Background/Aims: The intestinal pathophysiology in irritable bowel syndrome (IBS) is largely unknown. The lactulose breath test has been used to identify small bowel bacterial overgrowth in these patients. Methods: We studied intestinal transit in patients with IBS using of the SmartPill® (SP) wireless pH/pressure recording capsule and performed lactulose breath tests to look for physiologic abnormalities. Results: A total of 35/46 (76%) of the IBS patients had prolonged gastric emptying times. Constipation-predominant disease was associated with prolonged gut transit times. The mean hours ± SD for colonic transit time in the constipation group was 71.7 ± 61.1 (n = 13) compared with 22.5 ± 14.9 (n = 14) for diarrhea-predominant and 26.4 ± 21.5 (n = 20) for mixed clinical subtype (p = 0.0010). No correlation between small bowel transit time and abnormal breath hydrogen or methane excretion in the 46 combined patients with IBS was seen. Conclusions: Delayed gastric emptying was identified in IBS and in some patients may contribute to at least a component of their symptoms. Constipation-predominant IBS is associated with prolonged gut transit times. Otherwise, transit abnormalities do not appear to be important in IBS. Intestinal transit did not correlate with breath test results.

IBS was later classified by both limited and extended criteria and subjects asked about medically diagnosed IBS.The registry includes data collected on motion sickness symptoms and prior experience of nausea and vomiting immediately post-general anaesthetic.Results 3074 (94% female, age 56(17-85) years) cases were evaluable for IBS (96.9% with motion sickness data and 75.3% with post-general anaesthetic nausea data).The prevalence of IBS was 8% for limited Rome III IBS, 22.3% for extended Rome III IBS and 12.6% for medically diagnosed IBS.Motion sickness was associated with limited IBS, odds ratio 1.5(95%CI 1.12-2.01)(p=0.006) and medically diagnosed IBS, 1.4(95%CI 1.06-1.74)(p=0.015).Similarly nausea immediately post-general anaesthetic was associated with both (1.4(95%CI 1.03-1.84)(p=0.03) and 1.7(95%CI 1.34-2.17)(p=<0.005)respectively).However with extended criteria IBS the association with motion sickness was lost 1.2(95%CI 0.95-1.43)(p=NS) but maintained for post-general anaesthetic nausea 1.5(95%CI 1.22-1.80)(p=<0.005).Conclusions Post-general anaesthetic nausea is clearly associated with IBS.Motion sickness is associated with limited criteria Rome III and medically diagnosed IBS but not extended criteria IBS, a more heterogeneous phenotype with likely greater environmental influences.We suggest that these associations may indicate the common influence of altered central processing of stimuli in the generation of IBS, motion sickness and post-general anaesthetic nausea.

Purpose: There has been a recent significant increase in the percentage of colonoscopies (C) performed with propofol as opposed to moderate sedation. Since deep sedation can impair our natural response to significant pain, we reviewed our database to determine the frequency of mechanical perforations in patients receiving propofol as compared with moderate sedation (MS). Methods: Kelsey-Seybold Clinic is a large multispecialty clinic and accountable health care system with two out patient endoscopy units. All hospital transfers from the endsocopy units and all hospital admissions within 24 hours are reported to the chief of gastroenterology and quality management and recorded. We reviewed our database from January 1,2009 through April 30, 2012 for all reported mechanical perforations. Stastical analysis utillized chi-square test with Yates correction. Results: There were 40,643 colonoscopies by 11 different gastroenterologists and one colorectal surgeon of which 6299 (15.5%) were anesthesia assisted with propofol. Utilization of deep sedation varied from 3.6 to 26.1 5 among the endoscopists. The results are summarized in the table below. The rates of perforation were 0.0028 % for moderate sedation and 0.046 for propofol which was significant, p=0.0094. Conclusion: Although there could be other reasons for the higher rate of mechanical perforations in our patients that received propofol, these results suggest that endoscopists need to proceed carefully in patients undergoing deep sedation for colonoscopy.Table: No Caption available.

Background 82 Aims: Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-alpha, (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia.Methods: 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (PI) count >= 80 x 10(9)/L and an absolute neutrophil count (ANC) >= 1500/mm(3). Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (PI, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n = 1294).Results: 6 SNPs on chromosome 20 were positively associated with PI reduction (top SNP rs965469, p = 10(-10)). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with PI reduction (p = showed strong independent associations with PI reduction (p = 10(-12), p = 10(-7)) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with PI reduction (r = -0.28, p = 10(-17)) and Hb change largely attenuated the association between the ITPA variants and PI reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia.Conclusions: Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified. (C) 2011 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.

