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1.  Impact of switching from mycophenolate mofetil to enteric-coated mycophenolate sodium on gastrointestinal side effects in patients with autoimmune disease: a Phase III, open-label, single-arm, multicenter study 
The purpose of this study was to assess changes in gastrointestinal symptom severity in patients with autoimmune disease who were switched from mycophenolate mofetil to enteric-coated mycophenolate sodium (EC-MPS).
In this national, explorative, single-arm study, 111 patients were enrolled and switched to equimolar EC-MPS at baseline. The primary endpoint was change in the Gastrointestinal Symptom Rating Scale (GSRS) total score after 6–8 weeks of treatment (Visit 2). The optional follow-up visit was 6–12 weeks after completion of the study (Visit 2). Secondary endpoints were changes in GSRS subscale score; changes in gastrointestinal-related quality of life measured by the Gastrointestinal Quality of Life Index (GIQLI); and general health-related quality of life (HRQoL) measured by Psychological General Well-Being Index and assessment of overall treatment effect (OTE). Change was evaluated by paired t-tests.
At Visit 2, the mean ± standard deviation GSRS total score improved from 2.28±1.13 to 2.02±0.93 points. The change (−0.28±0.92 points, P=0.002) was statistically significant. The change at the follow-up visit (−0.36±0.94 points, P=0.001) was statistically significant and more than the minimal clinical important difference. GSRS subscores showed statistically significant and clinically relevant improvement for abdominal pain (−0.51±1.2 points, P<0.001) and indigestion (−0.42±1.33 points, P=0.002). Overall GIQLI score showed significant improvement from baseline to Visit 2 (−5.8±18.6 points, P=0.002). Per OTE, improvement was reported in 44.1% and 34.2% patients as rated by physicians and patients, respectively. The majority of patients (55%) reported OTE-HRQoL as unchanged. Diarrhea and nausea were the commonly reported adverse events.
Patients switched to EC-MPS experienced less gastrointestinal symptom burden and showed improvement in HRQoL.
PMCID: PMC4516030  PMID: 26229499
mycophenolate mofetil; enteric-coated mycophenolate sodium; autoimmune disease; patient-reported outcome; health-related quality of life
2.  Prevalence of mental health disorders in inflammatory bowel disease: an Australian outpatient cohort 
This study aimed to characterize prevalence of anxiety and depressive conditions and uptake of mental health services in an Australian inflammatory bowel disease (IBD) outpatient setting.
Eighty-one IBD patients (39 males, mean age 35 years) attending a tertiary hospital IBD outpatient clinic participated in this study. Disease severity was evaluated according to the Manitoba Index. Diagnosis of an anxiety or depressive condition was based upon the Mini-International Neuropsychiatric Interview and the Hospital Anxiety and Depression Scale.
Based on Hospital Anxiety and Depression Scale subscale scores >8 and meeting Mini-International Neuropsychiatric Interview criteria, 16 (19.8%) participants had at least one anxiety condition, while nine (11.1%) had a depressive disorder present. Active IBD status was associated with higher prevalence rates across all anxiety and depressive conditions. Generalized anxiety was the most common (12 participants, 14.8%) anxiety condition, and major depressive disorder (recurrent) was the most common depressive condition reported (five participants, 6.2%). Seventeen participants (21%) reported currently seeking help for mental health issues while 12.4% were identified has having at least one psychological condition but not seeking treatment.
We conclude that rates of anxiety and depression are high in this cohort, and that IBD-focused psychological services should be a key component of any holistic IBD service, especially for those identified as having active IBD.
PMCID: PMC4512611  PMID: 26213474
inflammatory bowel disease; psychological conditions; disease activity
3.  Risk factors for recurrent hospital-acquired Clostridium difficile infection in a Japanese university hospital 
Clostridium difficile infection (CDI) is a highly prevalent hospital-associated infection. Although most patients respond well to discontinuation of antibiotics, 20%–30% of patients relapse. To initiate early therapeutic measures, the risk factors for recurrent CDI must be identified, although very few Japanese studies have used standard surveillance definitions to identify these risk factors.
We retrospectively reviewed the medical records of patients with health care facility-onset CDI between August 2011 and September 2013. Patients with diarrhea who were positive for Clostridium difficile (via an enzyme immunoassay) were defined as having CDI. Clinical data (eg, demographics, comorbidities, medication, laboratory results, and clinical outcomes) were evaluated, and multivariate analysis was used to identify risk factors that were associated with recurrent CDI.
Seventy-six health care facility-onset CDI cases were identified, with an incidence rate of 0.8 cases per 10,000 patient-days. Fourteen cases (18.4%) were recurrent, with 13 patients having experienced a single recurrent episode and one patient having experienced three recurrent episodes. The 30-day and 90-day mortality rates were 7.9% and 14.5%, respectively. Multivariate analysis revealed that recurrent patients were more likely to have underlying malignant disease (odds ratio: 7.98; 95% confidence interval: 1.22–52.2; P=0.03) and a history of intensive care unit hospitalization (odds ratio: 49.9; 95% confidence interval: 1.01–2,470; P=0.049).
Intensive care unit hospitalization and malignancy are risk factors for recurrent CDI. Patients with these factors should be carefully monitored for recurrence and provided with appropriate antimicrobial stewardship.
