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issn:0954-691
1.  Parenting stress predicts depressive symptoms in adolescents with inflammatory bowel disease 
Objectives
Adolescents with inflammatory bowel disease (IBD) are at an increased risk for depression and poor IBD management. Although depression and family factors have been associated in cross-sectional analyses, their casual association over time has not been studied. The primary objective of this study was to assess the temporal association between parenting stress and adolescent depressive symptoms in IBD.
Methods
Along with a primary parent, adolescents [Mage(years) = 15.5 ± 1.4] with a confirmed diagnosis of Crohn's disease or ulcerative colitis and prescribed a treatment regimen of a 5-ASA medication and/or 6-MP/azathioprine were recruited from routine gastroenterology clinic visits at two pediatric medical centers. The current study was nested in a larger IBD self-management trial. Adolescents completed the Children's Depression Inventory. Parents completed a sociodemographic questionnaire and the Pediatric Inventory for Parents. Gastroenterologists provided disease severity assessments on the basis of the clinic appointment corresponding to the study visit or the most recent clinic appointment. Questionnaires were readministered ∼ 6 months after the initial visit.
Results
Participants include 93 families at baseline and 65 at follow-up (69.8% retention; N = 65). A cross-lagged panel analysis was used to detect causal directionality and change in adolescent depression and parenting stress over 6 months. Baseline parenting stress accounted for a significant amount of the variance in depressive symptoms at follow-up [R-change = 0.03, F(1,58) = 35.6, P < 0.05].
Conclusion
Parenting stress impacts adolescent depressive symptoms in IBD. Identification of parenting stress and adolescent depression should occur early and possibly in the context of routine clinic visits.
doi:10.1097/MEG.0000000000000149
PMCID: PMC4307594  PMID: 25003746
cross-lagged analysis; depression; diathesis-stress model; parent distress
2.  Procedure volume influences adherence to celiac disease guidelines 
Background
Although the prevalence of celiac disease in the USA approaches 1%, most cases are undiagnosed, in part, because of low adherence to the recommendation of submitting at least four specimens during duodenal biopsy. We aimed to determine whether physician and practice characteristics are associated with adherence to this recommendation.
Materials and methods
We used a large national pathology database to identify all adult patients who underwent duodenal biopsy during 2006–2009. Hierarchical modeling was used to determine whether procedure volume, the number of gastroenterologists per endoscopy suite, and the number of gastroenterologists per capita of the zip code of the practice were associated with adherence.
Results
We identified 92 580 patients (67% female, mean age 53.5 years) who met our inclusion/exclusion criteria. Specimens were submitted by 669 gastroenterologists from 200 endoscopy suites, located in 191 zip codes, with a mean of 3.4 gastroenterologists per suite. On multivariate analysis, a higher procedure volume was associated with a decreased adherence [odds ratio (OR) for each additional 100 procedures, 0.92; 95% confidence interval (CI), 0.88–0.97; P = 0.002]. An increased adherence was reported for gastroenterologists working at suites with higher numbers of gastroenterologists (OR for each additional gastroenterologist, 1.08; 95% CI, 1.04–1.13; P < 0.001) but not for a higher gastroenterologist density in the zip code of the practice (OR for each additional gastroenterologist per capita, 1.01; 95% CI, 0.99–1.03; P = 0.21).
Conclusion
High-volume physicians exhibit lower rates of adherence to biopsy guidelines, possibly because of the additional time required to submit at least four specimens. In contrast, a greater number of endoscopists working in an endoscopy suite are associated with an increased adherence, possibly because of peer education.
doi:10.1097/MEG.0b013e3283643542
PMCID: PMC4048920  PMID: 23995767
celiac disease; endoscopy; quality of healthcare
3.  Detection of Anti-Conductive Tissue Autoantibodies in a Patient with Chronic Intestinal Pseudo-Obstruction and Sick Sinus Syndrome 
A 26-year-old patient was diagnosed as suffering from chronic intestinal pseudo-obstruction with manometric and histopathologic features suggestive of a intestinal myopathy. Histology was characterized by smooth muscle degeneration without inflammatory or immune cells. The severe gut dysfunction required full parenteral nutritional support. Few months later, the patient developed symptomatic tachy-brady arrhythmia episodes with syncopes. A thorough diagnostic work-up led to a diagnosis of sick sinus syndrome which was managed by pacemaker implantation and β-blockers administration. This led to a partial improvement of tachy-brady arrhythmia episodes. Nonetheless, the patient continued to experience sustained supraventricular tachyarrhythmia runs, poorly responsive to increasing β-blocker doses. To investigate the origin of the cardiologic impairment, the patient was tested for anti-conductive tissue autoantibodies, which were positive, thus supporting a possible autoimmune origin of the dysrhythmia. Other autoantibodies tested for were negative. Based on these findings, the patient was treated with high dose steroids which were then tapered. The patient responded to the steroid treatment and did not experience further episodes of syncope and tachyarrhythmias. The severe gut dysfunction remained unchanged. This case highlights an association between severe gut dysfunction and cardiac conductive tissue abnormalities with autoantibodies to conductive tissue possibly causing the dysrhythmia. The severe gut and heart (likely autoimmune-mediated) dysfunction presented in this case provide a basis to assess further a link between intestinal and cardiac abnormal rhythmicity.
doi:10.1097/MEG.0b013e3283632dbc
PMCID: PMC4116339  PMID: 24081107
alpha-smooth muscle actin; anti-conductive tissue autoantibodies; chronic intestinal pseudo-obstruction; intestinal failure; sick sinus syndrome
4.  Bismuth-containing quadruple therapy for Helicobacter pylori: Lessons from China 
European journal of gastroenterology & hepatology  2013;25(10):10.1097/MEG.0b013e3283633b57.
