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1.  Improving uptake of screening for colorectal cancer: a study on invitation strategies and different test kit use 
The aim of this study was to compare the uptake of mail-delivered tests for colorectal cancer screening. We assessed the effect of an advance notification letter and a reminder letter, and analysed the proportion of inappropriately handled tests.
Materials and methods
Fifteen thousand randomly selected residents of Latvia aged 50–74 years were allocated to receive one of three different test systems: either a guaiac faecal occult blood test (gFOBT) or one of two laboratory-based immunochemical tests (FIT) – FOB Gold or OC-Sensor. Half of the target population received an advance notification letter; all nonresponders were sent a reminder letter.
The uptake of screening was 31.2% for the gFOBT, 44.7% for FOB Gold and 47.4% for the OC-Sensor (odds ratio 0.55; 95% confidence interval 0.51–0.60 for gFOBT vs. FOB Gold; odds ratio 0.90; 95% confidence interval 0.83–0.98 for FOB Gold vs. OC-Sensor). The uptake in the gFOBT group was improved by the advance notification letter (7.7%, P<0.0001). 30.9% returned tests were received after the reminder letter. The proportion of tests that could not be analysed because of inadequate handling was 0.9% for gFOBT, 4.4% for FOB Gold and 0.2% for the OC-Sensor (P=0.002 for gFOBT vs. OC-Sensor; P<0.001 for all comparisons vs. FOB Gold).
The use of FIT resulted in higher uptake. Receipt of a reminder letter was critical to participation, but the use of an advance notification letter was important mainly for gFOBT. The proportion of inappropriately handled tests was markedly higher for FOB Gold.
PMCID: PMC4423577  PMID: 25806603
advance notification letter; colorectal cancer screening; faecal immunochemical test; faecal occult blood test; uptake
2.  Labour productivity losses caused by premature death associated with hepatitis C in Spain 
Supplemental Digital Content is available in the text.
Background and aims
Hepatitis C virus (HCV) infection places a huge burden on healthcare systems. There is no study assessing the impact of HCV infection on premature deaths in Spain. The aim of this study was to estimate productivity losses because of premature deaths attributable to hepatitis C occurring in Spain during 2007–2011.
Materials and methods
We use data from several sources (Registry of Deaths, Labour Force Survey and Wage Structure Survey) to develop a simulation model based on the human capital approach and to estimate the flows in labour productivity losses in the period considered. The attributable fraction method was used to estimate the numbers of deaths associated with HCV infection. Two sensitivity analyses were developed to test the robustness of the results.
Our model shows total productivity losses attributable to HCV infection of 1054.7 million euros over the period analysed. The trend in productivity losses is decreasing over the period. This result is because of improvements in health outcomes, reflected in the reduction of the number of years of potential productive life lost. Of the total estimated losses, 18.6% were because of hepatitis C, 24.6% because of hepatocellular carcinoma, 30.1% because of cirrhosis, 15.9% because of other liver diseases and 10.7% because of HIV–HCV coinfection.
The results show that premature mortality attributable to hepatitis C involves significant productivity losses. This highlights the need to extend the analysis to consider other social costs and obtain a more complete picture of the actual economic impact of hepatitis C infection.
PMCID: PMC4415959  PMID: 25853930
hepatitis C; human capital approach; productivity losses; social costs
3.  Rates of cirrhosis and hepatocellular carcinoma in chronic hepatitis B and the role of surveillance: a 10-year follow-up of 673 patients 
Background and objectives
Development of cirrhosis and hepatocellular carcinoma (HCC) are critical milestones in the natural history of chronic hepatitis B virus (HBV) infection. There are no prospective data on the risk of these critical milestones in HBV patients in Singapore. The efficacy and justification of HCC surveillance is determined by the rate of HCC development. Our study aims to determine the rates of cirrhosis and HCC in HBV patients in Singapore and hence the appropriateness of HCC surveillance.
Materials and methods
A total of 673 HBV patients were enrolled between March 2003 and March 2004 and followed up for 10 years with regular surveillance for HCC using α-fetoprotein and abdominal ultrasound.
Overall, 62.6% of the patients were men, mean age 56.4 years. In all, 31% were hepatitis B e antigen-positive and 14.9% had cirrhosis at baseline. Seventy-four patients developed cirrhosis and 42 patients developed HCC after 10 years. The overall 10-year incidence of cirrhosis and HCC was 16.2% (1.6%/year) and 7.8% (0.8%/year), respectively. The overall incidence of HCC in cirrhotics was 29.7% (3.0%/year), highest within a year of diagnosis of cirrhosis (7.9%). The rate of cirrhosis was significantly higher in those aged more than 55 years (P=0.001). Sex and hepatitis B e antigen status did not affect the rate of cirrhosis. Factors with significantly higher overall rates of HCC were age 55 years or more (P=0.001), male sex (P=0.001), and baseline α-fetoprotein of 4.1 µg/l or more (P<0.0001). However, age more than 55 years was not significant in the development of HCC in cirrhotics.
The rate of cirrhosis in HBV patients in Singapore is about 1.6% per year. The rate of HCC is about 0.8% per year overall and 3.0% per year in cirrhotics, which justifies HCC surveillance.
PMCID: PMC4415961  PMID: 25831135
chronic hepatitis B; cirrhosis; hepatocellular carcinoma; surveillance
5.  Parenting stress predicts depressive symptoms in adolescents with inflammatory bowel disease 
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.
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.
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].
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.
