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Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS ( P = 3.5 × 10 -36 ) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio [OR] = 1.6; 95% confidence intervals [95%CI]: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB1*15:01 carriage, absence of HLA-A*02:01 , and high anti-EBNA1 antibody levels (OR = 24.9; 95%CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 [aa 140 to 149] and EBNA1 [aa 431 to 440]. HLA gene region was associated with anti-ANO2 antibody levels and HLA-DRB1*04:01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95%CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS., Competing Interests: Conflict of interest statement: Outside this work, T.O. has received unrestricted MS research grants, lecture and/or advisory board honoraria from: Biogen, Novartis, Merck, Sanofi, and Roche. Outside this work, P.K. is working at Roche Diagnostics in unrelated projects.

To determine factors influencing failure-to-rescue in patients with complications following cytoreductive surgery and HIPEC. A retrospective analysis of patients enrolled in the Indian HIPEC registry was performed. Complications were graded according to the CTCAE classification version 4.3. The 30- and 90-day morbidity were both recorded. Three hundred seventy-eight patients undergoing CRS with/without HIPEC for peritoneal metastases from various primary sites, between January 2013 and December 2017 were included. The median PCI was 11 [range 0-39] and a CC-0/1 resection was achieved in 353 (93.5%). Grade 3-4 morbidity was seen 95 (25.1%) at 30 days and 122 (32.5%) at 90 days. The most common complications were pulmonary complications (6.8%), neutropenia (3.7%), systemic sepsis (3.4%), anastomotic leaks (1.5%), and spontaneous bowel perforations (1.3%). Twenty-five (6.6%) patients died within 90 days of surgery due to complications. The failure-to-rescue rate was 20.4%. Pulmonary complications ( p  = 0.03), systemic sepsis ( p  < 0.001), spontaneous bowel perforations ( p  < 0.001) and PCI > 20 ( p  = 0.002) increased the risk of failure-to-rescue. The independent predictors were spontaneous bowel perforation ( p  = 0.05) and systemic sepsis ( p  = 0.001) and PCI > 20 ( p  = 0.02). The primary tumor site did not have an impact on the FTR rate ( p  = 0.09) or on the grade 3-4 morbidity ( p  = 0.08). Nearly one-fifth of the patients who developed complications succumbed to them. Systemic sepsis, spontaneous bowel perforations, and pulmonary complications increased the risk of FTR and multidisciplinary teams should develop protocols to prevent, identify, and effectively treat such complications. All surgeons pursuing this specialty should perform a regular audit of their results, irrespective of their experience., Competing Interests: Compliance with Ethical StandardsThe authors declare that they have no conflicts of interest.

Goals: To evaluate our experience with stool donor recruitment, screening, retention, and donor perception for fecal microbiota transplantation (FMT)., Background: Multiply recurrent Clostridium difficile infection is being increasingly managed with FMT from donor stools. However, donor selection and recruitment is challenging due to lack of standard evidence-based guidelines, donor exclusion criteria, frequency of screening and donor commitment., Methods: Data on donors screened using institutional guidelines with history, blood and stool testing and their perspectives on donation were analyzed., Results: Overall 42 potential donors (21 known and 21 standard) were prescreened. Of known donors (median age 34 y, 66.6% female), none failed prescreening, blood or stool tests. Twelve standard donors (57%) failed prescreening based on history (depression, diarrhea, autoimmune disease, recent antibiotic exposure, colon polyps, pregnancy). Nine (median age 35 y, 44.4% female) passed blood and stool testing. On repeat screening, 3 were excluded (2-positive stool shiga toxin (asymptomatic), 1-pregnancy). One donor opted out and 5 became long-term donors; 3 have donated >50 times and 2 have donated >25 times. On the basis of donor perception questionnaire, most standard donors were aware of FMT for C. difficile infection as a treatment option and would not consider 3-monthly blood and stool testing inconvenient., Conclusions: A significant proportion of healthy individuals who volunteered to become a standard donor failed prescreening and were not subjected to blood and stool testing. Repeat testing for asymptomatic donors may be a barrier to donor retention. Universal guidelines are needed to develop strategies to facilitate donor screening.