PMCID: PMC4507450  PMID: 26203270
Clostridium difficile; recurrent infection; risk factors
4.  Alcoholic liver disease in Nepal: identifying homemade alcohol as a culprit 
Though the type of alcohol consumed is not thought to be associated with alcoholic liver disease (ALD), some studies have shown a beverage-specific effect. In the present study, we aim to study the effects of locally brewed alcoholic beverages on the development of liver disease.
Patients and methods
This cross-sectional study was conducted at the internal medicine department of a university hospital in Nepal. All patients classified as having either alcohol abuse or alcohol dependence by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition were evaluated for the presence of ALD.
A total of 1,500 patients were screened, of which, 447 patients had ALD. Chronic liver disease (CLD) was detected in 144 patients (9.6%). Most of the patients consumed homemade locally brewed alcohol. On multivariate analysis, the following variables were found to be significantly associated with CLD: male sex (odds ratio [OR]: 1.81; 95% confidence interval [CI]: 1.12–2.94; P=0.02): rakshi consumption ≥30 units (OR: 2.53; 95% CI: 1.07–6.01; P=0.04); and tongba consumption (OR: 3.02; 95% CI: 1.22–7.50; P=0.02).
There was a significant increase in the risk of developing ALD with the consumption of rakshi and tongba after adjusting for total units consumed. The absence of striking differences between our patients with CLD and non-CLD patients with regards to the amount of alcohol consumed demonstrates that, although alcohol consumption is a prerequisite for the development of ALD, other factors like type of alcoholic beverage consumed may be involved.
PMCID: PMC4506025  PMID: 26203269
alcohol use disorders; alcoholic liver disease; locally brewed alcohol
5.  Partial hepatectomy induces delayed hepatocyte proliferation and normal liver regeneration in ovariectomized mice 
Estrogens play central roles in sexual development, reproduction, and hepatocyte proliferation. The ovaries are one of the main organs for estradiol (E2) production. Ovariectomies (OVXs) were performed on the female mice, and hepatocyte proliferation was analyzed. The ovariectomized mice exhibited delayed hepatocyte proliferation after partial hepatectomy (PH) and also exhibited delayed and reduced E2 induction. Both E2 administration and PH induced the gene expression of estrogen receptor α (ERα). The transcripts of ERα were detected specifically in periportal hepatocytes after E2 administration and PH. Moreover, the E2 concentrations and hepatocyte proliferation rates were highest in the proestrus period of the estrous cycle. Taken together, these findings indicate that E2 accelerated ERα expression in periportal hepatocytes and hepatocyte proliferation in the female mice.
PMCID: PMC4494181  PMID: 26170710
estrogen; ER; estrous cycle; hepatocyte proliferation; liver regeneration
6.  Differential response to microbial antigens by age of diagnosis in patients with Crohn’s disease 
Fifteen percent of incident Crohn’s disease (CD) cases are diagnosed at older ages and demonstrate colonic location and inflammatory behavior. Serologic responses to gut microbial antigens are associated with specific phenotypes, and may differ by age at diagnosis. Our aim was to identify an association between age at diagnosis of CD and responses to gut microbial antigens.
Patients and methods
Levels of anti-Saccharomyces cerevisiae antibodies (ASCA) immunoglobulins A and G (IgA and IgG), antibodies to Escherichia coli outer membrane porin-C (anti-Omp-C), antibodies to clostridial flagellin (anti-CBir-1), and perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) were compared in patients by age in three diagnosis groups: patients diagnosed at ages of <40, ≥40–59, and ≥60 years. For each antigen, patients with antibody levels in the first, second, third, and fourth quartile were assigned a score of 1, 2, 3, or 4, respectively. Individual scores were added to create a quartile sum score representing cumulative quantitative immune response.
Eighteen, 17, and 12 patients were diagnosed at ages <40, 40–59, and ≥60 years, respectively. The majority (71%) had ileocolonic disease in the youngest group, compared to 36% in the oldest group (P=0.001). Mean ASCA IgA and IgG titers were increased in the youngest age group compared to the older groups (P=0.19 and P=0.13, respectively). Mean quartile sum scores for antibody levels were 7.2±2.8 in those patients diagnosed at ages <40 years, 4.9±2.9 in the 40–59-year-old age group, and 5.6±2.6 in the ≥60-year-old age group (P=0.06).
A trend toward decreased cumulative immune responses to CD-associated gut antigens was observed in CD patients diagnosed at older ages compared to younger patients. Host responses to microbial antigens may be less important in older onset IBD and may contribute to the distinct phenotype in this group.
PMCID: PMC4467647  PMID: 26089697
serologic tests; Crohn’s disease; aging; phenotype
7.  Profile of rifaximin and its potential in the treatment of irritable bowel syndrome 
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by recurrent abdominal pain and abnormal bowel patterns. Alteration in gut flora, visceral hypersensitivity, and abnormal bowel motility are among numerous factors in the complex pathophysiology of IBS. Antibiotics have been used adjunctively to treat IBS for many years but are associated with various systemic side effects. Rifaximin is a nonabsorbable, broad-spectrum antimicrobial that inhibits bacterial RNA synthesis by binding the β-subunit of microbial RNA polymerase. It targets the gastrointestinal tract and works by reducing the quantity of gas-producing bacteria and altering the predominant species of bacteria present. In vivo animal studies suggest additional beneficial mechanisms of rifaximin, including reducing mucosal inflammation and visceral hypersensitivity. Clinical studies have demonstrated that rifaximin improves symptoms associated with IBS, such as bloating, flatulence, stool consistency, and abdominal pain, and has a side-effect profile similar to placebo. Although additional investigation into optimal dosing, treatment duration, and potential resistance is required, rifaximin presents as a safe and beneficial addition to the current management options for IBS.