Objective
Antimicrobial resistance has continued to undermine many popular anti-Helicobacter pylori therapies. Antibiotic resistance to commonly used anti-H. pylori drugs in China has increased remarkably making China an ideal site to identify regimens that remain effective despite widespread antimicrobial resistance. Bismuth is one of the few antimicrobials to which resistance does not develop. Factors contributing to H. pylori treatment success include host factors (e.g., genetic differences in metabolism of the drugs used), bacterial factors (e.g., susceptibility) and details of the regimen (e.g., doses, dosing interval, dosing in relation of meals, formulation, etc).
Methods
We reviewed the recent experience in China with bismuth-containing quadruple therapies. The experience consists of 16 studies with 25 arms involving 1,971 patients to identify successful regimens (defined as reliably obtaining 90% or greater eradication per protocol) deserving of further study.
Results
Despite high rates of resistance to commonly used antimicrobials, several regimens were able to achieve high success. These were characteristically 14 day regimens containing a proton pump inhibitor and either tetracycline and metronidazole or furazolidone and amoxicillin.
Conclusions
We propose approaches for further development including for optimization and simplification relation to convenience and side effects (e.g., twice rather than three or 4 times daily or administration at the noon and evening meal instead of at breakfast and evening) while maintaining effectiveness ≥ 90%. Studies in China identified regimens that were highly effective despite the high prevalence of resistance to metronidazole, fluoroquinolones, and macrolides. Multicenter randomized studies will be required to confirm which is best.
doi:10.1097/MEG.0b013e3283633b57
PMCID: PMC3865448  PMID: 23778309
Helicobacter pylori; treatment; quadruple therapy; review; treatment success
5.  Do indication and demographics for colonoscopy affect completion? A large national database evaluation 
European journal of gastroenterology & hepatology  2010;22(5):10.1097/MEG.0b013e3283352cd6.
Background and aim
Indication for colonoscopy has not been examined as a predictor of colonoscopy completion. We hypothesized that colonoscopy conducted for colorectal cancer screening might have higher in completion rates than colonoscopy conducted for other indications.
Methods
The study design was a retrospective cohort. Colonoscopies recorded within the Clinical Outcomes Research Initiative database conducted between 1 January 2002 and 30 June 2003 were analyzed. Indication included: average-risk screening; surveillance; nonspecific abdominal symptoms; bleeding symptoms; or family history of colorectal carcinoma. Demographic factors and indication for colonoscopy were evaluated for the outcome of incomplete colonoscopy using logistic regression analysis.
Results
129,549 Colonoscopy procedures were analyzed. Average risk screening seemed to be protective for completion (relative risk: 0.69; 95% confidence interval: 0.63–0.75). Bleeding and nonspecific symptoms had higher risk of incomplete procedure compared to other indications. Males had higher completion rates compared to females (relative risk: 0.62; 95% confidence interval: 0.58–0.66). Community setting had higher completion rates compared to academic or Veteran’s administration sites. Increasing age was associated with higher rate of incomplete colonoscopy.
Conclusion
Colonoscopy conducted for screening indication has comparable completion rates when compared with other indications. An overall completion rate of around 95% was noted in this study. This is the largest study to date verifying that completion rates are meeting recommended multisociety guidelines in the USA. Nonspecific abdominal symptoms in Caucasian population, female sex, advanced age, clinical setting, and ethnic groups African–American and Hispanic were found to have increased risk of incomplete procedure.
doi:10.1097/MEG.0b013e3283352cd6
PMCID: PMC3856575  PMID: 20032782
cancer; colonoscopy; completion rate; screening; surveillance
6.  Telehealth behavioral treatment for medication nonadherence: a pilot and feasibility study 
Objective
To evaluate an individually tailored multicomponent nonadherence treatment protocol using a telehealth delivery approach in adolescents with inflammatory bowel disease.
Methods
Nine participants, age 13.71±1.35 years, completed a brief treatment online through Skype. Medication nonadherence, severity of disease, and feasibility/acceptability data were obtained.
Results
Adherence increased markedly from 62% at baseline to 91% for mesalamine (δ = 0.63), but decreased slightly from 61% at baseline to 53% for 6-mercaptopurine /azathioprine. The telehealth delivery approach resulted in cost savings of $100 in mileage and 4 h of travel time/patient. Treatment session attendance was 100%, and the intervention was rated as acceptable, particularly in terms of treatment convenience.
Conclusion
Individually tailored treatment of nonadherence through telehealth delivery is feasible and acceptable. This treatment shows promise for clinical efficacy to improve medication adherence and reduce costs. Large-scale testing is necessary to determine the impact of this intervention on adherence and health outcomes.
doi:10.1097/MEG.0b013e32835c2a1b
PMCID: PMC3703848  PMID: 23325274
adherence; compliance; inflammatory bowel disease; medication; pediatric
7.  IL28B favorable genotype and ultra rapid viral response as earliest treatment predictors of sustained viral response among Georgian cohort infected with hepatitis C genotype one 
Objectives
Early identification of factors contributing to successful treatment of hepatitis C infection is important for researchers and clinicians. Studies conducted on the role of ultra rapid viral response (URVR) for prediction of sustained viral response (SVR) have shown its high positive predictive value (PPV). However, data on the combined effect of URVR with IL28B genotypes for prediction of SVR are lacking. Our aim was to study the role of URVR and IL28B genotypes for prediction of SVR among patients in Georgia infected with genotype 1.
