Streptococcus agalactiae (group B streptococcus; GBS) is a normal constituent of the intestinal microflora and the major cause of human neonatal meningitis. A single clone, GBS ST-17, is strongly ...associated with a deadly form of the infection called late-onset disease (LOD), which is characterized by meningitis in infants after the first week of life. The pathophysiology of LOD remains poorly understood, but our epidemiological and histopathological results point to an oral route of infection. Here, we identify a novel ST-17-specific surface-anchored protein that we call hypervirulent GBS adhesin (HvgA), and demonstrate that its expression is required for GBS hypervirulence. GBS strains that express HvgA adhered more efficiently to intestinal epithelial cells, choroid plexus epithelial cells, and microvascular endothelial cells that constitute the blood-brain barrier (BBB), than did strains that do not express HvgA. Heterologous expression of HvgA in nonadhesive bacteria conferred the ability to adhere to intestinal barrier and BBB-constituting cells. In orally inoculated mice, HvgA was required for intestinal colonization and translocation across the intestinal barrier and the BBB, leading to meningitis. In conclusion, HvgA is a critical virulence trait of GBS in the neonatal context and stands as a promising target for the development of novel diagnostic and antibacterial strategies.
Mutations in genes encoding components of the intraflagellar transport (IFT) complexes have previously been associated with a spectrum of diseases collectively termed ciliopathies. Ciliopathies ...relate to defects in the formation or function of the cilium, a sensory or motile organelle present on the surface of most cell types. IFT52 is a key component of the IFT-B complex and ensures the interaction of the two subcomplexes, IFT-B1 and IFT-B2. Here, we report novel IFT52 biallelic mutations in cases with a short-rib thoracic dysplasia (SRTD) or a congenital anomaly of kidney and urinary tract (CAKUT). Combining in vitro and in vivo studies in zebrafish, we showed that SRTD-associated missense mutation impairs IFT-B complex assembly and IFT-B2 ciliary localization, resulting in decreased cilia length. In comparison, CAKUT-associated missense mutation has a mild pathogenicity, thus explaining the lack of skeletal defects in CAKUT case. In parallel, we demonstrated that the previously reported homozygous nonsense IFT52 mutation associated with Sensenbrenner syndrome Girisha et al. (2016) A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy. Clin. Genet., 90, 536-539 leads to exon skipping and results in a partially functional protein. Finally, our work uncovered a novel role for IFT52 in microtubule network regulation. We showed that IFT52 interacts and partially co-localized with centrin at the distal end of centrioles where it is involved in its recruitment and/or maintenance. Alteration of this function likely contributes to centriole splitting observed in Ift52-/- cells. Altogether, our findings allow a better comprehensive genotype-phenotype correlation among IFT52-related cases and revealed a novel, extra-ciliary role for IFT52, i.e. disruption may contribute to pathophysiological mechanisms.
Morbid obesity is a risk factor of nonalcoholic steatohepatitis (NASH). Obstructive sleep apnea (OSA) could also be an independent risk factor for elevated liver enzymes and NASH. The relationships ...between liver injuries and OSA in morbidly obese patients requiring bariatric surgery were studied prospectively.
Every consecutive morbidly obese patient (BMI > or =40 kg/m2 or > or =35 kg/m2 with severe comorbidities) requiring bariatric surgery was included between January 2003 and October 2004. Polygraphic recording, serum aminotransferases (ALT, AST), gamma-glutamyltransferase (GGT) and liver biopsy were systematically performed. OSA was present when the apnea-hypopnea index (AHI) was >10/h.
62 patients (54 F; age 38.5 +/- 11.0 (SD) yrs; BMI 47.8 +/- 8.4 kg/m2) were included. Liver enzymes (AST, ALT or GGT) were increased in 46.6%. NASH was present in 34.4% and OSA in 84.7%. Patients with OSA were significantly older (P = 0.015) and had a higher BMI (P = 0.003). In multivariate analysis, risk factors for elevated liver enzymes were the presence of OSA and male sex. The presence of NASH was similar in patients with or without OSA (32.7% vs 44.4% of patients, P = 0.76).
In this cohort of morbidly obese patients requiring bariatric surgery, one-third of patients had NASH, a prevalence similar to previous studies. OSA was found to be a risk factor for elevated liver enzymes but not for NASH.
In patients with morbid obesity selected for bariatric surgery, previous studies have shown a prevalence of NASH varying from 2.6% to 91%. The prevalence of NASH and extensive fibrosis were studied ...in a prospective cohort of patients with morbid obesity requiring bariatric surgery, to identify predictive factors of NASH.
From July 01 to Sept 02, every patient requiring bariatric surgery had a liver biopsy. The diagnosis of NASH was established using Lee's criteria.
92 patients (85 women, age 38 +/- SEM 11 years) were analyzed. Mean BMI was 45.7 +/- 5.1 kg/m2. 35 patients had lobular inflammation. 9 patients had steatosis associated with lobular necrotic and inflammatory foci and ballooning degeneration or pericellular fibrosis. No cirrhosis or extensive fibrosis was evidenced. The prevalence of NASH in this population was 9.8%. Waist/hips ratio and BMI were independent predictors of lobular inflammation, but only BMI was an independent factor of NASH in multivariate analysis.
In this prospective cohort of patients at bariatric surgery, the prevalence of NASH was 9.8%. BMI was the only predictive factor for NASH.
Background
With the increasing prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) has become a major cause of liver diseases. Small intestinal bacterial overgrowth (SIBO) could be ...related to NAFLD. Our aim was to determine the prevalence of SIBO and its relationship with liver lesions in morbidly obese patients.