PMCID: PMC4467648  PMID: 26089696
irritable bowel syndrome; rifaximin; small intestinal bacterial overgrowth; mucosal inflammation
8.  Web-based interventions for ulcerative colitis and Crohn’s disease: systematic review and future directions 
Behavioral intervention technologies (BITs), the application of psychological and behavioral interventions through the use of technology, provide the opportunity for clinicians to deliver care through a means that overcomes a number of treatment barriers. Web-based interventions are a subset of BITs developing as promising alternatives to face-to-face delivery of treatments and monitoring for patients with ulcerative colitis (UC) and Crohn’s disease (CD). A systematic review of literature resulted in five empirical studies of web-based interventions for UC and CD. Additionally, an informal search of a popular search engine yielded limited, currently available, web-based interventions for patients with UC and CD. Despite being an ideal population for the development and dissemination of online interventions, patients with UC and CD have far less treatment options compared to other behavioral health concerns. However, given the growing body of research involving web-based interventions for other conditions, researchers and clinicians targeting UC and CD management and treatment have the benefit of being able to utilize the BIT model, an existing conceptual framework for the development of web-based interventions for both conditions. The BIT model is presented and applied to the treatment of UC and CD, as well as a technology development program, Purple, and usability guidelines to guide clinical researchers in the future development, evaluation, and dissemination of BITs for patients with UC and CD.
PMCID: PMC4433044  PMID: 26005356
ulcerative colitis; Crohn’s disease; internet interventions; behavioral intervention technologies; BIT model; IBD
9.  Degos disease – malignant atrophic papulosis or cutaneointestinal lethal syndrome: rarity of the disease 
Degos disease is a very rare syndrome with a rare type of multisystem vasculopathy of unknown cause that affects the skin, gastrointestinal tract, and central nervous system. Other organs such as the kidneys, lungs, pleura, liver, heart, and eyes, can also be involved.
To highlight the incidence of Degos disease with regard to age and sex, discuss the necessity of its accurate and early diagnosis, and demonstrate the most current techniques for its diagnosis; to discuss whether early therapeutic intervention can impact patient prognosis; and to present a literature review about this disease.
With a retrospective, observational, nonrandomized trial, we described the evolution of the different forms of Degos disease and referenced the literature.
Data sources
Research on rare documented cases in the literature, including two cases of potentially lethal form of the disease involving the skin and gastrointestinal system and, possibly, the lungs, kidneys, and central nervous system. A case of the benign form of the disease involving the skin was observed by the authors.
Main outcome measures
Differences between outcomes in patients with the cutaneointestinal form and skin-only form of the disease. There was one fatal outcome. We reviewed possible new approaches to diagnosis and treatment.
The study demonstrated the rapid evolution of the aggressive and malignant form of the disease. It also described newly accessible Phase I diagnostic tools being currently researched as well as new therapeutic approaches.
The rarity of the disease, with only eleven cases throughout the literature.
The gastrointestinal form of Degos disease can be lethal. Its vascular etiology has finally been confirmed; however, new and more accurate early diagnostic modalities need to be developed. There are new therapeutic possibilities, but the studies of them are still in the early stages and have not yet shown the full effectiveness of these new therapies.
PMCID: PMC4403817  PMID: 25926751
multisystem vasculopathy; diagnosis; lethal; gastrointestinal; Degos disease
10.  Managing refractory Crohn’s disease: challenges and solutions 
The goals of treatment for active Crohn’s disease (CD) are to achieve clinical remission and improve quality of life. Conventional therapeutics for moderate-to-severe CD include 5-aminosalicylic acid, corticosteroids, purine analogs, azathioprine, and 6-mercaptopurine. Patients who fail to respond to conventional therapy are treated with tumor necrosis factor (TNF)-α inhibitors such as infliximab and adalimumab, but their efficacy is limited due to primary nonresponse or loss of response. It is suggested that this requires switch to another TNF-α inhibitor, a combination therapy with TNF-α blockade plus azathioprine, or granulocyte and monocyte adsorptive apheresis, and that other therapeutic options having different mechanisms of action, such as blockade of inflammatory cytokines or adhesion molecules, are needed. Natalizumab and vedolizumab are neutralizing antibodies directed against integrin α4 and α4β7, respectively. Ustekinumab is a neutralizing antibody directed against the receptors for interleukin-12 and interleukin-23. Here, we provide an overview of therapeutic treatments that are effective and currently available for CD patients, as well as some that likely will be available in the near future. We also discuss the advantages of managing patients with refractory CD using a combination of TNF-α inhibitors plus azathioprine or intensive monocyte adsorptive apheresis.
