Enterocyte Shedding and Epithelial Lining Repair Following Ischemia of the Human Small Intestine Attenuate Inflammation

BACKGROUND: Recently, we observed that small-intestinal ischemia and reperfusion was found to entail a rapid loss of apoptotic and necrotic cells. This study was conducted to investigate whether the observed shedding of ischemically damaged epithelial cells affects IR induced inflammation in the human small gut. METHODS AND FINDINGS: Using a newly developed IR model of the human small intestine, the inflammatory response was studied on cellular, protein and mRNA level. Thirty patients were consecutively included. Part of the jejunum was subjected to 30 minutes of ischemia and variable reperfusion periods (mean reperfusion time 120 (+/-11) minutes). Ethical approval and informed consent were obtained. Increased plasma intestinal fatty acid binding protein (I-FABP) levels indicated loss in epithelial cell integrity in response to ischemia and reperfusion (p<0.001 vs healthy). HIF-1alpha gene expression doubled (p = 0.02) and C3 gene expression increased 4-fold (p = 0.01) over the course of IR. Gut barrier failure, assessed as LPS concentration in small bowel venous effluent blood, was not observed (p = 0.18). Additionally, mRNA expression of HO-1, IL-6, IL-8 did not alter. No increased expression of endothelial adhesion molecules, TNFalpha release, increased numbers of inflammatory cells (p = 0.71) or complement activation, assessed as activated C3 (p = 0.14), were detected in the reperfused tissue. CONCLUSIONS: In the human small intestine, thirty minutes of ischemia followed by up to 4 hours of reperfusion, does not seem to lead to an explicit inflammatory response. This may be explained by a unique mechanism of shedding of damaged enterocytes, reported for the first time by our group

Risk of urinary bladder cancer: a case-control analysis of industry and occupation

<p>Abstract</p> <p>Background</p> <p>Uncertainty remains about urinary bladder cancer (UBC) risk for many occupations. Here, we investigate the association between occupation, industry and UBC.</p> <p>Methods</p> <p>Lifetime occupational history was collected by in-person interview for 604 newly diagnosed UBC patients and 604 cancer-free controls. Each job title was assigned a two-digit industry code and a three-digit occupation code. Odds ratios (ORs) for UBC associated with ever being employed in an industry or occupation were calculated by unconditional logistic regression adjusting for age, gender and smoking status. We also examined UBC risk by duration of employment (>0 to <10, ≥10 years) in industry or occupation.</p> <p>Results</p> <p>Significantly increased risk of UBC was observed among waiters and bartenders (OR 2.87; 95% CI 1.05 to 7.72) and occupations related to medicine and health (OR 2.17; 95% CI 1.21 to 3.92), agricultural production, livestock and animal specialties (OR 1.90; 95% CI 1.03 to 3.49), electrical assembly, installation and repair (OR 1.69; 95% CI 1.07 to 2.65), communications (OR 1.74; 95% CI 1.00 to 3.01), and health services (OR 1.58; 95% CI 1.02 to 2.44). For these occupations we also observed a significant excess risk of UBC for long-term work (i.e. ≥10 years), with the exception of waiters and bartenders. Employment for 10 years or more was associated with increased risk of UBC in general farmers (OR 9.58; 95% CI 2.18 to 42.05), agricultural production of crops (OR 3.36; 95% CI 1.10 to 10.27), occupations related to bench working (OR 4.76; 95% CI 1.74 to 13.01), agricultural, fishery, forestry & related (OR 4.58; 95% CI 1.97 to 10.65), transportation equipment (OR 2.68; 95% CI 1.03 to 6.97), and structural work (OR 1.85; 95% CI 1.16 to 2.95).</p> <p>Conclusions</p> <p>This study provides evidence of increased risk of UBC for occupations that were previously reported as at-risk. Workers in several occupation and industry groups have a significantly higher risk of UBC, particularly when duration of employment is 10 years or more.</p

A copula model for marked point processes

The final publication (Diao, Liqun, Richard J. Cook, and Ker-Ai Lee. (2013) A copula model for marked point processes. Lifetime Data Analysis, 19(4): 463-489) is available at Springer via http://dx.doi.org/10.1007/s10985-013-9259-3Many chronic diseases feature recurring clinically important events. In addition, however, there often exists a random variable which is realized upon the occurrence of each event reflecting the severity of the event, a cost associated with it, or possibly a short term response indicating the effect of a therapeutic intervention. We describe a novel model for a marked point process which incorporates a dependence between continuous marks and the event process through the use of a copula function. The copula formulation ensures that event times can be modeled by any intensity function for point processes, and any multivariate model can be specified for the continuous marks. The relative efficiency of joint versus separate analyses of the event times and the marks is examined through simulation under random censoring. An application to data from a recent trial in transfusion medicine is given for illustration.Natural Sciences and Engineering Research Council of Canada (RGPIN 155849); Canadian Institutes for Health Research (FRN 13887); Canada Research Chair (Tier 1) – CIHR funded (950-226626