Methods
Of a total of 156 patients enrolled in the study, 143 were included in the final analyses. Viral load testing for monitoring viral response was done at 3, 24, and 48, 72 hours and at 1, 2, and 4 weeks after treatment initiation. IL28B single nucleotide polymorphisms in rs12979860 were genotyped by real time PCR methods.
Results
Our study revealed URVR as the earliest treatment predictor among genotype 1 patients harboring IL28B C/C genotype (PPV-100%). Moreover, C/C genotype was found have a high PPV among genotype 1 patients without URVR or RVR unlike patients infected with genotype 2 or 3. URVR and IL28B C/C genotype were not as predictive of an SVR among genotype 2 and 3 patients; however RVR were highly predictive of an SVR in these patients.
Conclusions
Our results suggest that testing for IL28B genotypes and viral load at week one and two may improve the ability to predict an SVR among HCV genotype 1 patients; this information can be useful to encourage patients to remain on treatment.
doi:10.1097/MEG.0b013e328353fd11
PMCID: PMC3368996  PMID: 22569080
HCV viral load; SNPs; interferon treatment
8.  Family functioning and health-related quality of life in adolescents with pediatric inflammatory bowel disease 
Objectives
To examine the relationship between family functioning and health-related quality of life (HRQOL) in a sample of adolescents with inflammatory bowel disease (IBD), and to specify the domains of family functioning with which these families experience difficulties.
Methods
Sixty-two adolescents, aged 13–17 years, with a confirmed diagnosis of IBD completed assessments of HRQOL. Each adolescent’s primary caregiver completed a measure of family functioning. Pediatric gastroenterologists provided data for disease severity assessments.
Results
A series of multivariate analyses of variance showed that adolescents from families with clinically elevated difficulties in problem solving, communication, and general family functioning endorsed lower HRQOL (i.e., social functioning, general well-being) after statistically controlling the effects of disease severity and diagnosis. As many as 25% of families reported clinically elevated difficulties across domains of family functioning.
Conclusions
Findings suggest that family functioning may be an important predictor of HRQOL among the adolescents with IBD, and that many families experience difficulties in their daily interactions. Close monitoring of family functioning may be a salient feature for prevention and intervention efforts and beneficial in promoting optimal psychosocial outcomes among the adolescents with IBD.
doi:10.1097/MEG.0b013e3283417abb
PMCID: PMC3677963  PMID: 21079514
adolescents; family functioning; inflammatory bowel disease; quality of life
9.  Cholangiocarcinoma and dominant strictures in patients with primary sclerosing cholangitis; a 25 year single centre experience 
Background
Dominant biliary strictures occur commonly in patients with primary sclerosing cholangitis (PSC), who have a high risk of developing cholangiocarcinoma. The natural history and optimal management of dominant strictures remains unclear, with some reports suggesting that endoscopic interventions improve outcome.
Methods
We describe a 25 year experience in patients with PSC related dominant strictures at a single tertiary referral centre.
Results
128 patients with PSC (64% males, mean age at referral 49 years) were followed for a mean of 9.8 years. 80 patients (62.5%) with dominant biliary strictures had a median of 3 (range 0–34) interventions, compared to 0 (0–7) in the 48 without dominant strictures (p<0.001). Endoscopic interventions included: (i) stenting alone (46%), (ii) dilatation alone (20%), (iii) dilatation and stenting (17%), and (iv) none or failed intervention (17%, of whom most required percutaneous transhepatic drainage). The major complication rate for ERCP was low (1%). The mean survival of those with dominant strictures (13.7 years) was worse than for those without dominant strictures (23 years), with much of the survival difference related to a 26% risk of cholangiocarcinoma developing only in those with dominant strictures. Half of those with cholangiocarcinoma presented within four months of diagnosis of PSC, highlighting the importance of thorough evaluation of new dominant strictures.
Conclusions
Repeated endoscopic therapy in PSC patients is safe but the prognosis remains worse in the subgroup with dominant strictures. In our series, dominant strictures were associated with a high risk of developing cholangiocarcinoma.
doi:10.1097/MEG.0b013e3283554bbf
PMCID: PMC3584158  PMID: 22653260
Cholangiocarcinoma; dominant stricture; endoscopic retrograde cholangiopancreatography; primary sclerosing cholangitis
10.  Evaluation of a Group-Based Behavioral Intervention to Promote Adherence in Adolescents with Inflammatory Bowel Disease 
Objective
To pilot test the feasibility and acceptability of a family-based group behavioral intervention to improve medication adherence in adolescents diagnosed with Inflammatory Bowel Disease (IBD).
Methods
Participants were 40 adolescents age 11-18 years diagnosed with IBD and their primary caregivers, who were randomized to either a 4-session Family-Based Group Behavioral Treatment or Usual Care over a 6-week period. Adherence was measured using a mutli-method, multi-informant assessment involving caregiver- and patient-report, pill count data, and electronic monitoring.
Results
Adherence rates ranged from 66-89% for 6-MP/azathioprine and 51-93% for mesalamine across assessment methods. The intervention was feasible, as evidenced by the 99% treatment session attendance rate, and acceptable based on patient and caregiver report. Repeated measures ANOVA tests revealed nonsignificant differences between the conditions from baseline to post-treatment assessments for pill count, electronic monitor, and primary caregiver-reported adherence (p's> .05). There was a statistically significant improvement in patient-reported mesalamine adherence represented by a significant main effect for Condition (F = 22.24, p< .01; δ = .79) and Condition X Time interaction (F = 13.32, p< .05; δ = .69).