PMCID: PMC4307594  PMID: 25003746
cross-lagged analysis; depression; diathesis-stress model; parent distress
6.  Procedure volume influences adherence to celiac disease guidelines 
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.
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).
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.
PMCID: PMC4048920  PMID: 23995767
celiac disease; endoscopy; quality of healthcare
7.  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.
PMCID: PMC4116339  PMID: 24081107
alpha-smooth muscle actin; anti-conductive tissue autoantibodies; chronic intestinal pseudo-obstruction; intestinal failure; sick sinus syndrome
8.  Bismuth-containing quadruple therapy for Helicobacter pylori: Lessons from China 
European journal of gastroenterology & hepatology  2013;25(10):10.1097/MEG.0b013e3283633b57.
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).
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.
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.
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.
PMCID: PMC3865448  PMID: 23778309
Helicobacter pylori; treatment; quadruple therapy; review; treatment success
9.  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.
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.
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.
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.
PMCID: PMC3856575  PMID: 20032782
cancer; colonoscopy; completion rate; screening; surveillance
10.  Telehealth behavioral treatment for medication nonadherence: a pilot and feasibility study 
To evaluate an individually tailored multicomponent nonadherence treatment protocol using a telehealth delivery approach in adolescents with inflammatory bowel disease.
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.
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.
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.
PMCID: PMC3703848  PMID: 23325274
adherence; compliance; inflammatory bowel disease; medication; pediatric
11.  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 
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.
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.
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.
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.
PMCID: PMC3368996  PMID: 22569080
HCV viral load; SNPs; interferon treatment
12.  Family functioning and health-related quality of life in adolescents with pediatric inflammatory bowel disease 
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.
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.
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.
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.
PMCID: PMC3677963  PMID: 21079514
adolescents; family functioning; inflammatory bowel disease; quality of life
13.  Cholangiocarcinoma and dominant strictures in patients with primary sclerosing cholangitis; a 25 year single centre experience 
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.
We describe a 25 year experience in patients with PSC related dominant strictures at a single tertiary referral centre.
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.
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.
PMCID: PMC3584158  PMID: 22653260
Cholangiocarcinoma; dominant stricture; endoscopic retrograde cholangiopancreatography; primary sclerosing cholangitis
14.  Evaluation of a Group-Based Behavioral Intervention to Promote Adherence in Adolescents with Inflammatory Bowel Disease 
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).
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.
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).
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.
PMCID: PMC3233635  PMID: 21989119
Inflammatory bowel disease; adherence; self-management; medication
15.  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.
PMCID: PMC3233637  PMID: 21900826
16.  Elevated hepatic fatty acid oxidation, high plasma fibroblast growth factor 21, and fasting bile acids in nonalcoholic steatohepatitis 
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.
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.
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.
Elevated bile acids and FGF21 may be responsible for the higher hepatic fatty acid oxidation in NASH.
PMCID: PMC3493151  PMID: 21448070
bile acids; fatty acid oxidation; fibroblast growth factor 21; nonalcoholic steatohepatitis
17.  Helicobacter pylori infection upregulates interleukin-18 production from gastric epithelial cells 
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.
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.
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.
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.
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.
PMCID: PMC3372857  PMID: 18946358
caspase; cytotoxicity; gastric ulcer; Helicobacter pylori; IL-18
18.  HLA-DQ Genotype Is Associated with Accelerated Small Bowel Transit in Patients with Diarrhea-Predominant Irritable Bowel Syndrome 
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.
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.
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.
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.
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.
PMCID: PMC3089653  PMID: 21490506
HLA-DQ; small bowel transit; diarrhea-predominant irritable bowel syndrome
19.  Oral Medication Adherence and Disease Severity in Pediatric Inflammatory Bowel Disease 
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.
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.
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.
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.
PMCID: PMC3073772  PMID: 21304318
Adherence; disease severity; inflammatory bowel disease; behavior; Barriers; Crohn’s disease; Ulcerative colitis
20.  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.
PMCID: PMC3193174  PMID: 19194304
focus groups; inflammatory bowel disease; patient-reported outcomes; qualitative research; symptom domains; ulcerative colitis
21.  Cavernous hemangioma of the liver: factors affecting disease progression in general hepatology practice 
Although for asymptomatic hepatic hemangiomas, conservative management is generally recommended, factors affecting disease course are still not very well understood.
To determine disease characteristics of cavernous hemangioma and factors affecting its progression in patients from a general hepatology clinic in Tehran, Iran.
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.
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).
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.
PMCID: PMC3076672  PMID: 21383624
liver; hemangioma; ultrasonography
22.  Human Telomerase Activity, Telomerase and Telomeric Template Expression in Hepatic Stem Cells and in Livers from Fetal and Postnatal Donors 
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.
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.
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.
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.
PMCID: PMC2743773  PMID: 19240645
telomerase; htert; hter; hepatoblast; hepatic stem cell; hepatocyte
23.  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.
PMCID: PMC2744965  PMID: 19212213
hepatitis C; hepatocellular carcinoma; interferon; ribavirin; screening; sustained virologic response
24.  Association of gastric disease with polymorphisms in the inflammatory related genes IL-1B, IL-1RN, IL-10, TNF and TLR4 
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.
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.
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.
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.
PMCID: PMC2802816  PMID: 19295440
25.  Serum levels of preoperative α-fetoprotein and CA19-9 predict survival of hepatic carcinoma patients after liver transplantation 
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).
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.
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.
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.
PMCID: PMC3979888  PMID: 24589829
biomarker; CA19-9; α-fetoprotein; hepatocellular carcinoma; liver cancer; liver transplantation; survival

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