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Background & Aims\ud Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations.\ud \ud Methods\ud We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls.\ud \ud Results\ud We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09–1.18; P = 1.8 × 10−11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86–0.93; P = 7.5 × 10−9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10−9).\ud \ud Conclusions\ud We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Background & Aims: In hepatitis C infection, several studies have examined the role of the major histocompatibility complex (MHC) in determining outcome, with variable results. To clarify the importance of MHC, we examined class II DR and DQ antigens in a homogenous cohort of women exposed to hepatitis C genotype 1b from a single inoculum. Methods: Of 243 participants, 95 had spontaneous viral clearance and 148 are chronically infected. The frequencies of HLA class II DR and DQ antigens were compared between the 2 groups and between liver biopsy findings of 145 chronically infected subjects. Results: DRB1*0101 and DQB1*0501 alleles were more frequent in subjects who sustained viral clearance than in chronically infected subjects (32.3% and 36.8% vs. 8.8% and 14.2%, respectively; P = 0.002). DRB1*03011 and DQB1*0201 occurred more frequently in chronically infected subjects than in those who cleared the virus (41.5% and 42.6% vs. 16.7% and 15.8%, respectively; P = 0.001). Both DRB1*03011 and DQB1*0201 were significantly less frequent in those with higher inflammatory scores on liver biopsy. Conclusions: We show that in a homogenous cohort of women infected with the same hepatitis C virus, several HLA antigens are associated with either viral clearance or persistence. This suggests a strong role for host immunogenetic factors in determining outcome in hepatitis C infection. GASTROENTEROLOGY 2000;118:1124-1130

Background & Aims: The ability of viruses to escape the host immune response represents a globally important problem related to a wide variety of pathogens. Hepatitis C is one of the major causes of liver disease worldwide. Clearance rates of this virus are low, and this condition normally involves a chronic inflammatory process. This raises a possibility that the virus may have developed mechanisms enabling it to evade T-cell-mediated immune surveillance. The aim of this study was to investigate the effect of the hepatitis C envelope protein E2 on LFA-1-stimulated T-cell migration and macrophage inflammatory protein (MIP-1α, MIP-1β) secretion. Methods: T cells were stimulated through the leukocyte function-associated molecule-1 (LFA-1) receptor by incubating with either intracellular adhesion molecule 1 (ICAM-1)-Fc fusion protein or anti-LFA-1 immobilized on 8-well chamber slides. Subcellular localization of protein kinase C (PKC)-β, CD81, and LFA-1 was determined by immunofluorescence analysis. Lipid raft formation was assessed using the Cellomics Kineticscan reader. MIP-1α and MIP-1β levels were detected by enzyme-linked immunosorbent assay. Results: We report that the hepatitis C envelope protein E2 can dramatically inhibit T-lymphocyte motility and chemokine release induced via LFA-1 integrin ligation. We have demonstrated a novel T-lymphocyte-directed viral inhibitory mechanism involving the PKC-β enzyme as a definitive intracellular target. E2-CD81 interaction stimulates translocation of PKC-β to lipid rafts, thereby preventing its association with the centrosome and microtubule cytoskeleton, which is crucial to the process of T-cell migration. Conclusions: These studies identify a mechanism whereby the hepatitis C virus can evade the host immune response by inhibition of T-cell migration.

Symptoms of incontinence are common, particularly among older people, and incontinence can have a severe effect on the quality of life of some individuals at any age. A number of treatments are available, most of which aim to reduce the occurrence of incontinent episodes or to limit the effects of the disorder on everyday life. In research and clinical practice, it is essential that the symptoms and effects of incontinence be properly assessed and recorded. The only valid means of measuring patients' perspectives is through the use of psychometrically robust self-report questionnaires. Incontinence may be experienced as part of the symptom complex of a range of conditions (e.g., benign prostatic diseases or fistulas), and the effect of incontinence on quality of life varies depending on the severity of the condition and other psychosocial and medical factors. Questionnaires with acceptable levels of psychometric testing are identified and recommended for use in clinical practice and research investigations according to the following categories: (1) questionnaires to assess symptoms of incontinence, (2) generic health-related quality-of-life questionnaires to assess the effect of incontinence on quality of life, and (3) incontinence-specific measures to assess the effect and bothersomeness of incontinence on quality of life.