Conclusions
Findings suggest potential for use of behavioral intervention to improve medication adherence in this population. This intervention may be more effective with more complex regimens (e.g., multiple doses per day) such as those prescribed with mesalamine. Further research is needed to examine this type of intervention in more diverse samples with more active disease. Use of alternative adherence measurement approaches, including electronic pill boxes and/or real-time self-report (e.g., via text messaging, electronic diaries, etc.) is also recommended.
doi:10.1097/MEG.0b013e32834d09f1
PMCID: PMC3233635  PMID: 21989119
Inflammatory bowel disease; adherence; self-management; medication
11.  Sex and race differences in the prevalence of Fatty Liver Disease as measured by CT liver attenuation in European American and African American participants of the NHLBI Family Heart Study 
Liver attenuation (LA) (Hounsfield Units, HU) by computed tomography (CT) is a validated quantitative measure inversely related to liver fat burden. We examined race-and sex- differences on the distribution of LA (one of the first stages of fatty liver disease) and the predictors of these mean differences in European American (EA) and African American (AA) participants of the Family Heart Study. A total of 1242 (1064 EA, 178 AA) and 1477 (1150 EA, 327 AA) men and women, respectively, underwent CT examination from which LA and abdominal adipose volume were measured. LA (adjusted for phantom and field center) was the dependent variable in linear mixed models (to control for family relatedness) that tested for mean differences by race and by sex. Independent explanatory variables included age, body mass index, visceral adipose tissue volume, subcutaneous adipose tissue volume, alcohol consumption, TG, HDL-C, and insulin resistance. Mean LA varied significantly by sex, [(men) 57.76 ±10.03 HU and (women) 60.03 ±10.91 HU, p=0.0002], but not by race. Higher LA was associated with older age, while higher values of VAT, triglycerides, and insulin resistance were associated with lower LA in men and women. In contrast, alcohol consumption and BMI were associated with lower LA only among men. In analyses stratified by race LA was associated with alcohol consumption, VAT, and insulin resistance in both EA and AA and with age, BMI, and HDL-C in EA participants only. Our study findings confirm that there are important sex differences and race by sex interaction effects on the distribution of liver attenuation, the prevalence of FLD, and on the influence of metabolic risk factors on LA and FLD.
doi:10.1097/MEG.0b013e32834a94fb
PMCID: PMC3233637  PMID: 21900826
12.  Elevated hepatic fatty acid oxidation, high plasma fibroblast growth factor 21, and fasting bile acids in nonalcoholic steatohepatitis 
Background
Data from studies in patients with nonalcoholic steatohepatitis (NASH) suggest an increased hepatic fatty acid oxidation. We have previously shown higher fasting plasma bile acid concentrations in patients with NASH. In-vivo and in-vitro studies suggest that bile acids by binding to peroxisome proliferator-activated receptor α activate fibroblast growth factor 21 (FGF21) and increase hepatic fatty acid oxidation.
Methods
Plasma bile acid levels were quantified in healthy controls (n = 38) and patients with biopsy-proven NASH (n = 36). Plasma concentration of fatty acids, β-hydroxybutyrate, insulin, glucose, leptin, alanine aminotransferase, FGF21, and 8-hydroxydeoxyguanosine, a measure of oxidative stress, were measured in 16 healthy controls and 10 patients with NASH in the fasted state and in response to 3 h of infusion of intralipid. In a subgroup of these patients (n = 6 each), plasma ceramide subspecies were quantified.
Results
Fasting plasma bile acids, FGF21, and leptin concentrations were significantly higher in patients with NASH. In response to intralipid infusion there was an increase in plasma β-hydroxybutyrate and free fatty acid levels in both controls and NASH; however, the ratio of β-hydroxybutyrate/free fatty acid was higher in NASH (P = 0.02). Plasma FGF21 concentration increased in response to intralipid in patients with NASH only (P < 0.01). Plasma leptin, insulin, glucose, and alanine transferase concentrations did not change in either group after infusion of intralipid. Increase in total ceramides in response to intralipid was greater in NASH.
Conclusion
Elevated bile acids and FGF21 may be responsible for the higher hepatic fatty acid oxidation in NASH.
doi:10.1097/MEG.0b013e328345c8c7
PMCID: PMC3493151  PMID: 21448070
bile acids; fatty acid oxidation; fibroblast growth factor 21; nonalcoholic steatohepatitis
13.  Helicobacter pylori infection upregulates interleukin-18 production from gastric epithelial cells 
Background
Helicobacter pylori infection induces a biased T helper type 1 (Th1) response that produces IFN-γ and Fas ligand (FasL). Th1 cytokines are associated with apoptosis in the gastric epithelial cells.
Aim
We aimed to define the role of the recently cloned IL-18, a IFN-γ inducing factor, in gastric mucosal injury induced by H. pylori infection.
Methods
Twenty-seven gastric ulcer (GU) patients and 20 functional dyspepsia (FD) patients were enrolled in this study. Mucosal biopsy samples were obtained from the gastric antrum and GU site during endoscopy. Samples were used for histological examination, H. pylori culture and in-situ stimulation for 48 h in the presence of 10 µg/ml phytohemagglutinin-P. IL-18, IFN-γ, and soluble FasL (sFasL) levels in culture supernatants were assayed by the enzyme-linked immunosorbent assay method. IL-18, IL-1β-converting enzyme (ICE) and caspase-3 were evaluated by western blotting in gastric cancer cell lines (MKN45) cocultured with H. pylori.