Protective effect of leptin against ischemia-reperfusion injury in the rat small intestine

BACKGROUND: The small intestine is extremely sensitive to ischemia-reperfusion (I/R) injury and a range of microcirculatory disturbances which contribute to tissue damage. Previous studies have shown that leptin plays an important physiological role in the microvasculature. The aim of this study was to evaluate the protective effects of leptin in I/R – induced mucosal injury in the small intestine. METHODS: Forty rats were divided into 5 groups (n = 8). Group I was subjected to a sham operation. Following mesenteric ischemia in group II (control); physiologic saline 1 cm(3), in group III; leptin 100 μg/kg, and physiologic saline 1 cm(3), in group IV; N(G)-L-arginine methyl ester (L-NAME) 20 mg/kg, and physiologic saline 1 cm(3), in group V; leptin 100 μg/kg, L-NAME 20 mg/kg, and physiologic saline 1 cm(3 )were given intra-peritoneally. In these groups, an I/R procedure was performed by occlusion of the superior mesenteric artery for 45 min followed by 120 min reperfusion. After reperfusion, the small intestines were resected for malondialdehyde (MDA) and nitric oxide (NO) concentration and histopathologic properties. Mucosal lesions were scored between 0 and 5. Tissue MDA and NO concentration and histopathologic grades were compared statistically. RESULTS: Tissue MDA level significantly increased (P < 0.05), tissue NO level significantly decreased in group V animals, compared to group III animals respectively (P < 0.001). Histopathologically, intestinal injury significantly decreased in the leptin treated ischemic group. CONCLUSION: Leptin can be used safely in mesenteric occlusive diseases, since it induces NO formation and release in mesenteric vessels

Interaction between COMT rs5993883 and second generation antipsychotics is linked to decreases in verbal cognition and cognitive control in bipolar disorder

Abstract Background Second generation antipsychotics (SGAs) are increasingly utilized in Bipolar Disorder (BD) but are potentially associated with cognitive side effects. Also linked to cognitive deficits associated with SGA-treatment are catechol-O-methyltransferase (COMT) gene variants. In this study, we examine the relationship between cognition in SGA use and COMT rs5993883 in cohort sample of subjects with BD. Methods Interactions between SGA-treatment and COMT rs5993883 genotype on cognition was tested using a battery of neuropsychological tests performed in cross-sectional study of 246 bipolar subjects. Results The mean age of our sample was 40.15 years and was comprised of 70 % female subjects. Significant demographic differences included gender, hospitalizations, benzodiazepine/antidepressant use and BD-type diagnosis. Linear regressions showed that the COMT rs5993883 GG genotype predicted lower verbal learning (p = 0.0006) and memory (p = 0.0026) scores, and lower scores on a cognitive control task (p = 0.004) in SGA-treated subjects. Interestingly, COMT GT- or TT-variants showed no intergroup cognitive differences. Further analysis revealed an interaction between SGA-COMT GG-genotype for verbal learning (p = 0.028), verbal memory (p = 0.026) and cognitive control (p = 0.0005). Conclusions This investigation contributes to previous work demonstrating links between cognition, SGA-treatment and COMT rs5993883 in BD subjects. Our analysis shows significant associations between cognitive domains such as verbal-cognition and cognitive control in SGA-treated subjects carrying the COMT rs5993883 GG-genotype. Prospective studies are needed to evaluate the clinical significance of these findings.http://deepblue.lib.umich.edu/bitstream/2027.42/134550/1/40359_2016_Article_118.pd

Genetic Diversity, Morphological Uniformity and Polyketide Production in Dinoflagellates (Amphidinium, Dinoflagellata)

Dinoflagellates are an intriguing group of eukaryotes, showing many unusual morphological and genetic features. Some groups of dinoflagellates are morphologically highly uniform, despite indications of genetic diversity. The species Amphidinium carterae is abundant and cosmopolitan in marine environments, grows easily in culture, and has therefore been used as a ‘model’ dinoflagellate in research into dinoflagellate genetics, polyketide production and photosynthesis. We have investigated the diversity of ‘cryptic’ species of Amphidinium that are morphologically similar to A. carterae, including the very similar species Amphidinium massartii, based on light and electron microscopy, two nuclear gene regions (LSU rDNA and ITS rDNA) and one mitochondrial gene region (cytochrome b). We found that six genetically distinct cryptic species (clades) exist within the species A. massartii and four within A. carterae, and that these clades differ from one another in molecular sequences at levels comparable to other dinoflagellate species, genera or even families. Using primers based on an alignment of alveolate ketosynthase sequences, we isolated partial ketosynthase genes from several Amphidinium species. We compared these genes to known dinoflagellate ketosynthase genes and investigated the evolution and diversity of the strains of Amphidinium that produce them