Obesity and GERD impair esophageal epithelial permeability through 2 distinct mechanisms.

BACKGROUND: The mechanism by which obesity leads to damage independent of reflux is unclear. We aimed to determine the influence of obesity on mean nocturnal baseline impedance (MNBI), a functional measure of the epithelial barrier, in the presence and absence of acid reflux, using ambulatory pH impedance measurements. METHODS: Twenty-four-hour pH impedance studies performed off medications in Caucasian men with a normal endoscopic examination were assessed for level of acid exposure and MNBI. Four patient groups were studied: Group 1, Not obese and normal acid exposure; Group 2, Obese and normal acid exposure; Group 3, Not obese and increased acid exposure; and Group 4, Obese with increased acid exposure. RESULTS: One hundred patients were studied (25 in each group). Mean esophageal mucosal impedance (MI) was substantially lower in obese patients without reflux (Group 2) and non-obese patients with reflux (Group 3) compared to normal controls (non-obese, no reflux, Group 1). MI was progressively lower in the distal (vs the proximal) esophagus in GER patients, compared to those without GER. This difference persisted in the presence or absence of obesity. In contrast, in obese patients, the mean MI was significantly lower throughout the esophagus when compared to the non-obese patients and also persisted in the presence and absence of accompanying reflux. Obesity and reflux were both independently negatively correlated with MI. CONCLUSION: Obesity is associated with abnormal esophageal MNBI. In contrast to gastro-esophageal reflux, this decrease is pan-esophageal. These data may support a systemic mechanism by which obesity alters the esophageal barrier function.

High risk of post-infectious irritable bowel syndrome in patients with Clostridium difficile infection.

BACKGROUND: Infectious enteritis is a commonly identified risk factor for irritable bowel syndrome (IBS). The incidence of Clostridium difficile infection (CDI) is on the rise. However, there is limited information on post-infectious IBS (PI-IBS) development following CDI and the host- and infection-related risk factors are not known. AIM: To determine the incidence and risk factors for PI-IBS following CDI. METHODS: A total of 684 cases of CDI identified from September 2012 to November 2013 were surveyed. Participants completed the Rome III IBS questionnaire and details on the CDI episode. Predictive modelling was done using logistic regression to evaluate risk factors for PI-IBS development. RESULTS: A total of 315 CDI cases responded (46% response rate) and 205 were at-risk (no pre-CDI IBS) for PI-IBS development. A total of 52/205 (25%) met the Rome III criteria for IBS ≥6 months following CDI. IBS-mixed was most common followed by IBS-diarrhoea. In comparison to those without subsequent PI-IBS, greater percentage of PI-IBS patients had CDI symptoms >7 days, nausea, vomiting, abdominal pain during CDI, anxiety and a higher BMI. Using logistic regression, CDI symptoms >7 days [Odds ratio (OR): 2.96, P = 0.01], current anxiety (OR: 1.33, P < 0.0001) and a higher BMI (OR: 1.08, P = 0.004) were independently associated with PI-IBS development; blood in the stool during CDI was protective (OR: 0.44, P = 0.06). CONCLUSIONS: In this cohort study, new-onset IBS is common after CDI. Longer CDI duration, current anxiety and higher BMI are associated with the diagnosis of C. difficile PI-IBS. This chronic sequela should be considered during active management and follow-up of patients with CDI.

Voriconazole exposure and the risk of cutaneous squamous cell carcinoma in allogeneic hematopoietic stem cell transplant patients.

BACKGROUND: Voriconazole is a commonly used antifungal medication in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients. In solid organ transplantation, voriconazole use has been associated with the development of cutaneous squamous cell carcinoma (SCC). We sought to determine if voriconazole use was associated with SCC in patients undergoing allo-HSCT. METHODS: We retrospectively reviewed consecutive adult patients who underwent allo-HSCT at Mayo Clinic from January 2007 through July 2012. Multivariable Cox models were created to assess the relationship of SCC with two time-dependent voriconazole exposure variables: (i) history of voriconazole exposure (yes/no), and (ii) cumulative days of voriconazole use. RESULTS: In our cohort of 381 allo-HSCT patients, SCC developed in 26 of 312 patients exposed to voriconazole (25 post-voriconazole) and in 1 of 69 patients who received alternative antifungal agent(s). Cumulative incidence of SCC was estimated to be 19% at 5 years post allo-transplant. Cumulative days of voriconazole use was found to be a risk factor for SCC, and this relationship persisted in a multivariable model using previously identified risk factors as covariates (hazard ratio 1.859 for each 180 days of use, P < 0.001). CONCLUSION: This is the first study, to our knowledge, to identify cumulative days of voriconazole use as a risk factor for SCC development following allo-HSCT, and may help guide appropriate antifungal use in this patient population.