Results
All 27 GU patients and ten out of 20 FD patients were found to be H. pylori-positive, whereas ten FD patients were H. pylori-negative. Antral mucosal tissues from H. pylori-positive FD patients contained (P < 0.01) higher levels of IL-18, IFN-γ, and sFasL than those from uninfected FD patients. IL-18, IFN-γ, and sFasL levels at the ulcer site were significantly (P < 0.01) higher than those at distant sites in the antrum. A significant relationship was seen between IL-18 and IFN-γ levels at the ulcer site (r = 0.7, P < 0.01). H. pylori eradication led to a significant decrease in the levels of IL-18, IFN-γ, and sFasL at the ulcer site. Western blotting showed that IL-18, ICE, and caspase-3 were activated in gastric cancer cell lines cocultured with H. pylori.
Conclusion
This study suggests that H. pylori infection enhanced mucosal injury by stimulating a Th1 response, which was mediated by IL-18 upregulation as well as activation of ICE and caspase-3.
doi:10.1097/MEG.0b013e32830edb15
PMCID: PMC3372857  PMID: 18946358
caspase; cytotoxicity; gastric ulcer; Helicobacter pylori; IL-18
14.  HLA-DQ Genotype Is Associated with Accelerated Small Bowel Transit in Patients with Diarrhea-Predominant Irritable Bowel Syndrome 
Background
Colonic transit (CT) is accelerated in 46% of patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Improvement in IBS-D with gluten withdrawal is associated with HLA-DQ2 positivity; the mechanism of improvement is unclear.
Objective
To determine if HLA-DQ2 or HLA-DQ8 positive IBS-D patients have faster small bowel (SB) or CT than HLA-DQ2 and HLA-DQ8 negative patients.
Methods
Among 94 IBS-D patients who previously provided DNA samples, 64 had undergone validated measurements of CT (geometric center at 24h [GC24]); 50 of the patients also had measurement of gastric emptying (GE) and 54 of SB transit (colonic filling at 6h [CF6h]). HLA-DQ status was determined by tag SNP approach. Associations of CF6h and GC24 with HLA-DQ2 and HLA-DQ8 status were assessed using analysis of covariance (ANCOVA), adjusting for BMI.
Results
Mean age was 40.8±1.6y; 98.5% were female. In 60/64 patients, celiac disease was excluded by serology or histology. There were no significant differences in age or BMI among the different HLA-DQ groups. Independently, patients positive for HLA-DQ2 had numerically greater CF6h compared to HLA-DQ2 negative (p=0.065), and those positive for HLA-DQ8 had greater CF6h compared to HLA-DQ8 negative patients (p=0.021). GE was not associated with HLA-DQ2 and HLA-DQ8 status. Patients positive for both HLA-DQ2 and HLA-DQ8 had greater CF6 (p=0.013) and numerically higher, but not significant, GC24 (p=0.38) compared to HLA-DQ2 and HLA-DQ8 negative patients.
Conclusion
IBS-D patients positive for HLA-DQ8 or for both HLA-DQ2 and HLA-DQ8 have faster SB transit. The mechanism of the accelerated SB transit and the effect of gluten withdrawal on SB function in IBS-D deserve further investigation.
doi:10.1097/MEG.0b013e328346a56e
PMCID: PMC3089653  PMID: 21490506
HLA-DQ; small bowel transit; diarrhea-predominant irritable bowel syndrome
15.  Oral Medication Adherence and Disease Severity in Pediatric Inflammatory Bowel Disease 
Objective
The purpose of this study was to examine the relationship of oral medication adherence and perceived adherence barriers with disease severity in a sample of adolescents with IBD.
Methods
Participants included 62 adolescents, aged 13–17 years, diagnosed with IBD and their parents. Measures of parent- and patient-rated oral medication adherence and related barriers, behavioral and emotional functioning per parent- and self-report, and disease severity per physician reported medical chart data were obtained.
Results
Fifteen percent of the sample reported clinically elevated depressive symptoms and 24% reported clinically elevated internalizing behavioral problems. Number of reported adherence barriers was 2.6 ± 1.5, and no participants reported zero barriers. Parental ratings of medication adherence (t = −2.11, p < .05) and perceived barriers to adherence (t = 2.05, p < .05) significantly predicted disease severity after statistically controlling for the contributions of behavioral and disease parameters to disease severity.
Conclusions
Results suggest that oral medication adherence and perceived adherence barriers are significantly related to disease severity in adolescents with IBD. These patients also may be at risk for increased behavioral and emotional problems which may impact health outcomes as well. Clinicians should make particular efforts to attend to medication adherence issues with their patients. Working with patients and families to develop solutions for eliminating adherence barriers might result in better disease outcomes.
doi:10.1097/MEG.0b013e328344019c
PMCID: PMC3073772  PMID: 21304318
Adherence; disease severity; inflammatory bowel disease; behavior; Barriers; Crohn’s disease; Ulcerative colitis
16.  Patient reported symptoms during an ulcerative colitis flare: A Qualitative Focus Group Study 
It has been assumed that the symptoms measured in disease activity indices for ulcerative colitis reflect those symptoms that patients find useful in evaluating the severity of a disease flare. In this qualitative focus group study, we aimed to identify which symptoms are important to patients and to compare these symptoms with a comprehensive list of commonly measured symptoms to determine/evaluate whether the patient-reported important symptoms are represented in current disease activity indices for ulcerative colitis. Patients in this sample confirmed 15 symptoms but not 11 other symptoms found in common ulcerative colitis activity indices. Patients identified an additional 14 symptoms not included in commonly used ulcerative colitis activity indices, which they believed to be important in evaluating the onset or severity of an ulcerative colitis flare. Current indices capture only a portion of the clinical symptoms that are important to patients in an ulcerative colitis flare, and may neither accurately measure nor fully reflect patients’ experience of ulcerative colitis. These findings present an opportunity to develop better patient-centered measures of ulcerative colitis.