PMCID: PMC4401331  PMID: 25914555
adalimumab; granulocyte and monocyte adsorptive apheresis; combination therapy; complete remission
11.  CCR9 antagonism: potential in the treatment of Inflammatory Bowel Disease 
Inflammatory Bowel Disease (IBD), mainly comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic condition that primarily affects the intestine and is characterized by leukocytic infiltration. Blocking the migration of leukocytes from the circulation is therefore a reasonable therapeutic goal. Recent clinical trials using this approach have shown promise, with the monoclonal antibody to α4β7 integrin, vedolizumab, and previously with the monoclonal antibody to the α4 subunit, natalizumab. Directly targeting the subset of α4β7 expressing cells that co-express CC chemokine receptor 9 (CCR9), using the orally administered antagonist, CCX282-B, also known as vercirnon, has also been evaluated in Phase II and III trials that have produced mixed results. Although CCX282-B showed efficacy in inducing response in active CD in early studies, this was not confirmed in a Phase III study. CCX282-B was also more effective than placebo in maintaining remission, and this result has yet to be confirmed in Phase III. The efficacy of blocking CCR9 in UC, where vedolizumab was effective, has not been tested. The prospect of targeting CCR9 in IBD remains attractive. Much of the local accumulation of inflammatory cells in the intestine arises from migration rather than local proliferation and genetic and pharmacological targeting of CCR9 or its ligand in preclinical models that mimic UC and CD ameliorate inflammation in some cases. Furthermore, binding of chemokine ligands to receptor is a critical step in activating integrin binding, so there is a potential for synergistic action between integrin and chemokine antagonists. CCR9 is expressed on a smaller proportion of circulating cells than α4β7 integrin, which may offer greater specificity of effect, particularly in long term use. Furthermore, while α4β7 is widely expressed on T and B cell subsets, CCR9 is mainly expressed on effector memory Th1 cells. Indications for the use of intestine-specific integrin and chemokine receptor targeting may also extend beyond IBD, to include, for example, postoperative ileus, and primary sclerosing cholangitis.
PMCID: PMC4396201  PMID: 25897254
Crohn’s disease; ulcerative colitis; CCL25; CCX282-B; Traficet-EN; GSK10605786; CC chemokine receptor 9
12.  Inflammatory bowel disease and anxiety: links, risks, and challenges faced 
Inflammatory bowel disease (IBD) causes severe physical symptoms and is also associated with psychological comorbidities. Abnormal anxiety levels are found in up to 40% of patients with IBD. Anxiety symptoms are often related to flares of IBD but may persist in times of remission. Detection of anxiety disorder (AD) in patients with IBD can be challenging. Patients with anxiety may also exhibit symptoms in keeping with functional gastrointestinal disorders (FGID). Evidence for the effectiveness of pharmacological and psychological therapies for anxiety stems from patients without IBD. Studies in patients with IBD have either been small or shown negative results. In light of this, a combined approach involving IBD physicians to improve disease control and psychologists or psychiatrists to treat anxiety is advised. This review examines the evidence of anxiety issues in IBD with a focus on extent of the problem, risk factors for anxiety, and the effectiveness of interventions.
PMCID: PMC4376063  PMID: 25848313
inflammatory bowel disease; Crohn’s disease; ulcerative colitis; anxiety
13.  IBS-like symptoms in patients with ulcerative colitis 
Ulcerative colitis (UC) and irritable bowel syndrome (IBS) are chronic gastrointestinal disorders that, until recently, have been considered dichotomous conditions falling on either side of a functional-organic divide. However, persistent gastrointestinal symptoms, akin to those of IBS, are observed in up to one in three patients with quiescent UC. Whether these lower gastrointestinal symptoms are secondary to coexistent IBS or occult UC disease activity is uncertain, but when objective evidence of disease activity is lacking, escalation of conventional pharmacotherapy in such patients is often ineffective. The etiologies of both UC and IBS remain unclear, but dysregulation of the enteric nervous system, an altered microbiome, low-grade mucosal inflammation, and activation of the brain–gut axis is common to both; this suggests that some overlap between the two conditions is plausible. How best to investigate and manage IBS-type symptoms in UC patients remains unclear. Studies that have assessed patients with UC who meet criteria for IBS for subclinical inflammation have been conflicting in their results. Although evidence-based treatments for IBS exist, their efficacy in UC patients reporting these types of symptoms remains unclear. Given the disturbances in gut microbiota in UC, and the possible role of the brain–gut axis in the generation of such symptoms, treatments such as probiotics, fecal transfer, antidepressants, or psychological therapies would seem logical approaches to use in this group of patients. However, there are only limited data for all of these therapies; this suggests that randomized controlled trials to investigate their efficacy in this setting may be warranted.
PMCID: PMC4340328  PMID: 25733921
irritable bowel syndrome; ulcerative colitis; antidepressants; psychological therapies; probiotics
14.  A pilot trial on subjects with lactose and/or oligosaccharides intolerance treated with a fixed mixture of pure and enteric-coated α- and β-galactosidase 
Lactose and complex carbohydrates maldigestion, common food intolerances due to low gut content of α- and β-galactosidase, lead to abdominal symptoms including pain, diarrhea, bloating, flatulence, and cramping. Commonly, intolerant patients are advised by physicians to avoid the offending foods (dairy foods, cereals, beans, etc). This food-limiting option, however, has possible nutritional risks. We have therefore evaluated the impact of using pure, enteric-coated α- plus β-galactosidase on gut symptoms in intolerant subjects instead of avoidance of the offending foods.
Sixteen subjects intolerant to lactose and/or complex carbohydrates were enrolled and evaluated in terms of gut symptoms with 1) uncontrolled diet, 2) diet devoid of offending foods, and 3) uncontrolled diet along with pure, enteric-coated α- and β-galactosidase (DDM Galactosidase®).
Even with the uncontrolled diet, intolerant subjects treated with DDM Galactosidase® exhibited reduced gut symptoms (bloating, flatulence, diarrhea, and constipation) significantly better than the control treatment as well as having a diet devoid of offending foods.