Investigation of PNPLA3 and IL28B genotypes on diabetes and obesity after liver transplantation: insight into mechanisms of disease.

To identify genetic risks for obesity and diabetes postliver transplantation (LT), LT recipients underwent genotyping for IL28B rs12979860 (n = 295) and PNPLA3 rs738409 (n = 205) polymorphism in both donors and recipients. The development of obesity and diabetes/impaired fasting glucose (IFG) was determined 1-5 years post-LT. Recipient PNPLA-3 genotype was independently associated with obesity (BMI > 30) at 3 years posttransplant (genotype CC 33.7%, CG 48.3% and GG 82.4%, p = 0.002), with an odds ratio (OR 2.54, CI 1.38-4.66, p = 0.003), associated with the G allele. Diabetes/IFG diagnosed within 5 years posttransplant associated with PNPLA-3 non-CC genotype (HR 1.59, 1.12-2.26, p = 0.010), but not IL28B TT genotype (HR 1.46, 0.94-2.27, p = 0.092). No genotype variable was independently predictive of diabetes/IFG. The combination of PNPLA-3 non-CC and IL28B TT genotype was associated with increased risk of diabetes/IFG compared to PNPLA-3 CC, IL28B non-TT (HR 2.64, CI 1.30-5.39, p = 0.008). Donor genotypes were not associated with any of the outcomes analyzed. In conclusion, PNPLA-3 non-CC genotype is associated with posttransplant obesity but not independently with diabetes/IFG. The lack of donor related risk suggests a peripheral rather than central mechanism of insulin resistance in liver transplant recipients.

Disease severity and therapy as predictors of cardiovascular risk in psoriasis: a population-based cohort study.

BACKGROUND: Previous studies suggest an increased risk of cardiovascular disease in psoriasis, but the relative contributions of traditional risk factors and markers of disease severity are unclear. We examined the effect of psoriasis disease characteristics on cardiovascular risk after adjusting for traditional cardiovascular risk factors. METHODS: Study populations included (a) case-cohort sample of 771 patients nested within a population-based psoriasis incidence cohort, and (b) cohort of 1905 patients with incident and prevalent psoriasis patients. Both cohorts were followed-up to ascertain disease and treatment characteristics, traditional cardiovascular risk factors and cardiovascular outcomes. Cox proportional hazards regression models were used to identify predictors of cardiovascular outcomes. RESULTS: After adjusting for traditional risk factors, increasing number of psoriasis-affected body sites at disease onset (HR: 1.53 per additional site, 95% CI: 1.20, 1.95) was significantly associated with an increased risk of cardiovascular outcomes. Phototherapy (HR: 3.76, 95% CI: 2.45, 5.77) and systemic therapy (HR: 2.17, 95% CI: 1.50, 3.13) were associated with a higher risk of cardiovascular outcomes in univariate analyses, but these relatively strong associations disappeared after adjusting for cardiovascular risk factors. CONCLUSIONS: Increasing number of psoriasis-affected body sites may be a severity indicator in psoriasis and is associated with an increased cardiovascular risk. Due to low number of patients exposed to systemic therapy, this study had limited power to examine the effect of treatment on cardiovascular risk. Strong associations with phototherapy and systemic therapy suggest that the cardiovascular risk in psoriasis is confined to patients with severe disease.

Neurological complications following adult lung transplantation.