doi:10.1097/MEG.0b013e328326cacb
PMCID: PMC3193174  PMID: 19194304
focus groups; inflammatory bowel disease; patient-reported outcomes; qualitative research; symptom domains; ulcerative colitis
17.  Cavernous hemangioma of the liver: factors affecting disease progression in general hepatology practice 
Background
Although for asymptomatic hepatic hemangiomas, conservative management is generally recommended, factors affecting disease course are still not very well understood.
Aim
To determine disease characteristics of cavernous hemangioma and factors affecting its progression in patients from a general hepatology clinic in Tehran, Iran.
Methods
We reviewed medical records of 198 patients with cavernous hemangioma of the liver visiting a large private hepatology clinic in Tehran from 1997 to 2007. Of a total of 198 cases, 129 could be followed up for a period of 3.2±2.5 years, and 80 of these had 1 to 5 repeat sonographies.
Results
Patients were between 27 and 84 years old (mean age 44.3±10.9), and 131 (66.2%) were female. Thirty-six patients (18.2%) had giant hemangiomas. Abdominal pain was the primary reason for evaluation in 100 (50.5%) patients. Abdominal pain at the beginning of follow-up was significantly associated with having irritable bowel syndrome (OR=8.3; 95%CI: 3.1-28.7) or other GI diseases (OR=3.9; 95%CI: 2.6-10.2), but not with hemangioma size, number or location. During follow-up, having a single giant lesion at the time of diagnosis, adjusted for age, sex and presence of IBS, was a strong predictor of persistent pain during follow-up (OR=11.1; 95%CI: 3.2-38.6). In repeat sonographies, 35% showed increased size, which was significantly associated only with having a single lesion (p=0.04).
Conclusion
Many symptoms in hepatic hemangioma are attributable to accompanying GI diseases. Patients with a single giant lesion are more likely to have persistent pain, and single lesions are more likely to grow in size.
doi:10.1097/MEG.0b013e3283451e7d
PMCID: PMC3076672  PMID: 21383624
liver; hemangioma; ultrasonography
18.  Human Telomerase Activity, Telomerase and Telomeric Template Expression in Hepatic Stem Cells and in Livers from Fetal and Postnatal Donors 
Background
Even though telomerase activity has been analyzed in various normal and malignant tissues, including liver, it is still unknown to what extent telomerase can be associated with specific maturational lineage stages.
Methods
We assessed human telomerase activity, protein and gene expression for the telomerase reverse transcriptase, as well as expression of the telomeric template RNA hter in hepatic stem cells and in various developmental stages of the liver from fetal to adult. Additionally, the effect of growth factors on telomerase activity was analyzed in hepatic stem cells in vitro.
Results
Telomerase was found to be highly active in fetal liver cells and was significantly higher than in hepatic stem cells, correlating with gene and protein expression levels. Activity in postnatal livers from all donor ages varied considerably and did not correlate with age or gene expression levels. The hter expression could be detected throughout development. A short stimulation by growth factors of cultured hepatic stem cells did not increase telomerase activity.
Conclusions
Telomerase is considerably active in fetal liver and variably in postnatal livers. Although telomerase protein is present at varying levels in liver cells of all donor ages, gene expression is associated solely with fetal liver cells.
doi:10.1097/MEG.0b013e32832973fc
PMCID: PMC2743773  PMID: 19240645
telomerase; htert; hter; hepatoblast; hepatic stem cell; hepatocyte
19.  Hepatocellular carcinoma after sustained virologic response in hepatitis C patients without cirrhosis on a pre-treatment liver biopsy 
Among hepatitis C patients, lack of cirrhosis and sustained virologic response reduce the risk of hepatocellular carcinoma. Japanese studies document multiple cases of hepatocellular carcinoma among these patients, but only one case has been reported outside of Asia. We identified five patients with hepatitis C in our university-based hepatology practice who developed hepatocellular carcinoma despite sustained virologic response and lack of cirrhosis on their pre-treatment liver biopsy. At the time of hepatocellular carcinoma diagnosis, two remained noncirrhotic, one had clearly progressed to cirrhosis, and two lacked repeat histology. We present these patients in a case series format and discuss several important implications of their cases. Physicians often base screening and treatment decisions on an initial liver biopsy performed years prior. Because fibrosis may advance, and because sustained virologic response and lack of cirrhosis do not fully protect against hepatocellular carcinoma, future study should further evaluate the risk of hepatocellular carcinoma among hepatitis C patients after SVR.
doi:10.1097/MEG.0b013e32831101b7
PMCID: PMC2744965  PMID: 19212213
hepatitis C; hepatocellular carcinoma; interferon; ribavirin; screening; sustained virologic response
20.  Association of gastric disease with polymorphisms in the inflammatory related genes IL-1B, IL-1RN, IL-10, TNF and TLR4 
Objectives
Increasing evidence suggests that polymorphisms in key mediator genes of Helicobacter pylori (H. pylori) -induced inflammation, influence susceptibility to developing non-cardia gastric cancer. This study aimed to investigate if single nucleotide polymorphisns (SNPs) in a series of inflammatory genes were associated with the development of the most common pathologies thought to precede gastric cancer development namely; H. pylori associated gastritis and intestinal metaplasia.