Background: Gut microbiota play a key role in maintaining homeostasis in the human gut. Alterations in the gut microbial ecosystem predispose to Clostridium difficile infection (CDI) and gut inflammatory disorders such as inflammatory bowel disease (IBD). Fecal microbiota transplantation (FMT) from a healthy donor can restore gut microbial diversity and pathogen colonization resistance; consequently, it is now being investigated for its ability to improve inflammatory gut conditions such as IBD. In this study, we investigated changes in gut microbiota following FMT in 38 patients with CDI with or without underlying IBD., Results: There was a significant change in gut microbial composition towards the donor microbiota and an overall increase in microbial diversity consistent with previous studies after FMT. FMT was successful in treating CDI using a diverse set of donors, and varying degrees of donor stool engraftment suggesting that donor type and degree of engraftment are not drivers of a successful FMT treatment of CDI. However, patients with underlying IBD experienced an increased number of CDI relapses (during a 24-month follow-up) and a decreased growth of new taxa, as compared to the subjects without IBD. Moreover, the need for IBD therapy did not change following FMT. These results underscore the importance of the existing gut microbial landscape as a decisive factor to successfully treat CDI and potentially for improvement of the underlying pathophysiology in IBD., Conclusions: FMT leads to a significant change in microbial diversity in patients with recurrent CDI and complete resolution of symptoms. Stool donor type (related or unrelated) and degree of engraftment are not the key for successful treatment of CDI by FMT. However, CDI patients with IBD have higher proportion of the original community after FMT and lack of improvement of their IBD symptoms and increased episodes of CDI on long-term follow-up.

Background: Clostridium difficile infection (CDI) recurs in 20-30% of patients., Aim: To describe the predictors of recurrence in out-patients with CDI., Methods: Out-patient cases of CDI in Olmsted County, MN residents diagnosed between 28 June 2007 and 25 June 2010 were identified. Recurrent CDI was defined as recurrence of diarrhoea with a positive C. difficile PCR test from 15 to 56 days after the initial diagnosis with interim resolution of symptoms. Patients who had two positive tests within 14 days were excluded. Cox proportional hazard models were used to assess the association of clinical variables with time to recurrence of CDI., Results: The cohort included 520 out-patients; 104 had recurrent CDI (cumulative incidence of 17.5% by 30 days). Univariate analysis identified increasing age and antibiotic use to be associated with recurrent CDI. Severe CDI, peripheral leucocyte count and change in serum creatinine >1.5-fold were not. In a multiple variable model, concomitant antibiotic use was associated with risk of recurrent CDI (HR = 5.4, 95% CI 1.6-17.5, P = 0.005), while age (HR per 10 year increase = 1.1, 95% CI 0.9-1.3, P = 0.22); peripheral leucocyte count >15 × 10(9) /L (HR = 1.0, 95% CI 0.5-2.1, P = 0.92); and change in serum creatinine greater than 1.5-fold (HR = 0.8, 95% CI 0.4-1.5, P = 0.44) were not., Conclusions: Antibiotic use was independently associated with a dramatic risk of recurrent Clostridium difficile infection in an out-patient cohort. It is important to avoid unnecessary systemic antibiotics in patients with Clostridium difficile infection, and patients with ongoing antibiotic use should be monitored closely for recurrent infection., (© 2014 John Wiley & Sons Ltd.)

Background: Community-acquired Clostridium difficile infection (CA-CDI) is an increasingly appreciated condition. It is being described in populations lacking traditional predisposing factors that have been previously considered at low-risk for this infection. As most studies of CDI are hospital-based, outcomes in these patients are not well known., Aim: To examine outcomes and their predictors in patients with CA-CDI., Methods: A sub-group analysis of a population-based epidemiological study of CDI in Olmsted county, Minnesota from 1991-2005 was performed. Data regarding outcomes, including severity, treatment response, need for hospitalisation and recurrence were analysed., Results: Of 157 CA-CDI cases, the median age was 50 years and 75.3% were female. Among all CA-CDI cases, 40% required hospitalisation, 20% had severe and 4.4% had severe-complicated infection, 20% had treatment failure and 28% had recurrent CDI. Patients who required hospitalisation were significantly older (64 years vs. 44 years, P < 0.001), more likely to have severe disease (33.3% vs. 11.7%, P = 0.001), and had higher mean Charlson comorbidity index scores (2.06 vs. 0.84, P = 0.001). They had similar treatment failure and recurrence rates as patients who did not require hospitalisation., Conclusions: Community-acquired Clostridium difficile infection can be associated with complications and poor outcomes, including hospitalisation and severe Clostridium difficile infection. As the incidence of community-acquired Clostridium difficile infection increases, clinicians should be aware of risk factors (increasing age, comorbid conditions and disease severity) that predict the need for hospitalisation and complications in patients with community-acquired Clostridium difficile infection., (© 2012 Blackwell Publishing Ltd.)