DDM Galactosidase® is a valid and safe optional treatment to counteract lactose and complex carbohydrate intolerance in subjects who prefer not to avoid, at least partially, offending foods.
PMCID: PMC4340330  PMID: 25733920
lactase; lactose intolerance; complex carbohydrate intolerance
15.  Value of portal venous system radiological indices in predicting esophageal varices 
Portal hypertension results from increased resistance to portal blood flow and has the potential complications of variceal bleeding and ascites. The splenoportal veins increase in caliber with worsening portal hypertension, and partially decompress by opening a shunt with systemic circulation, ie, a varix. In the event of portosystemic shunting, there is a differential decompression across the portal vein and splenic vein (portal vein > splenic vein), with a resultant decrease in the ratio of portal vein diameter to that of splenic vein. Portal vein to splenic vein diameter ratio and gradient could be valuable tools in predicting the presence of portosystemic shunting.
We retrospectively reviewed patients with cirrhosis who underwent esophagogastroduodenoscopy (EGD) for variceal screening and had a computerized tomogram (CT) of the abdomen within 6 months of the index endoscopic study, between January 2009 and December 2013. Patients on nonselective beta blockers, patients with presinusoidal portal hypertension (portal vein thrombosis or extrinsic compression), and patients who had undergone portosystemic shunting procedures (transjugular intrahepatic portosystemic shunt [TIPS]) or balloon-occluded retrograde transvenous obliteration (BRTO) were excluded from the study. Splenic and portal vein diameters were measured (in mm) just proximal and distal to the splenomesenteric venous confluence, respectively.
A total of 164 patients were included in the study; of these, 60% (n=98) were male and 40% (n=66) were female. The mean age of the study population was 58.7 years. A total of 126 patients (77%) had varices, while 38 patients (33%) did not. The mean Model for End-Stage Liver Disease (MELD) score was 5.9 for those who had varices as compared with 7.03 for those who did not. The mean of ratios of portal vein to splenic vein diameters in patients with varices was 1.27 (±0.2), while it was 1.5 (±0.23) in those without varices. This difference was statistically significant (P<0.001). The mean of the gradients between the portal vein and splenic vein diameters was 2.7 (±2) mm for patients with varices as compared with 5 (±1.8) mm in those without varices. This difference was also statistically different (P<0.001). These correlations were statistically significant even after controlling for age, sex, and MELD. These radiological indices also had statistically significant correlations with the presence of gastric varices (P=0.018 for the ratio and P=0.01 for the gradient). A discriminant function analysis was performed that generated the equation: D = 2.68 (ratio of portal vein to splenic vein diameters) + 0.187 (gradient of portal vein to splenic vein diameters, in mm) − 4.152. This equation had a very high sensitivity, of 95%, but low specificity, of 26.3%, in predicting the presence of esophageal varices.
Both venous diameter ratio (portal vein size/splenic vein size) and venous diameter gradient in mm (portal vein size – splenic vein size) calculated from CTs of the abdomen were good predictors of presence of esophageal varices. These parameters might be useful in stratifying patients at risk of developing esophageal varices who are poor candidates for endoscopic evaluation.
PMCID: PMC4329997  PMID: 25709491
portal vein diameter; splenic vein diameter; portal hypertension; portal vein to splenic vein ratio; portosplenic venous size gradient
16.  Effect of genistein on basal jejunal chloride secretion in R117H CF mice is sex and route specific 
Cystic fibrosis (CF) results from the loss or reduction in function of the CFTR (cystic fibrosis transmembrane conductance regulatory protein) chloride channel. The third most common CFTR mutation seen clinically is R117H. Genistein, a naturally occurring phytoestrogen, is known to stimulate CFTR function in vitro. We aimed to determine whether route of administration of genistein could mediate differential effects in R117H male and female CF mice. Mice were fed (4 weeks) or injected subcutaneously (1 week) with the following: genistein 600 mg/kg diet (600Gd); genistein-free diet (0Gd); genistein injection 600 mg/kg body weight (600Gi); dimethyl sulfoxide control (0Gi). In male R117H mice fed 600Gd, basal short circuit current (Isc) was unchanged. In 600Gd-fed female mice, there was a subgroup that demonstrated a significant increase in basal Isc (53.14±7.92 μA/cm2, n=6, P<0.05) and a subgroup of nonresponders (12.05±6.59 μA/cm2, n=4), compared to 0Gd controls (29.3±6.5 μA/cm2, n=7). In R117H mice injected with 600Gi, basal Isc was unchanged in both male and female mice compared to 0Gi controls. Isc was measured in response to the following: the adenylate cyclase activator forskolin (10 μM, bilateral), bumetanide (100 μM, basolateral) to indicate the Cl− secretory component, and acetazolamide (100 μM, bilateral) to indicate the HCO3− secretory component; however, there was no effect of genistein (diet or injection) on any of these parameters. Jejunal morphology (ie, villi length, number of goblet cells per villus, crypt depth, and number of goblet cells per crypt) in R117H mice suggested no genistein-mediated difference among the groups. Serum levels of genistein were significantly elevated, compared to respective controls, by either 600Gd (equally elevated in males and females) or 600Gi (elevated more in females versus males). These data suggest a sex-dependent increase in basal Isc of R117H mice and that the increase is also specific for route of administration.
