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Nephrogenic systemic fibrosis (NSF) is a scleroderma-like systemic fibrosing condition of unknown etiology described in patients with renal insufficiency. Gadolinium exposure has been strongly associated with the development of NSF though the mechanism of such injury is not known. There are only few reported cases of NSF in the setting of acute renal failure and fewer reported cases where skin lesions developed after kidney function had returned to normal. We report a case of NSF in a young Hispanic woman with lupus nephritis but normal creatinine, who received gadolinium during a brief episode of prerenal acute kidney injury not requiring dialysis, secondary to sepsis.

There is increasing evidence that a subset of gastrointestinal motility disorders is associated with the presence of circulating antibodies. These antibodies are directed against various molecular targets, the best known being anti-neuronal nuclear antibody (ANNA-1, aka anti-Hu) associated with paraneoplastic motility disorders. There is also evidence that the presence of distinct auto-antibody profiles is associated with non-paraneoplastic motility disorders. This review will focus on the types of antibodies associated with gastrointestinal motility disorders and the significance of these antibodies. The review will also suggest algorithms for the work up and treatment of patients with circulating antibodies associated with gastrointestinal motility disorders

Background: Irritable Bowel Syndrome (IBS) has been associated with changes in the rectosigmoid mucosal expression of immune (TNFSF15, TLRs) and nonimmune (tight junctions, mucus and serotonergic) factors. In a recent microarray based study on Campylobacter jejuni post-infectious IBS (PI-IBS), patients were found to have an increased rectal mucosal expression of CCL11, CCL13, Calpain 8 (pro-inflammatory), GABRE and decreased expression of NR1D1, GPR161. Aim: To determine changes in colonic mucosal RNA expression among patients with C. jejuni PI-IBS in comparison to healthy volunteers using whole transcriptome sequencing. Methods: Sigmoid colonic biopsies were obtained from 5 PI-IBS patients (3 females) and 7 age-matched healthy volunteers (5 females). Biopsies were preserved in RNALater at -80°C. Total RNA was isolated using the RNeasy Plus Mini Kit (Qiagen, Valencia, CA). All samples had RNA Integrity Numbers >7.0. RNA library preparation was performed using the Illumina TruSeq RNA Sample Prep v2 (San Diego, CA) and sequencing was performed as paired-end 51 base reads on an Illumina HiSeq 2000 with 3 samples/ lane using TruSeq SBS Sequencing Kit Version 3. Base calling was performed using Illumina's RTA version 1.12.4.2. Analysis (alignment statistics, in-depth quality control, gene and exon expression, fusion transcripts, and single nucleotide variants) was done using MAP-RSeq v1.2.1.3. Differential expression between samples was done using edgeR algorithm. Results were also compared to our recently published transcriptomic data from rectosigmoid biopsies of IBS-D patients (Am J Physiol 306: G1089-G1098, 2014). Results: Overall, mRNA expressions of 20 genes were changed in patients with C. jejuni PI-IBS as compared to healthy volunteers (P values obtained using false detection rate (FDR) threshold of 5% ranged from 10-5 to 10-9) (Table 1). The genes that stood out as potentially relevant to pathophysiology of PI-IBS included: neurotransmitter-related genes (↑neuropeptide Y receptor type 2, ↑Galanin, ↓nitric oxide synthase 2 (inducible), and ↓indoleamine 2, 3-dioxygenase 1), proteases (↑Secretory leukocyte peptidase inhibitor, ↓Matrix metallopeptidase 3), chemokines (↑chemokine C-C motif ligand 18, ↓chemokine C-X-C motif ligand 10 and 11), carbohydratemetabolism (↑aldolase B, ↑sucrase-isomaltase), ion channels and transporters (↑bestrophin 4, ↑calbindin 2, ↑solute carrier family 3). With the exception of aldolase B expression, there was no overlap with the IBS-D dataset. Conclusion: Transcriptome sequencing of sigmoid colonic mucosa in C. jejuni PI-IBS shows distinct transcriptomic differences from healthy controls and from non-post-infectious IBS-D. These data provide the rationale to explore the role of mucosal factors in the pathophysiology of C. jejuni PI-IBS. Table 1: Gene expression identified by edgeR showing relative expression in C. jejuni PIIBS compared to healthy volunteers