Objectives: Although a majority of patients with pouchitis respond favorably to antibiotic therapy, many relapse frequently, and nonabsorbable and non-antibiotic-based agents are desirable for reducing bacterial resistance and the systemic adverse effects associated with long-term antibiotic exposure. AST-120 (a spherical carbon adsorbent) comprises highly adsorptive, porous carbon microspheres with the ability to adsorb small-molecular-weight toxins, inflammatory mediators,and harmful bile acids. The aim of this pilot trial was to evaluate the efficacy and tolerability of AST-120 in the treatment of active pouchitis., Methods: Eligible patients were recruited from two subspecialty pouchitis clinics. Inclusion criteria were(i) ileal pouch-anal anastomosis performed for ulcerative colitis; (ii) active pouchitis with Pouchitis Disease Activity Index (PDAI) scores > or =7; and (iii) discontinuation of antibiotic therapy for at least 2 weeks. Exclusion criteria included Crohn's disease of the pouch, isolated cuffitis, pouch strictures, abscess, and sinuses. All eligible patients received AST-120 in 2-g sachets (oral) open label, thrice a day for 4 weeks. The primary efficacy end point was remission as defined by a PDAI score of < 7 points; the main secondary end point was clinical response, defined by a reduction of the PDAI score of > or =3 points., Results: Nineteen of 20 patients completed the trial. Eleven patients (55.0 % ) had a clinical response to the therapy and 10 patients (50.0 % ) entered remission. Median reduction in the PDAI symptom, endoscopy, and histology subscores, and PDAI total scores after 4 weeks were -2( P = 0.002), -2 ( P = 0.003), 0 ( P = 0.32), and -4 ( P = 0.001) points, respectively. The agent was well tolerated; one patient experienced transient mild elevation of alkaline phosphatase of uncertain significance and one patient experienced an upper respiratory infection after taking one dose of AST-120 and was excluded from the fi nal analysis for the calculation of pre- and post-trial PDAI scores., Conclusions: AST-120 seems to be effective and well tolerated in treating patients with active pouchitis.A randomized, placebo-controlled trial is warranted for assessing the long-term efficacy and safety of AST-120 in the disease.

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.

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.

Our hypothesis was that rumination syndrome is associated with gastric sensory and motor dysfunction. We studied gastric and somatic sensitivity, reflex relaxation of the lower esophageal sphincter (LES), and gastric compliance and accommodation postprandially and postglucagon. A barostatically controlled gastric bag and esophageal manometry were used to compare gastric sensorimotor functions and LES relaxation to gastric distension in 12 patients with rumination syndrome and 12 controls. During bag distensions, patients had greater nausea, bloating, and aggregate score, but not pain, compared with controls (P < 0.05). At 4 and 8 mmHg gastric distension, LES tone reduction was greater in patients than in controls (P < 0.05). Gastric compliance, accommodation to a standard meal, and response to glucagon were not different in patients and controls; however, 6 of 12 patients had no gastric accommodation; the latter patients had significantly greater pain perception during distension (P < 0.05) but normal somatic sensitivity compared with healthy controls. Rumination syndrome is characterized by higher gastric sensitivity and LES relaxation during gastric distension. A subgroup of patients also had absent postprandial accommodation.