PMCID: PMC4321419  PMID: 25674010
genistein; intestine; secretion; CFTR; R117H
17.  Influence of perception of colorectal cancer risk and patient bowel preparation behaviors: a study in minority populations 
Large disparities exist in the utilization rates of screening modalities for colorectal cancer (CRC) in different socioeconomic areas. In this study, we evaluated whether the quality of bowel preparation differed significantly among populations with a high risk of CRC compared with that among the general population after matching for potential confounding factors.
Hispanic and African American patients who underwent routine screening or surveillance colonoscopies in an outpatient setting between 2003 and 2013 were included in this retrospective study. Patients who underwent colonoscopies for emergent indications and repeat routine screening colonoscopies because of prior history of inadequate bowel preparation were excluded from this study. The patients were divided into three groups: patients having an average risk of being diagnosed with CRC (group 1); patients having a high risk of being diagnosed with CRC because of a personal history of adenomatous polyps (group 2); and patients having a high risk of being diagnosed with CRC because of a family history of CRC in first-degree relatives (group 3). All the patients were given preprocedural counseling and written instructions for bowel preparation. Data on demographic information, method of bowel preparation, quality of bowel preparation, comorbidities, and prescription medications were collected.
In all, 834 patients had a “high-risk for CRC” surveillance colonoscopy in view of their personal history of adenomatous polyps and were included in group 2. In total, 250 patients had a “high-risk for CRC” screening colonoscopy in view of their family history of CRC in first-degree relatives and were included in group 3. Further, 1,000 patients were selected to serve as controls (after matching for age, sex and ethnicity) and were included in group 1. Bowel preparation was graded as good, fair, or poor by the endoscopist performing the study. We observed a significantly higher number of good bowel preparations in group 2 and group 3 (P=0.0001) when compared with group 1 (controls) after adjusting for comorbidities and usage of prescription medication that could potentially cause colonic dysmotility. These differences were significant in both Hispanic and African American patients.
Our study showed that perception of CRC risk significantly influenced the bowel preparation behaviors of patients belonging to minority populations, with a significantly greater number of patients with a high risk of CRC having adequate bowel preparations.
PMCID: PMC4315465  PMID: 25670910
colorectal cancer; bowel preparation; quality; screening colonoscopy; high-risk populations; minority populations
18.  Reduced expression of aquaporins in human intestinal mucosa in early stage inflammatory bowel disease 
The aim of this study was to investigate the relationship between aquaporin (AQP) water channel expression and the pathological features of early untreated inflammatory bowel disease (IBD) in humans.
Patients suspected to have IBD on the basis of predefined symptoms, including abdominal pain, diarrhea, and/or blood in stool for more than 10 days, were examined at the local hospital. Colonoscopy with biopsies was performed and blood samples were taken. Patients who did not meet the diagnostic criteria for IBD and who displayed no evidence of infection or other pathology in the gut were included as symptomatic non-IBD controls. AQP1, 3, 4, 5, 7, 8, and 9 messenger RNA (mRNA) levels were quantified in biopsies from the distal ileum and colon by quantitative real-time polymerase chain reaction. Protein expression of selected AQPs was assessed by confocal microscopy. Through multiple alignments of the deduced amino acid sequences, the putative three-dimensional structures of AQP1, 3, 7, and 8 were modeled.
AQP1, 3, 7, and 8 mRNAs were detected in all parts of the intestinal mucosa. Notably, AQP1 and AQP3 mRNA levels were reduced in the ileum of patients with Crohn’s disease, and AQP7 and AQP8 mRNA levels were reduced in the ileum and the colon of patients with ulcerative colitis. Immunofluorescence confocal microscopy showed localization of AQP3, 7, and 8 at the mucosal epithelium, whereas the expression of AQP1 was mainly confined to the endothelial cells and erythrocytes. The reduction in the level of AQP3, 7, and 8 mRNA was confirmed by immunofluorescence, which also indicated a reduction of apical immunolabeling for AQP8 in the colonic surface epithelium and crypts of the IBD samples. This could indicate loss of epithelial polarity in IBD, leading to disrupted barrier function.
AQPs 1 and 8 and the aquaglyceroporins AQPs 3 and 7 are the AQPs predominantly expressed in the lower intestinal tract of humans. Their expression is significantly reduced in patients with IBD, and they are differentially expressed in specific bowel segments in patients with Crohn’s disease and ulcerative colitis. The data present a link between gut inflammation and water/solute homeostasis, suggesting that AQPs may play a significant role in IBD pathophysiology.
PMCID: PMC4296881  PMID: 25624769
inflammatory bowel disease; Crohn’s disease; ulcerative colitis; aquaporins; aquaglyceroporins
19.  Celiac disease in children: is it a problem in Kuwait? 
Celiac disease (CD) is a chronic inflammatory disease of the small intestine triggered by gluten ingestion. The objective of this study is to describe our experience with CD children in Kuwait.
The records of children with CD seen in the pediatric gastroenterology unit between February 1998 and December 2010 were retrospectively reviewed. Patients were referred because of symptoms or positive CD antibody screening of a high-risk group (type 1 diabetes and Down syndrome).