Methods
A total of 250 patients were genotyped for 11 SNPs in the IL-1B, IL-1RN, TNF, TLR4 and IL-10 genes. The study population comprised H. pylori uninfected (‘normal’) control patients (n=96), H. pylori positive gastritis (n=91) and intestinal metaplasia patients (n=63). Genotyping was performed using Taqman allelic discrimination assays. Odds ratios for gastric disease groups were adjusted for potential confounding factors.
Results
No differences were identified in frequency of carriage, or homozygosity, for any of the ‘risk’ alleles investigated across the patient groups. There was no evidence to suggest an association with increased risk of developing either chronic gastritis or intestinal metaplasia with SNPs in the IL-1B, IL-1RN, TNF, TLR4 and IL-10 genes.or haplotypes tested.
Conclusion
This study found no evidence of an association with increased risk of developing either chronic gastritis or intestinal metaplasia with the SNPs or haplotypes tested.
doi:10.1097/MEG.0b013e3283140eea
PMCID: PMC2802816  PMID: 19295440
21.  Serum levels of preoperative α-fetoprotein and CA19-9 predict survival of hepatic carcinoma patients after liver transplantation 
Objective
The aim of this study was to assess serum levels of presurgical α-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9) as prognostic markers in patients with hepatic carcinoma after liver transplantation (LT).
Methods
A total of 226 patients were recruited for the analysis of serum AFP and CA19-9 levels, on the basis of which the tumor marker type (TMT) was defined and evaluated for prognostic prediction. Overall survival (OS) and relapse-free survival (RFS) were analyzed using Kaplan–Meier curves, and univariate and multivariate Cox models.
Results
One-year and 5-year OS were 79.0 and 58.0%, respectively, whereas RFS were 70.3 and 62.2%, respectively, in this cohort of patients. There were six variables predicting both OS and RFS, including TMT, tumor size, number of tumor lesions, extrahepatic or vascular invasion, and histopathological grade. Among these, TMT, tumor size, and extrahepatic invasion were all independent predictors of OS and RFS among these patients. Further, on the basis of TMT, novel LT selection criteria for patients with hepatic carcinoma, which supplemented the Milan criteria, were adopted, because the patients within the Milan criteria (n=107) and those exceeding Milan but fulfilling the proposed criteria (n=30) had similar 5-year OS (77.8 vs. 79.3%, P=0.862) and RFS (85.5 vs. 75.1%, P=0.210) rates.
Conclusion
The data from this study showed that serum levels of preoperative AFP and CA19-9 were able to predict survival of patients with hepatic carcinoma after LT. This study included novel criteria, adding serum AFP and CA19-9 levels to the selection criteria for LT eligibility of patients, in addition to the Milan criteria.
doi:10.1097/MEG.0000000000000070
PMCID: PMC3979888  PMID: 24589829
biomarker; CA19-9; α-fetoprotein; hepatocellular carcinoma; liver cancer; liver transplantation; survival
22.  Preoperative model for end-stage liver disease score as a predictor for posthemihepatectomy complications 
Background
As diagnostic techniques advance and surgical outcomes improve, the rate of utilization of liver hemihepatectomy for various indications will continue to increase.
Objectives
To explore the preoperative predictors of liver hemihepatectomy postoperative complications.
Patients and methods
This study included retrospective analysis of the clinical data of patients who underwent either liver hemihepatectomy or extended hemihepatectomy at Georg August University Hospital-Goettingen for the period 2002–2012. The outcomes were either postoperative complications or death of the patient (within 3 months from the end of the operation). Modified classification of surgical complications was adopted in the current study. The preoperative model for end-stage liver disease (MELD) score, aspartate aminotransferase, creatinine, international normalized ratio, and bilirubin in addition to the demographic characteristics of the patients and intraoperative blood loss were analyzed as predictive for postliver hemihepatectomy complications.
Results
The study included 144 patients who underwent liver hemiheptectomy or extended hemihepatectomy through the study period (2002–2012). Postoperative complications were reported among patients out of 144 (52.1%). The most frequent complications were pleural effusion (26.7%), biliary leakage (21.3%), wound dehiscence (13.3%), ascites, and intra-abdominal abscess (6.7%). Death was reported among six patients of those who developed complications (8%). There were four cases of hepatic cirrhosis (one macroscopic and three microscopic). Two of the microscopic cases had no postoperative complications (grade 1), whereas one case had grade 3a and the macroscopic case had postoperative complication grade 1. Their MELD scores ranged between 6 and 10 preoperatively. The association between preoperative MELD score and development of posthemihepatetomy was statistically significant, P=0.002. Death was reported in six cases, yielding a mortality rate of 4.17%. MELD score preoperatively was the only significant predictor for postoperative complications.
Conclusion
The rate of complications following hemihepatectomy remains high, with 52.1% of the patients in the current study having at least one complication as all of our patients underwent either hemihepatectomy or extended hemihepatectomy. A 4.17% mortality rate has been reported. A higher preoperative MELD score is the only significant predictor for the development of posthemihepatectomy complications.
doi:10.1097/MEG.0000000000000035
PMCID: PMC4004640  PMID: 24743499
hemihepatectomy; MELD score; postoperative complication
23.  Constipation-related direct medical costs in 16 887 patients newly diagnosed with chronic constipation 
Background
Chronic constipation is a common condition, but the exact impact on healthcare budgets in Western Europe is poorly documented.
