Epithelial‐microbial crosstalk in polymeric Ig receptor deficient mice

Innate and adaptive mucosal defense mechanisms ensure a homeostatic relationship with the large and complex mutualistic gut microbiota. Dimeric IgA and pentameric IgM are transported across the intestinal epithelium via the epithelial polymeric Ig receptor (pIgR) and provide a significant portion of the first line of natural or adaptive antibody‐mediated immune defense of the intestinal mucosa. We found that colonic epithelial cells from pIgR KO mice differentially expressed (more than twofold change) more than 200 genes compared with cells from WT mice, and upregulated the expression of antimicrobial peptides in a commensal‐dependent manner. Detailed profiling of microbial communities based on 16S rRNA genes revealed differences in the commensal microbiota between pIgR KO and WT mice. Furthermore, we found that pIgR KO mice showed increased susceptibility to dextran sulfate sodium‐induced colitis, and that this was driven by their conventional intestinal microbiota. Thus, in the absence of pIgR, the stability of the commensal microbiota is disturbed, gut homeostasis is compromised, and the outcome of colitis is significantly worsened.     

Physiological correlates of performance. Case study of a world-class rower

This report describes the changes in physiological capacity of a heavy-weight rower who obtained seven medals in World Championships and Olympic Games. The investigation was carried out over the last 6 years of the rower’s international competition career in comparison with peer champions, and the following 4 years. Over the first period, maximal oxygen uptake () remained above 6 l min⁻¹ which is an outstanding value. The training load measured over the last 18 months of the period increased from 119 to 142 km wk⁻¹ of rowing. Four years after the international competition period, had only declined by 3.6% although the training load had declined by 35%. These data suggest that the ability of this rower to compete at top level for years was related to ability to maintain an outstanding . Gross efficiency and ability to rely on anaerobic glycolysis did not emerge as relevant factors.     

A CXCL2 tandem repeat promoter polymorphism is associated with susceptibility to severe sepsis in the Spanish population

Sepsis describes a complex clinical syndrome resulting from a systemic inflammatory response to bacteria. Functional studies in animal models of sepsis have catalogued CXCL2 as a candidate gene for the development of the disease. We hypothesized that CXCL2 polymorphisms may confer susceptibility to sepsis and performed an association study using 178 severe sepsis patients and 357 population-based controls. We selected two polymorphisms from the promoter of the gene (-437A/G and -665(AC)n), and analyzed whether haplotypes or single loci were associated with disease susceptibility. An overall test of differentiation showed that haplotype distribution was not different between cases and controls (P=0.407). Likewise, -437A/G was not associated with disease susceptibility (heterozygote odds ratio (OR) 0.68 (0.47-1.03), and homozygote OR 0.86 (0.56-1.32); P=0.706). However, for the -665(AC)n, we found that the 24+/-1 repeat alleles were associated with susceptibility (heterozygote OR 2.82 (1.10-7.24), and homozygote OR 3.65 (1.41-9.43); P=0.0006). This association remained significant when using a multiple logistic regression analysis (OR 2.23; 95% confidence intervals (95% CI) 1.22-4.03; P=0.008) and after a genomic control adjustment (P=0.017). Although replicate studies and functional assays are needed, these results suggest that CXCL2 gene variants may contribute to the development of severe sepsis.     

Deletion 18q21.2q21.32 involving TCF4 in a boy diagnosed by CGH-array

We report on a 12 year-old boy presenting with severe developmental delay, dysmorphic features, limb anomalies, growth retardation, hypoplastic vermis and corpus callosum. Conventional and high-resolution cytogenetic analyses were normal. CGH-array allowed characterisation of a de novo 6.2 Mb 18q21.2q21.32 interstitial deletion involving TCF4, the recently identified gene responsible for Pitt-Hopkins syndrome (PHS). No tachypnoea-apnoea paroxysms were observed. We discuss the dysmorphic features particularly involving the ears, which might be helpful towards PHS and 18q21 deletion diagnosis.     