The full spectrum of neurologic complications and their impact on survival in lung recipients has not been reported. A retrospective cohort review of the Mayo Clinic Lung Transplant Registry (1988-2008) was performed to determine the range of neurologic complications in a cohort of adult lung recipients. Cox regression models were used to assess risk factors for neurological complications and death posttransplant. One hundred and twenty lung transplant recipients (53% women, median age at transplantation 53 years, range 21-73, median survival 4.8 years) were identified, of whom 95 had a neurological complication posttransplantation (median time to complication 0.8 years). Neurological complications were severe in 46 patients (requiring hospitalization or urgent care and evaluation) and were most often perioperative stroke or encephalopathy. Age predicted neurological complications of any type, whereas lung allocation score, bilateral lung transplantation, sex, underlying lung disease, elevated hemoglobin A1C, renal insufficiency and smoking history did not. Neurological complications of any severity (HR 4.3, 95% CI 2.2-8.6, p < 0.001) and high severity (HR 7.2, 95% CI 3.5-14.6, p < 0.001) were associated with increased risk of death. Neurological complications are common after lung transplantation, affecting 92% of recipients within 10 years. Severe neurologic complications are also common, affecting 53% of recipients within 10 years.

Asimadoline, a kappa-opioid agonist, and satiation in functional dyspepsia.

BACKGROUND: Asimadoline, a kappa-opioid agonist, reduces visceral sensitivity in experimental animal models and may decrease satiation and postprandial fullness in healthy individuals. However, its effect on satiation in functional dyspepsia is unclear, and any symptom benefit has not been explored. AIM: To evaluate the effects of asimadoline on satiation volume and postchallenge symptoms in functional dyspepsia. METHODS: A randomized, double-blind trial evaluated gastric satiation and symptoms before and after 8 weeks of asimadoline 0.5 mg (n = 13) or 1.0 mg (n = 13) or placebo (n = 14) b.d. in patients with functional dyspepsia (Rome II). Gastrointestinal Symptom Rating Scale and Nepean Dyspepsia Index were used to assess symptoms during the 8-week treatment. RESULTS: Over 8 weeks of treatment, asimadoline had no significant effect on maximum-tolerated volume or aggregate symptom score with nutrient drink challenge, and on the mean of the total daily symptom severity score compared to placebo. In a post hoc analysis, asimadoline 0.5 mg significantly increased the maximum-tolerated volume (1217 mL +/- 90.2) compared to placebo (807 mL +/- 111.8) in patients with higher postprandial fullness scores (P = 0.01). CONCLUSION: Asimadoline overall did not significantly alter maximum-tolerated volume, symptoms postnutrient challenge or symptoms over 8 weeks in functional dyspepsia.

A novel partial 5HT3 agonist DDP733 after a standard refluxogenic meal reduces reflux events: a randomized, double-blind, placebo-controlled pharmacodynamic study.

BACKGROUND: DDP733, a selective partial 5HT(3) receptor agonist, increases lower oesophageal sphincter pressure in experimental animal models. However, its effect on gastro-oesophageal reflux or lower oesophageal sphincter pressure in humans remains unknown. AIM: To evaluate the effect of DDP733 on reflux episodes in healthy volunteers receiving a refluxogenic meal. METHODS: A randomized, double-blind, placebo-controlled cross-over study evaluated the pharmacodynamic effects of DDP733 (0.5, 0.8 and 1.4 mg). Healthy subjects underwent oesophageal manometry and intra-oesophageal multichannel intraluminal impedance and pH after a refluxogenic meal. RESULTS: DDP733 0.5 mg significantly (P = 0.013) reduced the rate of reflux episodes after a refluxogenic meal from 10 (+/-2.2) on placebo to 6 (+/-1.2) on drug over a 2-h period. DDP733 0.8 and 1.4 mg had no significant effect on reducing the number of reflux episodes. Significant differences in resting lower oesophageal sphincter pressure and the proportion of time pH was <4 (placebo minus drug) after a refluxogenic meal were not observed. No serious adverse events were reported. CONCLUSION: In healthy subjects, the partial 5HT(3) agonist DDP733 at a dose of 0.5 mg significantly reduces the rate of reflux events, but did not result in a significant change in lower oesophageal sphincter pressure at 1 h postdosing.

Varicella zoster virus-associated disease in adult kidney transplant recipients: incidence and risk-factor analysis.

Varicella zoster virus (VZV)-related disease, particularly herpes zoster, is a complication of organ transplantation due to long-term immunosuppression. We determined the incidence and risk factors for post-transplant VZV infection by retrospectively reviewing the medical records of a cohort of 612 adult renal transplant recipients transplanted at Mayo Clinic Rochester between October 1, 2001 and October 1, 2004. Thirty-seven subjects developed herpes zoster, corresponding to a follow-up time-adjusted incidence of 11.2% at 4 years post transplant. The incidence rate of zoster was relatively constant between 6 months and 4 years, yielding an average incidence of approximately 28 per 1000 person-years. The risk of developing post-transplant zoster increased with increasing age at transplant, with each decade conferring a 1.42-fold (P=0.009) increase in risk of zoster development. Seronegativity at time of transplant conferred over 3 times the risk of development of post-transplant zoster (hazard ratio 3.4; P=0.04) compared with seropositivity. Adult kidney transplant recipients are at high risk for the development of post-transplant zoster.