Objectives
The aim of this study was to (a) investigate chronic constipation-related direct medical costs in patients with newly diagnosed chronic constipation and (b) study differences in costs according to natural history.
Patients and methods
We identified 16 887 patients newly diagnosed with chronic constipation in a Dutch health insurance database (∼1.3 million patients) in 2006–2009. Individuals with chronic constipation were selected on the basis of chronic laxative use (≥90 days/year) and diagnostic related groups for chronic constipation. On the basis of the episodes of laxative use and diagnostic related groups, individuals were categorized as having persistent, episodic, and nonrecurrent disease. Unadjusted costs for laxatives and hospital care for chronic constipation and constipation-related comorbidities were assessed and compared between patients with nonrecurrent, episodic, and persistent disease. Factors associated with costs were identified using Cox regression analyses.
Results
The mean total chronic constipation-related direct medical costs in the first year after diagnosis were €310±845 and consisted of laxatives (45%) and hospital care for chronic constipation (26%) as well as constipation-related comorbidities (29%). Costs were highest in patients with persistent disease (€367±882) compared with patients with episodic (€292±808) and nonrecurrent (€263±613) disease (P<0.01). Male sex was associated with higher costs, whereas increasing age, diabetes, and use of opioids were associated with lower costs.
Conclusion
Pharmacy costs and hospital care costs for chronic constipation-related comorbidities were the largest cost drivers for total constipation-related direct medical costs in patients with newly diagnosed chronic constipation. Direct medical costs differed according to patient characteristics.
doi:10.1097/MEG.0000000000000167
PMCID: PMC4186732  PMID: 25229982
chronic constipation; costs; healthcare utilization
24.  Gut dysfunction in patients with multiple sclerosis and the role of spinal cord involvement in the disease 
Objectives
Bowel and bladder symptoms are highly prevalent in patients with multiple sclerosis (MS). Bladder dysfunction (affecting 75% of these patients) is caused by disease in the spinal cord, whilst the pathophysiology of bowel dysfunction is unknown. Pathways regulating both the organs lie in close proximity to the spinal cord, and coexistence of their dysfunction might be the result of a common pathophysiology. If so, the prevalence of bladder symptoms should be greater in patients with MS and bowel symptoms. This hypothesis is tested in the study. We also evaluated how patient-reported symptoms quantify bowel dysfunction.
Patients and methods
The Neurogenic Bowel Dysfunction questionnaire and the presence of bladder symptoms were recorded in 71 patients with MS and bowel symptoms. Disability, a surrogate clinical measure of spinal cord disease, was assessed using the Expanded Disability Status Scale. Bowel and bladder symptoms were quantified by patient-reported frequency, expressed in time percentage (0, 25, 50, 75 or 100% of the time the symptom was perceived), and patient-reported severity on a visual analogue scale between 0 and 100.
Results
The prevalence of bladder symptoms was 85%, which is higher than that expected in an unselected population of patients with MS. Neurogenic Bowel Dysfunction score was significantly correlated with both patient-reported frequency (r=0.860, P<0.0001) and severity of bowel symptoms (r=0.659, P=<0.0001), as well as with the Expanded Disability Status Scale (r=0.526, P<0.0001).
Conclusion
Our findings suggest that gut dysfunction in patients with MS is secondary to spinal cord disease. Patient-reported bowel symptoms quantify bowel dysfunction well.
doi:10.1097/MEG.0b013e328361eaf8
PMCID: PMC4206376  PMID: 23669324
bladder dysfunction; constipation; faecal incontinence; multiple sclerosis
25.  Accuracy of GastroPanel for the diagnosis of atrophic gastritis 
Background
It has been suggested that GastroPanel might be a useful tool for the diagnosis of chronic atrophic gastritis (CAG) measuring four biomarkers in blood: basal gastrin-17 (G17), pepsinogen I and II (PGI and PGII), and Helicobacter pylori antibodies.
Aim
To determine the accuracy of GastroPanel for the diagnosis of CAG.
Methods
This was a prospective, blinded, multicenter study that included dyspeptic patients. G17, PGI, and PGII were determined by enzyme immunoassays. Three antrum and two corpus biopsies were obtained for standard histological analysis and rapid urease test. Biopsies were analyzed by a single blinded expert pathologist.
Results
Ninety-one patients were included (77% women, mean age 44 years, 51% H. pylori positive, 17% with CAG). G17 was reduced in patients with antrum CAG (5.4 vs. 13.4 pmol/l; P<0.01) and increased in patients with corpus CAG (11 vs. 24 pmol/l; P<0.05), but its accuracy was only acceptable in the case of corpus localization [area under the receiver operating characteristic curve (AUC), 74%]; PGII difference was almost statistically significant only when testing for corpus atrophy (33 vs. 21 μg/l; P=0.05; AUC=72%). The PGI and PGI/PGII ratio showed no significant differences (AUCs were all unacceptably low). Helicobacter pylori antibody levels were higher in H. pylori-infected patients (251 vs. 109 EIU, P=0.01; AUC=70). The accuracy of GastroPanel for the diagnosis of CAG was as follows: sensitivity 50%; specificity 80%; positive 25% and negative 92% predictive values; and positive 2.4 and negative 0.6 likelihood ratios.
Conclusion
GastroPanel is not accurate enough for the diagnosis of CAG; thus, its systematic use in clinical practice cannot be recommended.
doi:10.1097/MEG.0000000000000132
PMCID: PMC4232299  PMID: 25014624
antibodies; chronic atrophic gastritis; gastrin-17; Helicobacter pylori; pepsinogen I; pepsinogen II; serologic diagnosis

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