The present study aimed to compare the efficacy for the therapy of GERD of pantoprazole alone with a combination of pantoprazole and mosapride. The study was a prospective, randomized trial involving 68 patients suffering heartburn and/or regurgitation at least twice a week for 6 weeks. Sixty-one patients consented to be randomized to receive either pantoprazole 40 mg b.i.d. (n = 33, group A) or pantoprazole 40 mg b.i.d. plus mosapride 5 mg t.d.s. (n = 28, group B) for 8 weeks. Twenty-four-hour esophageal pH-metry and endoscopy were conducted at recruitment and endoscopy was repeated at 8 weeks in all the patients studied. There were no differences in symptomatic responses to therapy between the groups (69.7% vs 89.2%; P = 0.11). The mean symptom score after 8 weeks was significantly lower in group B (3.78 +/- 3.62 vs 1.67 +/- 2.09; P = 0.009). Nonerosive esophagitis was present in 29 patients. In patients with nonerosive GERD there was no significant difference in symptomatic response to either regimen (17/20 in group A and 7/9 in group B responded; P = 0.63). In erosive esophagitis, symptomatic responses occurred more frequently in group B, 18/19 (94.7%), than in group A, 6/13 (46.2%; P = 0.003). However endoscopic healing of esophagitis occurred equally with either regimen (6/11, 54.5% in group A; 12/17, 70.5% in group B; P = 0.44). In nonerosive GERD, the addition of mosapride offers no benefit over pantoprazole alone. A combination of pantoprazole and mosapride is more effective than pantoprazole alone in providing symptomatic relief to patients with erosive GERD.

A 75-year-old man with a refractory esophageal stricture underwent placement of a 20F pull-type PEG tube (MIC PEG Feeding Tube; Kimberly-Clark, Roswell, Ga) 5 months earlier. Because of tube occlusion, the indwelling PEG tube was replaced uneventfully using a balloon replacement tube (MIC Gastrostomy Feeding Tube; Kimberly-Clark) without fluoroscopic confirmation after traction removal of the original tube. Several hours later, the patient returned after development of severe abdominal pain when medications were administered through the gastrostomy tube. The tube was injected with water-soluble contrast under fluoroscopy that extravasated into the peritoneum.

μM propofol, the amplitude was significantly reduced in both distal and proximal colon (p

Background: IBS is one of the most prevalent functional gastrointestinal disorders. Earlier studies have shown that IBS patients are more likely to be impaired at work and during daily activities compared to non-IBS patients. However, factors of importance for this impairment have not yet been fully examined. Aim: To investigate the relationship between work impairment and other factors related to IBS. Methods: We included 533 patients with IBS (median age 34 (17-80) years, 420 females). The patients completed the Work Productivity and Activity Impairment Questionnaire:IBS (WPAI:IBS), as well as questionnaires to assess IBS symptom severity (IBS-SSS), GI-specific anxiety (VSI), somatic symptoms (PHQ-15), depression and anxiety (HAD), and fatigue (MFI). Uniand bivariate analyses were performed, as well as linear regression analyses to determine factors independently associated with the work productivity and activity impairment measures. Results: The IBS patients reported 7±19% (mean±SD) absenteeism (actual work time missed), 33±25% presenteeism (impairment while at work), 36±27% overall work productivity loss and 46±27% activity impairment. Female IBS patients reported greater activity impairment than males (47±27 vs. 41±27 %; p

regionand layer-specific activities in the human intestine. Its inhibitory effect involved decreased intracellular calcium level via closure of SOCs that belong to the TRPC3/TRPA1 family. Apart from milk thistle and iberis amara, all extracts contributed to the effects of STW5. Peppermint, angelica and liquorice mimicked its inhibitory action on muscle activity. The identification of region and target specific actions of STW5 and its components suggests their potential for treating small and large intestinal motility disorders.

Background and Aims: The dysregulation of microRNAs (miRNAs, miR) in Crohn's disease (CD) was observed, suggesting a role for miRNAs as contributors to CD susceptibility. We previously showed that the adherent-invasive E. coli (AIEC), which abnormally colonize the intestinal mucosa of CD patients, are able to adhere to and invade intestinal epithelial cells (IECs). Here, we elucidated the mechanism by which AIEC infection modulates expression of miRNAs to suppress the host defense response. Methods: Mature miRNA expression was quantified by quantitative RT-PCR. Direct binding of miRNAs to the 3'-untranslated regions of their mRNA targets was determined by luciferase assay. Binding of NFκB to miRNA gene promoter was assessed by Chromatin immunoprecipitation assay. Autophagic activity was assessed by Western blot analysis and immunofluorescent labelling of LC3. Intracellular bacterial number was determined by invasion assay and confocal microscopy. In vivo transfection of miRNAs or anti-miRNAs was performed using a mouse ileal loop model. Results: AIEC infection activated NF-kB pathway, driving the transcription of miR-30c and miR130a genes. The AIEC-induced miR-30c and miR-130a upregulation in turn resulted in a decrease in ATG5 and ATG16L1 expression and inhibited autophagic activity, leading to abnormal intracellular persistence of AIEC and enhanced pro-inflammatory response. A reverse correlation between expression of miR-30c and miR-130a and that of ATG5 and ATG16L1 in CD ileal biopsies was observed, supporting the pathological relevance of the in vitro data. Inhibition of miR-30c and miR-130a in vitro and in vivo effectively blocked the AIEC-induced defect in autophagy, suppressing AIEC intracellular replication and AIECinduced inflammation. Conclusions: We show here that AIEC infection suppresses autophagy response to replicate within host cells by regulating miRNA expression. Our study strongly reinforces the increasing evidence showing autophagy deficiency as a molecular pathway underlying the pathogenesis of CD. This raises autophagy-targeting miRNAs as promising therapeutic targets to inhibit the intracellular replication of CD-associated bacteria and the consequent bacterial-induced inflammation.

