Hirschsprung-associated enterocolitis develops independently of NOD2 variants

Backgroud/Purpose

Hirschsprung-associated enterocolitis (HAEC) represents a cause for significant pre- and postoperative morbidity and mortality in Hirschsprung disease (HD). Although multiple studies on HAEC have been performed and several mechanisms have been presumed, the pathogenesis of this condition remains unclear. As changes in colonic mucosal defense are key factors suggested in both Crohn's disease (CD) and HAEC pathogenesis, the aim of the current study was to investigate genetic alterations in the most important susceptibility gene for Crohn's enterocolitis (NOD2) to see whether carriers of polymorphisms within the NOD2 gene are predisposed to the development of HAEC.

Methods

Genotyping for the NOD2 variants in exon 4 (p.Arg702Trp [rs2066844]), exon 8 (p.Gly908Arg [rs2066845]), and exon 11 (p.1007fs [rs2066847]) was performed in 52 white children with HD (41 boys, 11 girls), 152 healthy controls, and 152 children with CD (onset of disease <17 years; mean, 11.8 years). Seventeen patients with HD (32.7%) were carriers of a RET germline mutation, 35 children (67.3%) had short segment disease, and 17 (32.7%) had long segment disease.

Results

Ten children (19.2%) with HD were heterozygous carriers of at least one NOD2 variant vs 17 (11.2%) in the healthy control group and 69 (45.4%) in the CD cohort. Hirschsprung-associated enterocolitis was observed in 7 children (13.5%), with 4 having short segment HD and 3 with long segment HD; but none of them were carriers of NOD2 variants.

Conclusion

Our study shows that NOD2 variants described to be causatively associated with CD do not predispose to the development of HAEC. As data on the molecular basis of HAEC are limited, the distinct mechanisms involved in the pathogenesis of this complication remain unclear.     

Blockade of the passive cell death pathway does not prevent tolerance induction to islet grafts

BACKGROUND: T-cell apoptosis is an important regulatory mechanism in transplant tolerance. The aim of this study was to identify specific apoptotic molecules important for tolerance induction. METHODS: Mice expressing the human Bcl-2 molecule in T cells or Bim -/- mice were used as islet allograft or rat islet xenograft recipients and treated with CTLA4-Fc and MR1 costimulation blockade. RESULTS: hBcl-2 transgenic mice and Bim -/- accepted islet allografts and rat islet xenografts for more than 100 days, similar to wildtype controls. Changes in the dose of the CTLA4-Fc and MR1 did not lead to differences in graft survival and there were no differences in the percentage of CD4+ T cells expressing Fas, CD25, or undergoing apoptosis. CONCLUSIONS: Inhibition of the passive cell death pathway in T cells did not block tolerance induction, suggesting that the mechanism by which apoptosis regulates the alloimmune response is more complex than first thought.     

Tissue oxygen saturation predicts the development of organ dysfunction during traumatic shock resuscitation

BACKGROUND: Near-infrared spectroscopy (NIRS) can continuously and noninvasively monitor tissue oxygen saturation (StO2) in muscle and may be an indicator of shock severity. Our purpose was to evaluate how well StO2 predicted outcome in high-risk torso trauma patients presenting in shock. METHODS: The primary outcome in this prospective study was multiple organ dysfunction syndrome (MODS). StO2 data were obtained upon hospital arrival and for 24 hours along with other known predictors of hypoperfusion and clinical outcomes. Clinicians were blinded to StO2 measurements. RESULTS: Seven Level I trauma centers enrolled 383 patients, 50 of whom developed MODS. Minimum StO2 performed similarly to maximum base deficit (BD) in discrimination of MODS patients. The sensitivity for both measures (StO2 cutoff = 75%; BD cutoff = 6 mEq/L) was 78%, the specificity was 34% to 39%, the positive predictive value was 18% to 20% and the negative predictive value was 88% to 91%. StO2 and BD were also comparable in predicting death. CONCLUSIONS: NIRS-derived muscle StO2 measurements perform similarly to BD in identifying poor perfusion and predicting the development of MODS or death after severe torso trauma, yet have the additional advantages of being continuous and noninvasive.     

Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A>G) mutation is pathogenic and causes Lynch syndrome

Approximately 25 % of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptomatic testing for clinical use is not recommended for relatives of individuals with variants classified as ‘of uncertain significance’. These relatives, including non-carriers, are considered at high-risk as long as the contribution of the variant to disease causation cannot be determined. This results in continuing anxiety, and the application of potentially unnecessary screening and prophylactic interventions. We encountered a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration in the MLH1 gene and we undertook to study the variant. The clinical significance of the variant remains unresolved in the literature. Data are presented on cancer incidence within five kindreds with the same germline missense variant in the MLH1 MMR gene. Extensive testing of relevant family members in one kindred, a review of the literature, review of online MMR mutation databases and use of in silico phenotype prediction tools were undertaken to study the significance of this variant. Clinical, histological, immunohistochemical and molecular evidence from these families and other independent clinical and scientific evidence indicates that the MLH1 p.Arg182Gly (c.544A>G) change causes Lynch syndrome and supports reclassification of the variant as pathogenic.     

Audit tool for external beam radiation therapy departments

PurposeDevelopment of a self-contained audit tool for external beam radiation therapy to assess compliance with the major recommendations from professional organizations and generally accepted standards of practice. Intensity modulated radiation therapy, stereotactic body radiation therapy, stereotactic radiosurgery, and volumetric modulated arc therapy were included in this review.Methods and MaterialsA physics quality working group developed a department vision, distinguished and summarized key references, and condensed important elements of good documentation practices. The results were then compiled in a checklist format and used to perform audits at 3 sites.ResultsThe final audit tool contains 65 items spanning a wide range of external beam radiation therapy practices. Several of the audit items address issues not commonly identified by other authoritative sources. A total of 48 process improvements were identified at the 3 sites audited.ConclusionsThe enclosed self-inspection list may be useful to a site as an annual review tool, as an aid in preparation for the American College of Radiology-American Society for Therapeutic Radiology and Oncology practice accreditation, or as a catalyst for general quality improvement. Sites can quickly identify opportunities for improvement by concentrating on high importance items and commonly identified areas of noncompliance.