Intraoperative fluorescence imaging of peritoneal dissemination of ovarian carcinomas. A preclinical study

Objective

Improvement of the management and outcome of ovarian cancers may require intraoperative detection and therapeutic intervention to treat minimal residual disease after complete surgery. The aim of this study was to validate the importance of fluorescence in the peroperative detection of human ovarian adenocarcinoma cells and to determine its efficiency in detecting infra millimetric tumor metastases.

Methods

A fluorescent RAFT-(cRGD)₄ tracer molecule (AngioStamp®) was used. The tracer is based on a biomarker, which has a very high affinity for the α_vβ₃ integrin, which is overexpressed in a large ratio of cancer cells and neovessel endothelial cells during angiogenesis. Infrared fluorescence was visualized with Fluobeam®, an open fluorescent imaging system that could potentially be used in peroperative conditions in the future.

Results

This novel technique allowed the specific detection of residual tumor deposits and inframillimetric metastases, smaller than 500 μm, which were resected under fluorescent guidance. AngioStamp® was able to detect all types of cell lines, derived from human ovarian adenocarcinomas, before or after chemotherapy treatment in animals. The effectiveness of AngioStamp® for the detection of various human ovarian adenocarcinomas was assessed on 10 different fragments of tumor, implanted subcutaneously in nude mice. All implanted tumor fragments were visualized by AngioStamp®.

Conclusions

The high rate of recurrence after apparently complete surgery and/or complete clinical response to chemotherapy implies that most patients have undetected minimal residual disease. Novel techniques such as laparoscopic or laparotomic fluorescence may prove to be crucial in reassessing the definition of primary outcome in ovarian cancer management.     

Delineation of EFTUD2 Haploinsufficiency‐Related Phenotypes Through a Series of 36 Patients

Mandibulofacial dysostosis, Guion‐Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss‐of‐function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.     

Mucin-bacterial interactions in the human oral cavity and digestive tract

Mucins are a family of heavily glycosylated proteins that are the major organic components of the mucus layer, the protective layer covering the epithelial cells in many human and animal organs, including the entire gastro-intestinal tract. Microbes that can associate with mucins benefit from this interaction since they can get available nutrients, experience physico-chemical protection and adhere, resulting in increased residence time. Mucin-degrading microorganisms, which often are found in consortia, have not been extensively characterized as mucins are high molecular weight glycoproteins that are hard to study because of their size, complexity and heterogeneity. The purpose of this review is to discuss how advances in mucus and mucin research, and insight in the microbial ecology promoted our understanding of mucin degradation. Recent insight is presented in mucin structure and organization, the microorganisms known to use mucin as growth substrate, with a specific attention on Akkermansia muciniphila, and the molecular basis of microbial mucin degradation owing to availability of genome sequences.     

Automated segmentation of the aorta from phase contrast MR images: Validation against expert tracing in healthy volunteers and in patients with a dilated aorta

Purpose:

To assess if segmentation of the aorta can be accurately achieved using the modulus image of phase contrast (PC) magnetic resonance (MR) acquisitions.

Materials and Methods:

PC image sequences containing both the ascending and descending aorta of 52 subjects were acquired using three different MR scanners. An automated segmentation technique, based on a 2D+t deformable surface that takes into account the features of PC aortic images, such as flow‐related effects, was developed. The study was designed to: 1) assess the variability of our approach and its robustness to the type of MR scanner, and 2) determine its sensitivity to aortic dilation and its accuracy against an expert manual tracing.

Results:

Interobserver variability in the lumen area was 0.59 ± 0.92% for the automated approach versus 10.09 ± 8.29% for manual segmentation. The mean Dice overlap measure was 0.945 ± 0.014. The method was robust to the aortic size and highly correlated (r = 0.99) with the manual tracing in terms of aortic area and diameter.

Conclusion:

A fast and robust automated segmentation of the aortic lumen was developed and successfully tested on images provided by various MR scanners and acquired on healthy volunteers as well as on patients with a dilated aorta. J. Magn. Reson. Imaging 2010;31:881–888. ©2010 Wiley‐Liss, Inc.