Methods
A glucose hydrogen (H
2
) breath test (positive if fasting breath H
2
concentration > 20 ppm and/or an increase of > 10 ppm over baseline within the first 2 h) was performed in obese patients referred for bariatric surgery (body mass index BMI > 40 kg/m
2
or > 35 in association with comorbidities) and in healthy non-obese subjects. In obese patients, a surgical liver biopsy was performed.
Results
One hundred and forty-six patients (129 women, age mean±SE: 40.7 ± 11.4 years) were prospectively included in the study. The mean BMI was 46.1±6.4 kg/m
2
. A liver biopsy was available in 137 patients and a breath test in 136. The frequency of positive breath tests was higher in obese patients (24/136, 17.1%) than in healthy subjects (1/40, 2.5%;
P
=0.031). In the univariate analysis, SIBO was not associated with clinical variables, but tended to be associated with more frequent severe hepatic steatosis (26.3 vs. 10.3%,
P
=0.127), whereas the frequency of sinusoidal or portal fibrosis, lobular necrosis and non-alcoholic steatohepatitis (NASH) were not different. In the multivariate analysis, SIBO (
P
=0.005) and the presence of a metabolic syndrome (
P
=0.006) were independent factors of severe hepatic steatosis.
Conclusion
In morbidly obese patients, bacterial overgrowth prevalence is higher than in healthy subjects and is associated with severe hepatic steatosis.
Objective
Neural tube defects (NTDs) are one of the most common congenital anomalies caused by a complex interaction of many genetic and environmental factors. In about 10% of cases, NTDs are ...associated with genetic syndromes or chromosomal anomalies. Among these, SOX3 duplication has been reported in some isolated cases. The phenotype associated with this microduplication is variable and includes myelomeningocele (MMC) in both sexes as well as hypopituitarism and cognitive impairment in males. In order to determine the prevalence of this anomaly in fetuses with MMC, a retrospective cohort of fetuses with MMC was analyzed by quantitative PCR (qPCR) targeting SOX3 locus.
Methods
The detection of an SOX3 microduplication by chromosomal microarray analysis (CMA) in two female fetuses with MMC prompted us to analyze retrospectively by qPCR this gene in a cohort of 53 fetuses with MMC.
Results
In addition to our two initial cases, one fetus harboring an Xq27.1q28 duplication that encompasses the SOX3 gene was detected.
Conclusion
Our data demonstrate that SOX3 duplication is a genomic imbalance involved in the pathogenesis of NTDs. In addition, our survey highlights the importance of CMA testing in fetuses with NTDs to enable genetic counseling upstream of any considerations of in utero fetal surgery.
What is already known about this topic?
In males, SOX3 genetic alterations are associated with X‐linked hypopituitarism and cognitive impairment.
More recently, Xq27.1 microduplications involving SOX3 gene have been reported in some isolated cases of MMC in both sexes.
What does this study add?
SOX3 microduplication is a genomic imbalance reported in a number of fetuses with MMC.
Our survey highlights the importance of investigating this anomaly using a broad genomic scan such as CMA that will detect SOX3 duplication and other CNVs in fetuses with NTDs for genetic counseling.
Thrombocytopenia‐absent radius (TAR) syndrome is characterized by radial defect and neonatal thrombocytopenia. It is caused by biallelic variants of RBM8A gene (1q21.1) with the association of a null ...allele and a hypomorphic noncoding variant. RBM8A encodes Y14, a core protein of the exon junction complex involved in messenger RNA maturation. To date, only two hypomorphic variants have been identified. We report on a cohort of 26 patients affected with TAR syndrome and carrying biallelic variants in RBM8A. Half patients carried a 1q21.1 deletion and one of the two known hypomorphic variants. Four novel noncoding variants of RBM8A were identified in the remaining patients. We developed experimental models enabling their functional characterization in vitro. Two variants, located respectively in the 5′‐untranslated region (5′‐UTR) and 3′‐UTR regions, are responsible for a diminished expression whereas two intronic variants alter splicing. Our results bring new insights into the molecular knowledge of TAR syndrome and enabled us to propose genetic counseling for patients' families.
Background:
White adipose tissue (WAT) can rapidly expand or regress under different nutritional conditions. The role of angiogenesis in the expandability of human adipose tissue is established. ...However, whether sc and omental WAT (scWAT and oWAT) angiogenesis could influence fat distribution and metabolic diseases is not known.
Aim:
The aim of this study was to analyze whether the capacity of angiogenesis in scWAT and oWAT correlates with fat accumulation and fat loss, fat distribution, adipocyte hypertrophy, and metabolic disorders in obese subjects.
Methods:
Samples of scWAT and oWAT were obtained during bariatric surgery in 29 obese nondiabetic subjects. Vascular density and inflammatory infiltrate were analyzed by immunohistochemistry, and expression of angiogenic genes was analyzed by quantitative PCR. These parameters were correlated with anthropometric and metabolic parameters.
Results:
Vascular density of scWAT correlated positively with body mass index, whereas vascular density of the oWAT correlated with waist circumference. There was no correlation of markers of angiogenesis and metabolic disorders. The number of vessels per adipocyte and the expression level of receptor 2 of vascular endothelial growth factor correlated with adipocyte area in scWAT and oWAT. Finally, weight loss after bariatric surgery correlated negatively with adipocyte hypertrophy and vascular density and positively with inflammation and angiogenesis of WAT.
Conclusion:
Angiogenesis may influence WAT expansion and plasticity but does not appear to be involved in the development of insulin resistance in subjects with severe obesity.
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