Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells.

The mechanisms by which commensal bacteria suppress inflammatory signalling in the gut are still unclear. Here, we present a cellular mechanism whereby the polarity of intestinal epithelial cells (IECs) has a major role in colonic homeostasis. TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappaB activation and cDNA microarray analysis. Whereas basolateral TLR9 signals IkappaBalpha degradation and activation of the NF-kappaB pathway, apical TLR9 stimulation invokes a unique response in which ubiquitinated IkappaB accumulates in the cytoplasm preventing NF-kappaB activation. Furthermore, apical TLR9 stimulation confers intracellular tolerance to subsequent TLR challenges. IECs in TLR9-deficient mice, when compared with wild-type and TLR2-deficient mice, display a lower NF-kappaB activation threshold and these mice are highly susceptible to experimental colitis. Our data provide a case for organ-specific innate immunity in which TLR expression in polarized IECs has uniquely evolved to maintain colonic homeostasis and regulate tolerance and inflammation.

Ankylosing spondylitis: patterns of radiographic involvement--a re-examination of accepted principles in a cohort of 769 patients.

PURPOSE: To re-examine the patterns of radiographic involvement in ankylosing spondylitis (AS). MATERIALS AND METHODS: This prospective study had institutional review board approval, and 769 patients with AS (556 men, 213 women; mean age, 47.1 years; age range, 18-87 years) provided written informed consent. Radiographs of the cervical spine, lumbar spine, pelvis, and hips were scored by using the Bath Ankylosing Spondylitis Radiology Index (BASRI) by an experienced radiologist. Differences in sacroiliitis grade between right and left sacroiliac joints, frequency of cervical- and lumbar-predominant involvement by sex, frequency of progression to complete spinal fusion, and association between hip arthritis and spinal involvement were computed for the cohort overall and for subgroups defined according to duration of AS in 10-year increments. RESULTS: Symmetric sacroiliitis was seen in 86.1% of patients. Lumbar predominance was more common during the first 20 years of the disease, after which the cervical spine and lumbar spine were equally involved. Men and women were equally likely to have cervical-predominant involvement. Complete spinal fusion was observed in 27.9% of patients with AS for more than 30 years and in 42.6% of patients with AS for more than 40 years. Patients with BASRI hip scores of 2 or greater had significantly higher BASRI spine scores. CONCLUSION: There were no sex differences in cervical-predominant involvement in AS. Hip arthritis was strongly associated with worse spinal involvement.

Ileocolic vascular curvature: a new CT finding of cecal volvulus.

PURPOSE: To evaluate the diagnostic performance of a proposed new CT observation in cecal volvulus, marked hook-like curvature of ileocolic vessels termed "ileocolic vascular curvature." METHODS: Contrast-enhanced CT scans of 14 patients with diagnoses of cecal volvulus on original CT reports were compared with scans of 40 control patients with dilated cecum but no cecal volvulus on original CT reports, accrued consecutively from January, 2006 through July, 2017. Two independent blinded readers retrospectively evaluated scans for cecal dilatation, ileocolic vascular curvature and seven previously reported CT features of cecal volvulus. Statistical methods included the exact binomial distribution to define 95% confidence intervals (95% CIs), logistic regression, receiver operating characteristic analysis, and the exact McNemar test. Pathology reports and clinical records served as reference standards. RESULTS: All patients had abdominal pain and cecal distension. All 14 patients with CT diagnoses of cecal volvulus, and no control patients, had cecal volvulus by reference standards. Ileocolic vascular curvature and ectopic cecal location were the only features independently and significantly associated with cecal volvulus in multivariable regression (odds ratio 178, p = 0.014, and 63, p = 0.013, respectively) and also the only features with both sensitivity (12/14 [85.7%, 95% CI 57.2-98.2%] and 13/14 [92.9%, 95% CI 66.1-99.8%], respectively) and specificity (40/40 [100.0%, 95% CI 91.2-100.0%] and 38/40 [95.0%, 95% CI 83.1-99.4%], respectively) that differed significantly from 50.0%. CONCLUSIONS: Ileocolic vascular curvature was independently and significantly associated with cecal volvulus and exhibited both substantial sensitivity and substantial specificity for cecal volvulus, and thus is potentially a valuable new CT finding of cecal volvulus.

Toll-like receptor signaling in intestinal epithelial cells contributes to colonic homoeostasis.

PURPOSE OF REVIEW: Since intestinal epithelium expresses Toll-like receptors, it was suggested that the intestinal epithelium is actively involved in the maintenance of colonic homeostasis. Here we describe our recent findings, which support an active contribution of colonic epithelium to intestinal homeostasis via a unique activation of epithelial TLR9. RECENT FINDINGS: Recent data indicate that stimulation of Toll-like receptors by intestinal microbiota supports colonic homeostasis. Several Toll-like receptors are expressed in intestinal epithelium. TLR9, an intracellular protein in immune cells, is expressed on the cell surfaces of intestinal epithelium, both on the apical and the basolateral membrane. TLR9 signaling varies in a domain-specific manner; whereas JNK is activated by TLR9 ligand both apically or basolaterally, NF-kappaB is activated only via basolateral stimulation. In apical TLR9 stimulation, IkappaB is phosphorylated and ubiquitinated but is not degraded, and NF-kappaB-dependent inflammatory signals are not transduced. Stimulation of apical TLR9 compromises the inflammatory cascade induced basolaterally by several other Toll-like receptor ligands, suggesting that apical exposure to luminal microbial DNA restrains intestinal inflammation. SUMMARY: These data indicate that certain luminal bacterial products support colonic homeostasis via activation of epithelial Toll-like receptors. The role of epithelial Toll-like receptor expression and activation in the pathogenesis of human inflammatory bowel disease is yet to be explored.

A simple route to difluorocarbene and perfluoroalkylidene complexes of iridium.

Primary perfluoroalkyl compounds of iridium undergo facile two-electron reduction to afford a simple route to difluorocarbene and perfluoroalkylidene complexes, two of which have been crystallographically characterized. Low-temperature protonation reactions illustrate that the thermodynamic site of protonation depends on the nature of the fluorinated carbene; the difluorocarbene complex undergoes protonation at iridium, while its perfluoroethylidene congener undergoes protonation at carbon.