Black Americans are disproportionally infected with hepatitis C virus (HCV) and are less likely than whites to respond to treatment with peginterferon (PEG-IFN) plus ribavirin (RBV). The impact of race on HCV treatment eligibility is unknown. We therefore performed a retrospective analysis of a phase 3B multicenter clinical trial conducted at 118 United States community and academic medical centers to evaluate the rates of and reasons for HCV treatment ineligibility according to self-reported race. In all, 4,469 patients were screened, of whom 1,038 (23.2%) were treatment ineligible. Although blacks represented 19% of treated patients, they were more likely not to be treated due to ineligibility and/or failure to complete required evaluations (40.2%) than were nonblack patients (28.5%; P < 0.001). After the exclusion of persons not treated due to undetectable HCV RNA or nongenotype 1 infection, blacks were 65% less likely than nonblacks to be eligible for treatment (28.1% > 17.0%; relative risk, 1.65; 95% confidence interval, 1.46-1.87; P < 0.001). Blacks were more likely to be ineligible due to neutropenia (14% versus 3%, P < 0.001), anemia (7% versus 4%, P = 0.02), elevated glucose (8% versus 3%, P < 0.001), and elevated creatinine (5% versus 1%, P < 0.001). Conclusion: Largely due to a higher prevalence of neutropenia and uncontrolled medical conditions, blacks were significantly less likely to be eligible for HCV treatment. Increased access to treatment may be facilitated by less conservative neutrophil requirements and more effective care for chronic diseases, namely, diabetes and renal insufficiency. (HEPATOLOGY 2011;54:70-78)

Purpose: IL-10 is an anti-inflammatory cytokine produced by monocytes and lymphocytes that influences immunoregulation and inflammation. In our previous studies we found an association between presence of AA polymorphism in the -1082 IL-10 allele (SNP) and reduced frequency of IBS in a large general medical population. Methods: We investigated the association of this SNP on type of IBS, postinfectious (PI) or idiopathic (I) compared with healthy controls and measured levels of fecal IL-10 in fecal samples in the populations under study. We enrolled 50 subjects with PI-IBS, 50 with I-IBS and 52 healthy subjects as controls. Subjects with either form of IBS completed a validated questionnaire establishing the diagnosis of IBS by Rome II criteria. The subjects provided blood and stool samples. DNA was extracted from blood and subjected to PCR amplification with primers specific for IL-10 with the AA, AT and TT SNPs in -1082 position identified by pyrosequencing. Stool samples were assayed for fecal IL-10 levels by ELISA with quantity correlated with presence of IL-10 genotype. Results: AA SNP was seen in 20 (40%) with PI-IBS, 16 (32%) with I-IBS, 36 (35%) for both IBS groups combined compared with 28 (52%) of controls (p = 0.037 for all IBS subjects vs. controls). The median concentrations of IL-10 in stools (pg/mL) for the four respective groups were: 2.78, 2.59, 1.85 and 5.79 (p = 0.023 for all IBS groups vs. controls). The two IBS groups did not differ in the frequency of SNP or fecal concentration of IL-10. Conclusion: Reduced frequency of AA SNP in the -1082 IL-10 gene and corresponding reductions in fecal levels of IL-10 are seen in both forms of IBS compared with healthy controls and may provide clues as to the pathogenesis of IBS.

Purpose: The pathogenesis of IBS is poorly understood. Etiopathogenic factors include genetics, predisposing enteric infection and psycho-emotional factors. Methods: We studied alterations in intestinal permeability in 25 subjects with post-infectious (PI) and 26 subjects with idiopathic (I) IBS and 9 healthy controls seen in a large medical clinic in Houston. Lactulose (5 g/dL) and mannitol (1 g/dL) were given orally to all study subjects and an overnight urine sample collected. Based on previous studies of sympathetic nervous system and serotonin metabolism in functional bowel disease, we measured total catecholamines and serotonin by HPLC in an aliquot of the overnight urine studied for permeability alterations. Subjects with either form of IBS completed a validated questionnaire establishing the diagnosis of IBS by Rome II criteria. Results: Frequency distribution analyses were performed to compare the IBS patients to the controls. A total of 45/51 (88%) of the IBS patients had an elevated lactulose/mannitol ratio 0.03 compared with 4/9 (44%) of the controls (p = 0.0117). Mean overnight catecholamine levels were 0.0783±0.1166 for the two IBS group combined compared with 0.1606± 0.1127 for controls (p=0.1670). The mean serotonin levels were similar in the IBS group (0.0363±0.0228) versus the controls (0.0292±0.0268) (p=0.5333). Conclusion: These results suggest an increase in small intestinal permeability is associated with IBS, which may help provide insight into the pathophysiology of this common disorder.

