergency treatment (SBET) for areas with moderate to low risk., Objective: To describe the type of malaria prevention prescribed to travel clinic attendees with a specific focus on changes over time following adaptation of recommendations., Methods: All pre-travel first consultation data recorded between November 2002 and December 2012 were included. Country-specific malaria preventive recommendations provided and medicines prescribed over time were analysed., Results: In total, 64 858 client-trips were recorded. 91% of travellers planned to visit a malaria endemic country. Among those clients, 42% were prescribed an antimalarial medicine as CP only, 36% as SBET only, and 3% both. Between 2002 and 2012, there was a 16% drop of CP prescription ( P  < 0.001) and a 21% increase of SBET prescription ( P  < 0.001). Among travellers receiving CP, the proportion of those prescribed mefloquine dropped from 82% in 2002 to 46% in 2012 while those prescribed atovaquone-proguanil (AP) increased from 7% to 39%. For those prescribed SBET, the proportion dropped from 46% to 30% for AP and increased from 2% to 61% for artemether-lumefantrine. CP prescription for travellers to India fell from 62% to 5% and SBET prescription increased from 40% to 88% after the change of recommendation from CP to SBET in 2005 for this country. Comparatively, CP prescription for travellers to Senegal, for which no change of recommendation occurred, remained relatively stable between 88% in 2002 and 89% in 2012., Conclusion: This study shows the considerable decline of antimalarial prescription for chemoprophylaxis that occurred over the 10-year period in favour of SBET., (© International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)