Forty-seven patients were diagnosed: 53% were symptomatic and 47% were identified by screening. The median age at diagnosis was 66 (range 7–189) months. All cases were biopsy-proven except one. The symptomatic patients were significantly younger than those identified following screening (P<0.004). In the whole group, 66% were females and 77% were Kuwaitis; 9% had a positive family history of CD. The estimated cumulative incidence was 6.9/105. The median duration of symptoms before diagnosis was 8.5 (range 2–54) months. Failure to thrive was the most common presenting complaint (72%) followed by diarrhea (64%) and abdominal distension (56%). Atypical manifestations were seen in 60% of patients. Underweight and short stature were confirmed in 19% and 17% of patients, respectively. Overweight and obesity were detected in 14% and 6%, respectively. CD serology was based on a combination of antiendomysial and antigliadin antibodies. The median follow up was 24 (range 12–144) months. All patients were commenced on a gluten free diet, but good compliance was only achieved in 78%.
The low frequency of childhood CD in Kuwait could probably be attributed to either an underestimation of the atypical presentations or failure of proper screening. Also, adherence to a gluten free diet is a major problem in our population.
PMCID: PMC4284061  PMID: 25565879
celiac disease; children; Kuwait
20.  Developments in flexible endoscopic surgery: a review 
Flexible endoscopy is increasingly developing into a therapeutic instead of a purely diagnostic discipline. Improved visualization makes early lesions easily detectable and allows us to decide ad hoc on the required treatment. Deep enteroscopy allows the exploration of even the small bowel – for long a “white spot” for gastrointestinal endoscopy – and to perform direct treatment. Endoscopic submucosal dissection is a considerable step forward in oncologically correct endoscopic treatment of (early) malignant lesions. Though still technically challenging, it is increasingly facilitated by new manipulation techniques and tools that are being steadily optimized. Closure of wall defects and hemostasis could be improved significantly. Even the anatomy beyond the gastrointestinal wall is being explored by the therapeutic use of endoluminal ultrasound. Endosonographic-guided surgery is not only a suitable fallback solution if conventional endoscopic retrograde cholangiopancreatography fails, but even makes necrosectomy procedures, abscess drainage, and neurolysis feasible for the endoscopist. Newly developed endoscopic approaches aim at formerly distinctive surgical domains like gastroesophageal reflux disease, appendicitis, and cholecystitis. Combined endoscopic/laparoscopic interventional techniques could become the harbingers of natural orifice transluminal endoscopic surgery, whereas pure natural orifice transluminal endoscopic surgery is currently still in its beginnings.
PMCID: PMC4278730  PMID: 25565878
flexible endoscopic surgery; endoscopic ultrasound; advanced techniques; natural orifice transluminal endoscopic surgery
21.  Endoscopic therapy in chronic pancreatitis: current perspectives 
Endoscopic therapy in chronic pancreatitis (CP) aims to provide pain relief and to treat local complications, by using the decompression of the pancreatic duct and the drainage of pseudocysts and biliary strictures, respectively. This is the reason for using it as first-line therapy for painful uncomplicated CP. The clinical response has to be evaluated at 6–8 weeks, when surgery may be chosen. This article reviews the main possibilities of endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) therapies. Endotherapy for pancreatic ductal stones uses ultrasound wave lithotripsy and sometimes additional stone extractions. The treatment of pancreatic duct strictures consists of a single large stenting for 1 year. If the stricture persists, simultaneous multiple stents are applied. In case of unsuccessful ERCP, the EUS-guided drainage of the main pancreatic duct (MPD) or a rendezvous technique can solve the ductal strictures. EUS-guided celiac plexus block has limited efficiency in CP. The drainage of symptomatic or complicated pancreatic pseudocysts can be performed transpapillarily or transgastrically/transduodenally, preferably by EUS guidance. When the biliary stricture is symptomatic or progressive, multiple plastic stents are indicated. In conclusion, as in many fields of symptomatic treatment, endoscopy remains the first choice, either by using ERCP or EUS-guided procedures, after consideration of a multidisciplinary team with endoscopists, surgeons, and radiologists. However, what is crucial is establishing the right timing for surgery.
PMCID: PMC4274042  PMID: 25565876
chronic pancreatitis; treatment; endoscopy; ERCP; endoscopic ultrasound
22.  Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts 
Cathelicidin (LL-37 in humans and mCRAMP in mice) represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors.
We examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane- and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelial–mesenchymal transition (EMT) of colon cancer cells and fibroblast-supported colon cancer cell proliferation.
Intravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane- and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentin-positive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-β1-induced EMT of colon cancer cells. Media conditioned by the human colonic CCD-18Co fibroblasts promoted human colon cancer HT-29 cell proliferation. Cathelicidin pretreatment inhibited colon cancer cell proliferation mediated by media conditioned by human colonic CCD-18Co fibroblasts. Cathelicidin disrupted tubulin distribution in colonic fibroblasts. Disruption of tubulin in fibroblasts reduced fibroblast-supported colon cancer cell proliferation.
Cathelicidin effectively inhibits colon cancer development by interfering with EMT and fibroblast-supported colon cancer cell proliferation.