PRESENTATIONSand randomized (1:1:1) to receive placebo (A); GS-9450, 10 mg QD (B); or GS-9450, 40 mg QD (C) for 24 weeks.The primary outcome was pre-specified histologic response (≥2-point decrease in Knodell necroinflammation score with no worsening in fibrosis score) between study groups from pre-treatment and Week 24 liver biopsies.Results: 307 subjects were randomized and treated [n = 103 (A), 101 (B), and 103 (C)].70% were male, 81% were Caucasian, mean age was 53, mean baseline (BL) ALT was 107 IU/mL, mean BL HAI and fibrosis scores were 8.0 and 2.8, and 9% were cirrhotic.Median ALT in GS-9450 groups improved at Week 4, with normalization in 46%, and was maintained through Week 20 in a majority.Adverse events led to treatment discontinuation in 1.9% (A), 5.0% (B) and 4.9% (C) of patients.During treatment, Grade 3 or 4 treatment emergent (TE) ALT elevations occurred in 6.8% (A), 5.0% (B), and 7.8% (C) of subjects.Notably, three subjects receiving GS-9450 developed marked simultaneous marked simultaneous ALT (7, 8, 28 × BL) and bilirubin (4.3, 6.8, 11.0 mg/dL) elevation by Week 8-12, and two others developed marked marked ALT elevation alone (11, 18 ×BL), resulting in study termination by the sponsor for possible drug-induced livery injury (DILI).Two placebo recipients also developed simultaneous elevation of ALT (2, 3 ×BL) and bilirubin (1.9, 3.3 mg/dL).50% of study subjects received study medication through Week 20, and 87 paired liver biopsies were obtained.Histologic improvement by pre-defined criteria occurred in 10/27 (37%), 5/28 (18%) and 5/32 (16%) of Group A, B, and C subjects, respectively.Conclusions: GS-9450 induced ALT improvement in patients with chronic HCV infection previously failing PEG/RBV, but was associated with presumptive DILI.The histology data do not support the concept of therapeutic caspase inhibition in chronic HCV infection.

BACKGROUND & AIMS: We recently identified a polymorphism upstream of interleukin (IL)-28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphism's clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR. METHODS: HCV-1 patients were genotyped as CC, CT, or TT at the polymorphic site, rs12979860. Viral kinetics and rates of rapid virologic response (RVR, week 4), complete early virologic response (week 12), and SVR were compared by IL-28B type in 3 self-reported ethnic groups: Caucasians (n = 1171), African Americans (n = 300), and Hispanics (n = 116). RESULTS: In Caucasians, the CC IL-28B type was associated with improved early viral kinetics and greater likelihood of RVR (28% vs 5% and 5%; P < .0001), complete early virologic response (87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P < .0001) compared with CT and TT. A similar association occurred within African Americans and Hispanics. In a multivariable regression model, CC IL-28B type was the strongest pretreatment predictor of SVR (odds ratio, 5.2; 95% confidence interval, 4.1-6.7). RVR was a strong predictor of SVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B type was associated with a higher rate of SVR (Caucasians, 66% vs 31% and 24%; P < .0001). CONCLUSIONS: In treatment-naive HCV-1 patients treated with pegylated interferon and ribavirin, a polymorphism upstream of IL-28B is associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome.

This study evaluated occurrence of travel and travelers' diarrhea in patients with irritable bowel syndrome (IBS). A survey was mailed to 591 patients of a clinical practice who had IBS. Based on survey responses, patients were categorized as having IBS, post-infectious IBS (PI-IBS), unclassified functional bowel disorder (UFBD), or post-infectious UFBD (PI-UFBD). Of 201 persons who returned questionnaires meeting inclusion criteria, 57.7%, 11.4%, 24.9%, and 6.0% had IBS, UFBD, PI-IBS, and PI-UFBD, respectively. Travel during six months before illness onset was more common in patients with PI-IBS or PI-UFBD than in persons with idiopathic IBS or UFBD (P = 0.006). Survey results demonstrated that 16.1% of post-infectious bowel disorder cases and 7.5% of overall IBS cases in a general medical population developed chronic disease within six months of an international trip. Symptoms of established functional bowel disorder in each clinical category were shown to worsen after travel-related acute diarrhea.

Background/Aims: Impaired fasting glucose is independently associated with reduced likelihood of SVR with current therapy (NEJM, 2009;361:580). However, the relationship between SVR, fasting blood glucose (FBG) and HBA1c has not been defined. Methods: 3070 treatment-naive, CHC genotype 1 patients (pts) received peginterferon (PegIFN) alfa-2b or alfa-2a plus ribavirin (RBV). All pts underwent pretreatment FBG determination and were categorized by their medical history of diabetes. Based on American Diabetes Association definition, pts with FBG ≥100mg/dL were defined as having impaired fasting glucose (IFG). Per protocol, pts with known diabetes and/or FBG ≥116mg/dL underwent HBA1c testing; those with HBA1c >8.5% were excluded. Pts with FBG between 100 and 115mg/dL did not have HBA1c testing. Virologic response rates were analyzed. Results: 3068 pts were included in the analysis. The frequency of IFG of ≥100mg/dL was 28.7% (880/3068) and of a medical history of diabetes was 6.7% (206/3068). Among those who underwent testing (n=324), median HBA1c was 6.1% (interquartile range 5.6% - 6.6%). SVR according to baseline FBG for all pts and according to HBA1c for the subset with testing are shown (Table). SVR rate was significantly lower among pts with IFG compared to those with FBG 8.5% were excluded from treatment. These data suggest that FBG should be routinely assessed prior to therapy; randomized trials are needed to determine if improvement in glucose control prior to treatment will lead to improved viral response. (%) (%) (%)