Supraesophageal reflux: validation of a symptom questionnaire.

OBJECTIVE: To develop and validate a questionnaire for supraesophageal manifestations of reflux (SER) that will facilitate its study in clinical and research settings. STUDY DESIGN: The Supraesophageal Reflux Questionnaire (SERQ) and previously validated Reflux Symptom Index (RSI) were subjected to multiple types of validity testing, including content validity, concurrent validity, reproducibility, and predictive validity. RESULTS: The concurrent validity and reproducibility of both instruments was good to excellent for most items tested. The predictive validity of the SERQ was superior to the RSI when it included the covariates of history of sinusitis, use of over-the-counter antacid medications, age, gender, and body mass index. CONCLUSIONS: The SERQ will serve as both a useful clinical and research tool by offering not only SER symptom information, like the RSI, but also information about the patient's medical history and medication usage that will facilitate use of the SERQ in research protocols. EBM RATING: B-2b.

Dyspepsia management in primary care: a management trial.

The aim was to evaluate the outcomes associated with four initial management strategies in new patients presenting to primary care physicians with dyspepsia. Patients with new symptoms (no alarm features) were randomised to empirical therapy (n = 11), Helicobacter pylori (HP) serology (n = 8), HP breath testing (n = 11) or oesophagogastroduodenoscopy (n = 13). Dyspepsia and health-related quality of life were assessed using standardised questionnaires at entry, 6 and 24 weeks post-trial enrollment. Outcomes were assessed by structured telephone interview every 6 weeks. In the initial HP testing arms, 21% were positive; 27% in the oesophagogastroduodenoscopy arm had inflammatory changes without ulcers at baseline. The majority (67%) received over the counter medication after initial management. Symptom-free status was similarly common in all groups (p = 0.49); only 20% pursued further evaluation. Total billed charges were higher in the oesophagogastroduodenoscopy group (US 2077 dollars) vs. empirical therapy (US 512 dollars), despite excluding the charge for initial oesophagogastroduodenoscopy, but overall, no effects on total medical charges were detected (p = 0.10). Regardless of initial management, most patients remained symptomatic, yet did not return for health care visits or undergo endoscopies. The cost of upfront endoscopy may not be the best choice for patients presenting with new dyspepsia.

CYP2C19 pharmacogenetics in the clinical use of proton-pump inhibitors for gastro-oesophageal reflux disease: variant alleles predict gastric acid suppression, but not oesophageal acid exposure or reflux symptoms.

BACKGROUND: The rate of metabolic inactivation of proton-pump inhibitors is determined by polymorphisms of CYP2C19. It is not known if CYP2C19 variant alleles affect responses to proton-pump inhibitor therapy in gastro-oesophageal reflux disease (GERD). AIM: To determine if the CYP2C19 genotype is associated with clinical effectiveness of proton-pump inhibitors during GERD therapy. METHODS: GERD patients undergoing ambulatory gastric and oesophageal pH monitoring were genotyped for CYP2C19 polymorphisms. RESULTS: Sixty subjects were enrolled. Forty-four subjects had two wild-type alleles, 15 had one variant, and one had two variant CYP2C19 alleles. The presence of a variant allele was significantly associated with a lower odds of gastric acid breakthrough during proton-pump inhibitor therapy [odds ratio 5.14, 95% confidence interval (CI) 1.17-22.61]. The presence of a variant allele was not associated with a lower odds of significant oesophageal acid exposure (odds ratio 2.50, 95% CI 0.60-10.52), or the occurrence of symptoms (incidence rate ratio 1.06, 95% CI 0.54-2.06). CONCLUSIONS: These results indicate that factors other than gastric acid secretion are important determinants of reflux in GERD patients. This suggests that CYP2C19 genotype testing will not be useful in proton-pump inhibitor therapy of GERD, except perhaps in identifying patients at risk for hypochlorhydria and consequent hypergastrinemia.