Yousif I. A-Rahim

From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease.

CD39/ENTPD1 hydrolyzes proinflammatory nucleotides to generate adenosine. As purinergic mediators have been implicated in intestinal inflammation, we hypothesized that CD39 might protect against inflammatory bowel disease. We studied these possibilities in a mouse model of colitis using mice with global CD39 deletion. We then tested whether human genetic polymorphisms in the CD39 gene might influence susceptibility to Crohns disease. We induced colitis in mice using Dextran Sodium Sulfate (DSS). Readouts included disease activity scores, histological evidence of injury, and markers of inflammatory activity. We used HapMap cell lines to find SNPs that tag for CD39 expression, and then compared the frequency of subjects with high vs. low CD39-expression genotypes in a case-control cohort for Crohns disease. Mice null for CD39 were highly susceptible to DSS injury, with heterozygote mice showing an intermediate phenotype compared to wild type (WT). We identified a common SNP that tags CD39 mRNA expression levels in man. The SNP tagging low levels of CD39 expression was associated with increased susceptibility to Crohns disease in a case-control cohort comprised of 1,748 Crohns patients and 2,936 controls (P = 0.005–0.0006). Our data indicate that CD39 deficiency exacerbates murine colitis and suggest that CD39 polymorphisms are associated with inflammatory bowel disease in humans.

Heme oxygenase-1-generated biliverdin ameliorates experimental murine colitis

Background: Heme oxygenase‐1 (HO‐1) seems to have an important protective role in acute and chronic inflammation. The products of heme catalysis, biliverdin/bilirubin, carbon monoxide (CO), and iron (that induces apoferritin) mediate the beneficial effects of HO‐1. Blockade of HO‐1 activity results in exacerbation of experimental colitis. We tested whether HO‐1 has protective effects in the development of colitis and determined that specific enzymatic products of HO‐1 are responsible for these effects. Methods: Colitis was induced by oral administration of dextran sodium sulfate (5%) to C57BL/6 mice for 7 days. HO‐1 was up‐regulated by cobalt‐protoporphyrin (5 mg/kg, intraperitoneally). Biliverdin, exogenous CO, or the iron chelator desferrioxamine was administered to other groups. Results: Cobalt‐protoporphyrin treatment resulted in significant up‐regulation of HO‐1 protein in mucosal and submucosal cells. Induction of HO‐1 was associated with significantly less loss of body weight in mice with induced colitis (−12% versus −22% in the control animals, P < 0.001). Development of diarrhea and gastrointestinal hemorrhage was substantially delayed in animals in which HO‐1 was induced, and mucosal injury was significantly attenuated. Administration of CO or desferrioxamine alone had no significant effects, whereas enhanced protection with lesser evidence of bowel inflammation was observed with systemic biliverdin administration (50 &mgr;mol/kg, 3 times per day, intraperitoneally). Conclusions: We conclude that heightened HO‐1 expression or administration of biliverdin ameliorates dextran sodium sulfate‐induced experimental colitis. Novel therapeutic strategies based on HO‐1 and/or biliverdin administration may have use in inflammatory bowel disease.

A Colon Video Analysis Framework for Polyp Detection

This paper presents an automated video analysis framework for the detection of colonic polyps in optical colonoscopy. Our proposed framework departs from previous methods in that we include spatial frame-based analysis and temporal video analysis using time-course image sequences. We also provide a video quality assessment scheme including two measures of frame quality. We extract colon-specific anatomical features from different image regions using a windowing approach for intraframe spatial analysis. Anatomical features are described using an eigentissue model. We apply a conditional random field to model interframe dependences in tissue types and handle variations in imaging conditions and modalities. We validate our method by comparing our polyp detection results to colonoscopy reports from physicians. Our method displays promising preliminary results and shows strong invariance when applied to both white light and narrow-band video. Our proposed video analysis system can provide objective diagnostic support to physicians by locating polyps during colon cancer screening exams. Furthermore, our system can be used as a cost-effective video annotation solution for the large backlog of existing colonoscopy videos.

Heightened NTPDase-1/CD39 expression and angiogenesis in radiation proctitis

Radiation proctitis is an inflammatory process associated with persistent and refractory lower gastrointestinal bleeding. Purinergic signaling regulates hemostasis, inflammation, and angiogenesis. For example, CD39, the vascular ectonucleotidase, blocks platelet activation and is required for angiogenesis. Whether CD39 expression is affected by radiation injury is unknown. The aim of this work was to study CD39 expression patterns after clinical radiation injury to the rectum. We prospectively enrolled eight patients with radiation proctitis and five gender-matched controls. Biopsies were taken from normal-appearing rectal mucosa of controls and from the normal sigmoid and abnormal rectum of patients. Expression patterns of CD39, P2Y2 receptor, CD31, CD61 integrin, and vascular endothelial growth factor receptor 2 were examined by immunostaining; levels of CD39 were further evaluated by Western blots. Chronic inflammatory lesions of radiation proctitis were associated with heightened levels of angiogenesis. Immunohistochemical stains showed increased vascular expression of CD39, as confirmed by Western blots. CD39 was co-localized with vascular endothelial markers CD31 and CD61 integrin, as well as expressed by stromal tissues. Development of neovasculature and associated CD39 expression in radiation proctitis may be associated with the chronic, refractory bleeding observed in this condition.

Robust distortion correction of endoscope

Endoscopic images suffer from a fundamental spatial distortion due to the wide angle design of the endoscope lens. This barrel-type distortion is an obstacle for subsequent Computer Aided Diagnosis (CAD) algorithms and should be corrected. Various methods and research models for the barrel-type distortion correction have been proposed and studied. For industrial applications, a stable, robust method with high accuracy is required to calibrate the different types of endoscopes in an easy of use way. The correction area shall be large enough to cover all the regions that the physicians need to see. In this paper, we present our endoscope distortion correction procedure which includes data acquisition, distortion center estimation, distortion coefficients calculation, and look-up table (LUT) generation. We investigate different polynomial models used for modeling the distortion and propose a new one which provides correction results with better visual quality. The method has been verified with four types of colonoscopes. The correction procedure is currently being applied on human subject data and the coefficients are being utilized in a subsequent 3D reconstruction project of colon.

Studies on Pyrazinoylguanidine

In a three-phase study, single oral doses of placebo, followed in 1 week by pyrazinoylguanidine (PZG; 900 mg), followed in 3 weeks by pyrazinoic acid (PZA; 300 mg) were given to 8 normal male subjects. Blood analyses performed 0, 2 and 4 h after administration of placebo or drug revealed that compared to mean 0 h values, PZG and also PZA, but not placebo, decreased mean values for serum glucose, insulin, C-peptide, triglycerides and free fatty acids. In all groups, serum potassium, urea, fibrinogen, high-density lipoprotein and low-density lipoprotein were unchanged. PZA, but not PZG, increased serum uric acid. PZG significantly reduced very-low-density lipoprotein whereas PZA only tended to do so. PZG was well tolerated and without any side effect, but in 7 of the 8 normal volunteers, PZA produced a variable vasomotor response over the blush area of the face and neck lasting from 30 min in 3 subjects to 4 h in 1 subject. Collectively, these results suggest generally similar metabolic responses of normal subjects to PZG and PZA after only a single oral dose of each. Previously, it was unrecognized that acute administration of PZG and PZA could produce such rapid metabolic changes.