Objective: Our aim was to identify qualitative or quantitative colonic motor patterns induced postprandially in a pilot study of patients with diarrhea due to functional disease or dysautonomia to identify objective endpoints for future studies., Methods: In patients with functional diarrhea (n = 5) or dysautonomia (n = 4) in whom GI transit was documented by scintigraphy, we studied colonic motility by combined manometry and barostat measurements for 1 h fasting and 2 h postprandially (1000-kcal meal). Data were compared with those of healthy control subjects., Results: There were no differences in compliance, overall phasic motility of the left colon, fasting tone, or maximal change in postprandial tone in the diarrhea group as compared with the control group. The diarrhea group showed more high amplitude propagated contractions 4.4 +/- 3.6 (SD)/2 h, p < 0.05) compared with the control group (0.7 +/- 1.4/2 h); the mean postprandial tonic response (12 +/- 14%, p < 0.05) and its duration were reduced in the diarrhea group compared with the control group (27 +/- 17%). Two dysautonomic patients showed a paradoxical relaxation of the colon postprandially., Conclusion: Reduced duration of increased colonic tone postprandially and increased number of high amplitude propagated contractions seem to be useful objective endpoints for future studies.

Our aims were to measure antral axial forces in patients with suspected upper gut dysmotilities and to compare the number of antral contractions detected by an axial force catheter and by manometric sensors in the distal antrum and pylorus. Fifteen patients (2 men, 13 women; mean age 42 years) underwent studies for 3 hr fasting, 2 hr postprandially, and up to 60 min after intravenous erythromycin (3mg/kg). Seven patients had gastroparesis or chronic intestinal pseudoobstruction, five functional disease, and three subacute obstruction. Postprandially, the number of peaks detected by the two methods was not significantly different; however, after erythromycin, the axial catheter detected more contractions (P = 0.02). Erythromycin significantly increased the number of postprandial axial forces (from 1.2 +/- 0.3/min to 2.5 +/- 0.3/min, P < or = 0.01) in the whole group and in the organic dysmotility group (P = 0.01). Erythromycin significantly increases the number of axial forces in functional and organic upper gut dysmotilities, but the axial force catheter is not advantageous over manometry for postprandial measurements of antral motility.

During voluntary hyperventilation an increase in the lymphocyte and thrombocyte counts occurs, paralleled by an increase in plasma epinephrine and norepinephrine. All these changes are rapidly reversible after hyperventilation and are followed by an increase in the neutrophil granulocyte count. The pathophysiological mechanisms of these changes were investigated by comparison of the hyperventilation-induced changes of the blood picture in 11 normal, 9 splenectomized and 12 beta-blocked volunteers. Splenectomy did not affect the hyperventilation-induced mobilization of lymphocytes and neutrophils but totally suppressed the change in the thrombocyte count. beta-blockade by 80 mg propranolol did not suppress the hyperventilation-induced increase in neutrophils. It reduced the absolute increase of lymphocytes and thrombocytes by half, but it also increased the baseline counts of these cells. The study shows that hyperventilation mobilizes thrombocytes from the spleen but not from extralienal pools, and that lymphocytes and neutrophils are mobilized from extralienal pools. Whereas neutrophil mobilization is not suppressed by beta-blockade, the reduction of hyperventilation-induced mobilization of lymphocytes and thrombocytes may be due to a reduction in the size of the mobilizable cell pools, and therefore cannot be interpreted as a sure indication that adrenergic mechanisms are involved in their hyperventilation-induced mobilization.

In a controlled study the changes of the plasma volume and plasma proteins induced by voluntary hyperventilation (HV) were investigated in nine splenectomized volunteers. The plasma volume changes were calculated from the changes of the hemoglobin and hematocrit. After 20 min of HV in supine position, which lead to a decrease of the venous CO2 partial pressure by 19 Torr and to an increase of plasma epinephrine and norepinephrine levels, the plasma volume was reduced by 12.9%. The intravascular masses of total protein, albumin, and several other proteins decreased during HV but a similar decrease of these proteins was also observed during the control study (C), i.e., rest in supine position without HV. The differences between changes during HV and C were not significant, indicating that the loss of protein was not due to HV. It is concluded that acute HV leads to a rapidly reversible loss of a virtually protein-free solution from the vascular space. The red cell compartment participated in fluid shifts in that the mean red cell volume decreased by 2.2% (P less than 0.02 compared with C). Comparison with earlier work shows that addition of erythrocytes from the normal spleen does not play a part in the HV-induced increase of hemoglobin and hematocrit.