Background and Aim: Several studies have looked at the effects of different types of fiber (i.e., prebiotics) on gut microbiota and symptoms in patients with IBS; however there is lack of consistent response to prebiotics among patients. In order to determine the reason for lack of predictable responses in patients, here we investigate the effect of a specific dietary change on gut microbial composition using humanized mice. Methods: Germ free (GF) mice were colonized with human feces (humanized) by gavage of 200μl of frozen feces mixed with an equal volume of pre-reduced PBS. Microbial composition was assessed by 16S rRNA based pyrosequencing using the 454-titanium platform. Non-targeted fecal metabolomics was performed using UPLC-MS. Data analysis was performed using QIIME and MetaboAnalyst. Results: GF mice were humanized using feces from three healthy human donors: two males and one female (n=4-8/donor). Four weeks following humanization, fecal samples were collected from each mouse. Un-weighted UniFrac based PCoA plots of the 16S rRNA microbial composition data demonstrate reproducible reconstitution of the corresponding human fecal inoculum in humanized mice. The metabolomic profile of each sample was used as a read-out of the microbiota functional status. PCoA of these metabolomicsbased "fingerprints" revealed that reproducible aspects of microbiota functional status are dictated by the human fecal inoculum. Together these data show that individual aspects of the human gut microbiota's composition and metabolomic activity can be reconstructed within humanized mice. The presence of most fecal metabolites was independent of the fecal source (human or humanized mouse) suggesting that much of the microbiota functional status is resilient to modification by the host species and largely shared between individuals. In order to determine if dietary intervention impacts all three groups of humanized mice similarly, diet was switched from standard diet to FOS-enriched diet (fructo-oligosaccharide, commonly used prebiotic; 10%w/v). Fecal samples were collected before and after dietary intervention. Un-weighted UniFrac based PCoA plots of the 16S rRNA microbial composition data show distinct diet-induced changes in microbial composition between the three groups of humanized mice, with only a small effect seen in one group. Conclusion: Gut microbial composition and function can be reliably reconstructed in humanized mice making them a good model to study effects of environmental factors on the human gut microbiota. The effect of prebiotics/dietary intervention on gut microbial composition depends on the initial microbial community composition. This study may therefore provide new insight into the observed differences in patient responses to prebiotics in previous studies.

Background & Aims Gastroparesis is a well-recognized complication of diabetes. In diabetics, up-regulation of heme oxygenase-1 (HO1) in gastric macrophages protects against oxidative stress-induced damage. Loss of up-regulation of HO1, the subsequent increase in oxidative stress, and loss of Kit delays gastric emptying; this effect is reversed by induction of HO1. Macrophages have pro- and anti-inflammatory activities, depending on their phenotype. We investigated the number and phenotype of gastric macrophages in NOD/ShiLtJ (nonobese diabetic [NOD]) mice after onset of diabetes, when delayed gastric emptying develops, and after induction of HO1 to reverse delay. Methods Four groups of NOD and db/db mice were studied: nondiabetic, diabetic with normal emptying, diabetic with delayed gastric emptying, and diabetic with delayed gastric emptying reversed by the HO1 inducer hemin. Whole mount samples from stomach were labeled in triplicate with antisera against F4/80, HO1, and CD206, and macrophages were quantified in stacked confocal images. Markers for macrophage subtypes were measured by quantitative polymerase chain reaction. Results Development of diabetes was associated with an increased number of macrophages and up-regulation of HO1 in CD206+ M2 macrophages. Onset of delayed gastric emptying did not alter the total number of macrophages, but there was a selective loss of CD206+/HO1+ M2 macrophages. Normalization of gastric emptying was associated with repopulation of CD206+/HO1+ M2 macrophages. Conclusions CD206+ M2 macrophages that express HO1 appear to be required for prevention of diabetes-induced delayed gastric emptying. Induction of HO1 in macrophages might be a therapeutic option for patients with diabetic gastroparesis.

To understand how different diets, the consumers' gut microbiota, and the enteric nervous system (ENS) interact to regulate gut motility, we developed a gnotobiotic mouse model that mimics short-term dietary changes that happen when humans are traveling to places with different culinary traditions. Studying animals transplanted with the microbiota from humans representing diverse culinary traditions and fed a sequence of diets representing those of all donors, we found that correlations between bacterial species abundances and transit times are diet dependent. However, the levels of unconjugated bile acids-generated by bacterial bile salt hydrolases (BSH)-correlated with faster transit, including during consumption of a Bangladeshi diet. Mice harboring a consortium of sequenced cultured bacterial strains from the Bangladeshi donor's microbiota and fed a Bangladeshi diet revealed that the commonly used cholekinetic spice, turmeric, affects gut motility through a mechanism that reflects bacterial BSH activity and Ret signaling in the ENS. These results demonstrate how a single food ingredient interacts with a functional microbiota trait to regulate host physiology.