PMCID: PMC4274046  PMID: 25565877
colon cancer; epithelial–mesenchymal transition; fibroblasts
23.  Targeted therapy of short-bowel syndrome with teduglutide: the new kid on the block 
Extensive intestinal resection impairs the absorptive capacity and results in short-bowel syndrome-associated intestinal failure (SBS-IF), when fluid, electrolyte, acid-base, micro-, and macronutrient homeostasis cannot be maintained on a conventional oral diet. Several factors, including the length and site of the resected intestine, anatomical conformation of the remnant bowel, and the degree of postresection intestinal adaptation determine the disease severity. While mild SBS patients achieve nutritional autonomy with dietary modification (eg, hyperphagia, small frequent meals, and oral rehydration fluids), those with moderate-to-severe disease may develop SBS-IF and become dependent on parenteral support (PS) in the form of intravenous fluids and/or nutrition for sustenance of life. SBS-IF is a chronic debilitating disease associated with a poor quality of life, and carries significant morbidity and health care costs. Medical management of SBS-IF is primarily focused on individually tailored symptomatic treatment strategies, such as antisecretory and antidiarrheal agents to mitigate fluid losses, and PS. However, PS administration is associated with potentially life-threatening complications, such as central venous thromboses, bloodstream infections, and liver disease. In pursuit of a targeted therapy to augment intestinal adaptation, research over the past 2 decades has identified glucagon-like peptide, an intestinotrophic gut peptide that has been shown to enhance intestinal absorptive capacity by causing an increase in the villus length, crypt depth, and mesenteric blood flow and by decreasing gastrointestinal motility and secretions. Teduglutide, a recombinant analog of glucagon-like peptide-2, is the first targeted therapeutic agent to gain approval for use in adult SBS-IF. Teduglutide was shown to result in significant (20%–100%) reduction in PS-volume requirement and have a satisfactory safety profile in three randomized control trials. Further research is warranted to see if reduction in PS dependency translates to improved quality of life and reduced PS-associated complications.
PMCID: PMC4266252  PMID: 25525380
short-gut syndrome; intestinal adaptation; glucagon-like peptide-2; teduglutide
24.  Systematic review of randomized controlled trials of probiotics, prebiotics, and synbiotics in inflammatory bowel disease 
Probiotics are microorganisms that are ingested either in combination or as a single organism in an effort to normalize intestinal microbiota and potentially improve intestinal barrier function. Recent evidence has suggested that inflammatory bowel disease (IBD) may result from an inappropriate immunologic response to intestinal bacteria and a disruption in the balance of the gastrointestinal microbiota in genetically susceptible individuals. Prebiotics, synbiotics, and probiotics have all been studied with growing interest as adjuncts to standard therapies for IBD. In general, probiotics have been shown to be well-tolerated with few side effects, making them a potential attractive treatment option in the management of IBD.
To perform a systematic review of randomized controlled trials on the use of probiotics, prebiotics, and synbiotics in IBD.
In our systematic review we found 14 studies in patients with Crohn’s disease (CD), 21 studies in patients with ulcerative colitis (UC), and five studies in patients with pouchitis. These were randomized controlled trials using probiotics, prebiotics, and/or synbiotics. In patients with CD, multiple studies comparing probiotics and placebo showed no significant difference in clinical outcomes. Adding a probiotic to conventional treatment improved the overall induction of remission rates among patients with UC. There was also a similar benefit in maintaining remission in UC. Probiotics have also shown some efficacy in the treatment of pouchitis after antibiotic-induced remission.
To date, there is insufficient data to recommend probiotics for use in CD. There is evidence to support the use of probiotics for induction and maintenance of remission in UC and pouchitis. Future quality studies are needed to confirm whether probiotics, prebiotics, and synbiotics have a definite role in induction or maintenance of remission in CD, UC, and pouchitis. Similar to probiotics, fecal microbiota transplantation provides an alternate modality of therapy to treat IBD by influencing the intestinal flora.
PMCID: PMC4266241  PMID: 25525379
inflammatory bowel disease; Crohn’s disease; ulcerative colitis; pouchitis; probiotics; prebiotics; synbiotics
25.  Pharmacokinetics and safety of dexlansoprazole MR in pediatric patients with symptomatic gastroesophageal reflux disease 
To evaluate the safety and pharmacokinetic profile of dexlansoprazole modified-release (MR) capsules in pediatric patients with symptomatic gastroesophageal reflux disease (GERD).
This Phase I, open-label study enrolled male and female patients (1 to 11 years of age) with GERD. Patients received dexlansoprazole MR 15 mg, 30 mg, or 60 mg (according to weight) once daily for 7 days. Blood samples for the measurement of plasma dexlansoprazole concentrations were collected for 24 hours after the day 7 dose. Dexlansoprazole plasma concentrations and pharmacokinetic parameters were summarized by dose group. Safety assessments included adverse events (AEs), clinical laboratory evaluations, fasting gastrin concentrations, physical examinations, electrocardiograms, and vital signs.
Thirty-six patients received study drug (12 per dose group), and 31 had evaluable pharmacokinetic data. There was a significant effect of weight on dose-normalized area under the curve (AUC, P=0.003) and dose-normalized maximum plasma concentration (Cmax) (P=0.013), indicating that for a given dose, dexlansoprazole exposure decreases as body weight increases. After adjusting for body weight, both dexlansoprazole Cmax and AUC increased in an approximately dose-proportional manner with increasing dexlansoprazole dose. A total of ten of 36 patients reported at least one treatment-emergent AE, with most events considered mild in intensity. The most common AEs were vomiting, abdominal pain, diarrhea, and nausea.
In 1- to 11-year-old patients with symptomatic GERD, weight-adjusted dexlansoprazole AUC and Cmax increased approximately dose-proportionally. However, for a given dose, dexlansoprazole exposure decreased with increasing body weight. Dexlansoprazole MR was well tolerated, and the incidence of AEs did not increase with increasing dose.
PMCID: PMC4266249  PMID: 25525378
TAK-390MR; dual delayed release; proton pump inhibitor

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