Clinical predictors of inflammatory bowel disease in a genetically well-defined Caucasian population.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC), the two main types of inflammatory bowel disease (IBD), are multifactorial conditions of unknown etiology. The objective of this study is to examine the combined gene-environment interactions influencing IBD susceptibility in a well-defined Caucasian cohort in rural mid-America. METHODS: Patients were diagnosed to have CD or UC using conventional radiologic, endoscopic, and/or histopathologic findings. Histological diagnosis was made by a single specialist gastrointestinal pathologist with a particular interest in IBD. Information regarding cigarette smoke exposure was obtained by administration of the Behavioral Risk Factor Surveillance System Survey (BRFSS) to all patients. Genomic DNA was extracted from peripheral blood leukocytes, and polymerase chain reaction (PCR) amplification and genotyping were performed for 11 Single Nucleotide Polymorphisms (SNP) in NOD2, IL23r, OCTN1 genes along with IGR. RESULTS: Our cohort consists of 1196 patients: 435 controls, 485 CD patients, and 276 UC patients. Only patients with genotype data for at least 7 of 11 SNPs were included in our data analysis. The control groups for all 11 SNPs were in Hardy-Weinberg Equilibrium. In genotype-association SNP analysis, all NOD2 SNPs (rs5743293, rs2066844, rs2066845) and the IL23r SNP (rs11465804) showed a significant association to IBD (p < 0.03). A multiple gene-interaction analysis showed an association between NOD2 and IL23r with UC (p = 0.04). There were no associations between any OCTN1 and IGR SNPs and IBD in this cohort. A multivariable logistic regression analysis showed that female gender, "current" or "former" smoking status, family history of IBD, and NOD2 SNP minor alleles were associated with CD. CONCLUSION: IBD remains to be challenging to properly diagnose, characterize, and treat. Our study proposes a combined genetic, phenotypic, and environmental approach in an attempt to better understand IBD. Previously demonstrated associations between OCTN1 and IGR and IBD were not confirmed.

Differential microRNA expression tracks neoplastic progression in inflammatory bowel disease-associated colorectal cancer.

One of the most serious complications faced by patients with inflammatory bowel disease (IBD) is the potential development of colorectal cancer (CRC). There is a compelling need to enhance the accuracy of cancer screening of IBD patients. MicroRNAs (miRNAs) are small nonprotein-coding RNAs that play important roles in CRC oncogenesis. In this study, we report differential miRNA expression in IBD patients with associated CRC from non-neoplastic tissue to dysplasia and eventually cancer. In addition, we identify and examine the role of dysregulated miRNAs in the TP53 pathway. In our CD patients, six miRNAs were upregulated from non-neoplastic tissue to dysplasia, but downregulated from dysplasia to cancer (miR-122, miR-181a, miR-146b-5p, let-7e, miR-17, miR-143) (P < 0.001). Six differentially expressed miRNAs affected the TP53 pathway (miR-122, miR-214, miR-372, miR-15b, let-7e, miR-17) (P < 0.001). Using two human colon cancer cell lines (HT-29 and HCT-116), E2F1, an upstream regulator of TP53, was downregulated in both cell lines transfected with let-7e (P < 0.05) as well as in HCT-116 cells transfected with miR-17 (P < 0.05). Additionally, cyclin G, a cell-cycle regulator miR-122 target was downregulated in both cell lines (P < 0.05). Unique differentially expressed miRNAs were observed in CD-associated CRC progression. Six of these miRNAs had a tumorigenic effect on the TP53 pathway; the effect of three of which was studied using cell lines.

Abdominal wall component release is a sensible choice for patients requiring complicated closure of abdominal defects.

BACKGROUND: Abdominal wall component release (AWCR) is an operation that frequently restores the abdominal wall integrity in both sick and anatomically complex patients. The patients reported herein are different from the widely reported but somewhat less complex trauma patient, such as following damage control laparotomy. AWCR has acceptable postoperative outcomes in terms of infection, hernia, and fistula rates. METHODS: We describe the application of AWCR in 63 consecutive patients, in whom only 11 (17%) had complementary prosthesis use. Unlike many previous reports of AWCR in trauma patients, 47 (75%) of these patients had permanent stomas. These patients had undergone a total of 103 prior abdominal operations (mean 1.7 operations, range 0-7); 29 patients had cancer (46%), 11 of which were recurrent, and 16 patients (22%) had serious complications of prior surgery. Interestingly, 20 patients (32%) had both prior abdominal operations and underlying cancer. RESULTS: In a median follow-up of 32 months (range 16-120 months), only 15 patients (5 of whom had a stoma) developed recurrent abdominal wall hernias with 5 of those being peristomal. No correlation was found between prior abdominal operations, intestinal stomas, and contamination source at time of surgery with recurrence of hernia (p > 0.05). The 41 patients (86%) with an intact abdominal wall (free of recurrent hernia) had a median follow-up of 27 months (range 13-117 months). Twelve patients (19%) had a source of abdominal/abdominal wall contamination present at the time of AWCR. Only 1 of the 11 patients in whom complementary prosthesis was used developed infection. Other infectious complications were noted in 12 patients (19%), including fistula in 1 patient who required reoperation. CONCLUSIONS: AWCR offers acceptable results in very high-risk patients with tolerable postoperative infection rates.

In vitro study of variables relevant to perioperative care of the surgical patient: glucose, osmolarity, and rewarming.

BACKGROUND: We sought to determine the effects of altering osmolarity and the reversibility of the detrimental immunologic effects of hypothermia on human monocyte HLA-DR surface expression and reactive oxygen species (ROS) formation. STUDY DESIGN: The effects of altering osmolarity on HLA-DR surface expression and ROS formation were assessed using lipopolysaccharide (LPS)-treated samples treated with either saline, glucose, or mannitol, incubated at 37°C for 2 hours. HLA-DR surface receptor expression and ROS formation were determined after incubation. The effects of the reversibility of hypothermia were measured by incubating LPS-treated samples at 34°C, 37°C, and 40°C for 1 hour. The samples were subsequently rewarmed at 40°C for 1 and 2 hours. The effects of rewarming on HLA-DR surface receptor expression and ROS formation were reassessed. RESULTS: In the osmolarity experiments, there was a 49% decrease in ROS formation in samples treated with mannitol as compared with saline and glucose. Alterations of osmolarity had no significant effect on HLA-DR surface expression. In the rewarming experiments, rewarming for either 1 or 2 hours abolished any significant differences in HLA-DR surface expression and ROS formation between samples preincubated at the different temperatures. CONCLUSIONS: The presumed inert mannitol was found to significantly decrease ROS formation, but had no effect on HLA-DR surface expression. In addition, the effects of hypothermia on HLA-DR surface expression or ROS formation may be better reversed within 2 hours than in 1 hour.