BACKGROUND: Esophageal adenocarcinoma (EAC) is a classic example of inflammationassociated cancer, which develops through GERD (gastro-esophageal reflux disease)-Barrett's esophagus (BE)-dysplasia-adenocarcinoma sequence. The incidence rate for EAC has increased 4-10% per year among men since 1976 in the USA, more rapidly than for any other type of cancer. Patients with Barrett's esophagus can progress to dysplasia and EAC at 30-60 times that of the general population. NF-kB plays a key role in inflammation process and TNF-α is a pro-inflammatory cytokine and a known NF-kB activator. It has been reported that TNF-α and TNFR1 are significantly increased in BE and EACs. Glutathione Peroxidase 7 (GPX7), a recent member of GPX family which currently has 8 members, is frequently silenced through location-specific hypermethylation during Barrett's tumorigenesis. Its functions remain largely uncharacterized. In this study, we investigated the potential role of GPX7 in regulating NF-kB activity. METHODS and RESULTS: In vitro experiments and de-identified human tissue samples were utilized for quantitative real-time PCR, immunofluorescence, luciferase reporter, immunoblotting and intracellular ROS (reactive oxygen species) assays. Reconstitution of GPX7 in BE and EAC cell models abrogated TNF-αinduced NF-kB reporter activity and nuclear translocation of NF-kB-p65 (P

Celiac disease is a gluten-sensitive enteropathy, characterized by villous atrophy, which is reversed by gluten withdrawal. A minority of patients with celiac-like enteropathy are resistant to gluten-free diet, so-called refractory sprue, or unclassified sprue. Refractory sprue is a diagnosis of exclusion; all other causes of a celiac-like enteropathy must be eliminated before a diagnosis of refractory sprue can be made. Recent evidence suggests that refractory sprue comprises a heterogenous group of patients with diverse underlying causes. A small proportion of these patients seem to have an adult form of autoimmune enteropathy, characterized by the presence of antienterocyte antibodies. However, a larger group of patients with refractory sprue now seem to have a cryptic intestinal T-cell lymphoma, characterized by the presence of phenotypically abnormal, monoclonal intraepithelial lymphocytes, despite benign cytology. Current therapeutic options include nutritional support and immunosuppressive therapy, but response is variable. The prognosis of refractory sprue may be poor; patients may die of severe malabsorption, or through synchronous or metachronous development of an enteropathy-associated T-cell lymphoma. Based on this recent evidence, patients with refractory sprue should be screened for antienterocyte antibodies and have T-cell receptor and monoclonal antibody studies performed; this could facilitate identification of cases of adult-onset autoimmune enteropathy and those of cryptic T-cell lymphoma. Moreover, early recognition of the malignant nature of the intestinal infiltrate in some cases of refractory sprue could permit the development of novel chemotherapeutic regimens for this condition.

The multidrug resistance (MDR) gene codes for a drug efflux pump P-glycoprotein 170 (Pgp-170) expressed on the surface of lymphocytes and intestinal epithelial cells. Inflammatory bowel disease (IBD) poorly responsive to medical therapy may relate to MDR expression because glucocorticoids are known Pgp-170 substrates.Using flow cytometry, we measured peripheral blood lymphocyte (PBL) MDR in 153 IBD patients and 50 healthy volunteers, and assessed the relationship between PBL, mucosal intraepithelial lymphocyte (IEL), and mucosal epithelial cell (EC) MDR expression in a further 20 IBD patients and 19 controls.Compared with controls, PBL MDR was significantly elevated in patients with Crohn's disease who required bowel resection for failed medical therapy (mean +/- SEM, 26.7 +/- 2.8 vs. 11.9 +/- 1.0; P0.0001) and patients with ulcerative colitis who required proctocolectomy for failed medical therapy (20.3 +/- 2.5 vs. 11.9 +/- 1.0; P = 0.001). PBL MDR remained stable over time and was not influenced by disease activity or glucocorticoid therapy. Both PBL and mucosal MDR expression appeared independent of disease activity, and there was a significant correlation between PBL MDR expression and both IEL expression (r = 0.92; P0.0001) and EC expression (r = 0.54; P0.001).PBL and mucosal MDR expression may play an important role in determining the response of IBD patients to glucocorticoid therapy.

Introduction:Previous micro array studies and validation with Rt-PCR in a patient cohort from our group have shown that GDF 15 is up regulated in BE. GDF15 is a member of the transforming growth factor-beta superfamily which includes TGF-beta and BMP ligands and may be involved in regulation of tissue differentiation and maintenance. TGF-beta and BMP ligands signal through cell receptors inducing Smad activation. Activated Smad 2/3 builds a complex with Smad 4. The activated Smad-complex accumulates in the nucleus and can initiate gene expression. This transcriptional cascade appears crucial in cell transformation and differentiation as seen in BE. The aim was to examine the signaling potential of GDF15 in this cascade. Methods: Recombinant human GDF15 was used in stimulating Het1a cells (human esophageal squamous epithelial cell line). Smad activation into the nucleus was measured with immunostaining using Smad 1/2/3 antibodies and their nuclear intensity after stimulation. The intensity of activated Smad in the nucleus and quantitative amount of GDF15 utilizing Rt-PCR in Oe 33 cells (esophageal cancer cell line) was measured and then compared with levels in HET1a cells. Results: We found that stimulation of Het1a cells with GDF 15 leads to a time and dose dependant Smad activation. We established that optimal induction of Smad activation in Het1a cells is at 5 ng/ml with GDF15 for 1 h (p