Maternally acquired genotoxic Escherichia coli alters offspring’s intestinal homeostasis

The neonatal gut is rapidly colonized by a newly dominant group of commensal Escherichia coli strains among which a large proportion produces a genotoxin called colibactin. In order to analyze the short- and long-term effects resulting from such evolution, we developed a rat model mimicking the natural transmission of E. coli from mothers to neonates. Genotoxic and non-genotoxic E. coli strains were equally transmitted to the offspring and stably colonized the gut across generations. DNA damage was only detected in neonates colonized with genotoxic E. coli strains. Signs of genotoxic stress such as anaphase bridges, higher occurrence of crypt fission and accelerated renewal of the mature epithelium were detected at adulthood. In addition, we observed alterations of secretory cell populations and gut epithelial barrier. Our findings illustrate how critical is the genotype of E. coli strains acquired at birth for gut homeostasis at adulthood.     

Clinical subtypes in Parkinson’s disease: the impact of MAPT haplotypes

The H1 haplotype of the MAPT gene influences the risk of PD and has been related to the development of PDD. We evaluated the influence of MAPT haplotypes on the expression of motor features in PD patients. We genotyped, for the MAPT haplotypes H1 and H2, a sample of 181 PD patients with distinct clinical subtypes: tremor dominant and non-tremor dominant (NTD). Our results indicate that the MAPT haplotypes contribute to the expression of motor features of PD. H1 homozygous PD patients are significantly more likely to present a NTD phenotype, a clinical subtype characterized by widespread pathological degeneration, than H2 carriers.     

Is Frailty a Predictor of Outcomes in Elderly Inpatients with Acute Kidney Injury? A Prospective Cohort Study

Background

Frailty and acute kidney injury are independently associated with an increased risk of morbidity and mortality. The degree of frailty can be assessed by the Clinical Frailty Score (CFS). This study assessed whether an individual's CFS was associated with acute kidney injury in acute elderly medical admissions and recorded the short-term outcomes.

Relative contribution of Ki-ras gene analysis and brush cytology during ERCP for the diagnosis of biliary and pancreatic diseases

Background: Ki-ras mutation analysis from material collected during ERCP has been claimed to improve the diagnosis of pancreatic and bile duct carcinomas as compared with conventional cytology. Our aim was to study the relative contribution of both Ki-ras analysis and brush cytology in patients with a significant stricture at ERCP. Methods: Brushings were collected in duplicate for both analyses in 142 patients in whom a definitive diagnosis was obtained by histology or a minimal follow-up of 6 months. Results: For pancreatic strictures, sensitivity, specificity, and accuracy of Ki-ras analysis vs. cytology in detecting malignancy were 81% vs. 66%, 72% vs. 100%, and 70% vs. 74%, respectively. For biliary strictures, they were 25% vs. 42%, 100% vs. 100%, and 35% vs. 43%, respectively. The combination of the two methods only marginally increased their sensitivity and accuracy in both types of strictures. Conclusion: Ki-ras analysis is a sensitive method for diagnosing pancreatic but not biliary carcinoma. However, its specificity is lowered by a high frequency of Ki-ras mutations in patients with chronic pancreatitis (25%) who did not manifest cancer development within a 6-month follow-up period. In pancreatic duct strictures, brush cytology appears to be more specific in detecting malignancy; specificity for Ki-ras and cytology are equivalent for the diagnosis of malignant bile duct strictures. Therefore, making a clinical decision on the sole basis of Ki-ras analysis is probably not justified in the majority of the cases. (Gastrointest Endosc 1998;47:479-85.)     

Mosaicism for Dominant Collagen 6 Mutations as a Cause for Intrafamilial Phenotypic Variability

Collagen 6‐related dystrophies and myopathies (COL6‐RD) are a group of disorders that form a wide phenotypic spectrum, ranging from severe Ullrich congenital muscular dystrophy, intermediate phenotypes, to the milder Bethlem myopathy. Both inter‐ and intrafamilial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL6‐RD families with marked intergenerational phenotypic heterogeneity. This variable expression seemingly masquerades as anticipation is due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. We also present an additional fifth simplex patient identified as a mosaic carrier. Parental mosaicism was confirmed in the four families through quantitative analysis of the ratio of mutant versus wild‐type allele (COL6A1, COL6A2, and COL6A3) in genomic DNA from various tissues, including blood, dermal fibroblasts, and saliva. Consistent with somatic mosaicism, parental samples had lower ratios of mutant versus wild‐type allele compared with the fully heterozygote offspring. However, there was notable variability of the mutant allele levels between tissues tested, ranging from 16% (saliva) to 43% (fibroblasts) in one mosaic father. This is the first report demonstrating mosaicism as a cause of intrafamilial/intergenerational variability of COL6‐RD, and suggests that sporadic and parental mosaicism may be more common than previously suspected.     

Deep analysis of immune response and metabolic signature in children with food protein induced enterocolitis to cow’s milk

Background

Food Protein-Induced Enterocolitis Syndrome (FPIES) is considered to be a non-IgE mediated food allergy. However, its pathogenesis remains poorly understood and biomarkers are lacking. We aimed to perform in-depth characterization of humoral and cellular immune responses in children with cow’s milk (CM)-FPIES and investigated whether there is a FPIES metabolomic signature.

Methods

Children with CM-FPIES and control subjects with an IgE-mediated CM allergy (IgE-CMA), both avoiding CM, were recruited on the day of an oral food challenge. Blood samples were collected before the challenge. Total and specific levels of IgE, IgG1-4, IgA, IgM and IgD to various whey and casein allergens and to their gastroduodenal digestion products were measured in plasma, using plasma from CM-tolerant peanut allergic patients (IgE-PA, not avoiding CM) as additional controls. Cytokine secretion and cellular proliferation were analyzed after stimulation of PBMC with different CM allergens. Metabolomic profiles were obtained for plasma samples using liquid chromatography coupled to high-resolution mass spectrometry.

Results

Nine children with CM-FPIES and 12 control subjects (6 IgE-CMA and 6 IgE-PA) were included. In children with CM-FPIES, total Ig concentrations were lower than in control subjects, specific Ig against CM components were weak to undetectable, and no specific IgE against CM digestion products were detected. Moreover, in CM-FPIES patients, we did not find any Th cell proliferation or associated cytokine secretion after allergen reactivation, whereas such responses were clearly found in children with IgE-CMA. Plasma metabolic profiles were different between CM allergic patients, with significantly lower concentrations of various fatty acids and higher concentrations of primary metabolites such as amino acids in CM-FPIES compared to IgE-CMA patients.

Conclusions

In CM-FPIES, both humoral and cellular specific immune responses are weak or absent, and this is not related to CM avoidance. A metabolomic signature was identified in patients with CM-FPIES that may be useful for the diagnosis and management of this disease.