Response to long-term lamivudine treatment (up to 5 years) in patients with severe chronic hepatitis B, role of genotype and drug resistance.

Lamivudine is effective in suppressing viral replication, normalizing alanine aminotransferase (ALT), and improving histological appearance in HBe positive and negative hepatitis. It is unclear whether hepatitis B virus (HBV) genotype influences the response to lamivudine. We report the long-term response of patients with chronic hepatitis B with and without cirrhosis at baseline treated with lamivudine according to HBV genotype. Retrospective review of charts of all patients treated with lamivudine monotherapy between 1993 and 2002. Response to therapy defined as ALT in the normal range, undetectable HBV DNA, and in the HBeAg positive group loss of HBeAg and/or the development of anti-HBe. HBV DNA measured by the Digene Hybrid capture assay (sensitivity 1.4 x 10(6) copies/mL). YMDD mutation at rtL180M and rtM204V/I measured by restriction digest of amplified products. Genotyping performed by sequencing and phylogenetic tree analysis of the preS region of the virus genome. Seventy-one patients treated with lamivudine for 6 months or more, 53 (75%) were male, average age 47 years, 38 (54%) were HBeAg+ and 33 (46%) HBeAg-. Mean baseline HBV DNA viral titre was 1280.2 copies/mL and 518 copies/mL respectively. Cirrhosis was present in 30 (42%). Sera were examined for YMDD mutations at last patient visit in 61 (86%), and were detected in 45 (74%), there being no association with a particular genotype. Data from up to 5 years on lamivudine indicated no difference in biochemical or virological response between genotypes. Cirrhosis was more prevalent with specific genotypes. We found no influence of HBV genotype on the development of resistance to lamivudine, however liver disease severity was influenced by genotype.

Effects of folylpolyglutamate synthetase modulation on chemosensitivity of colon cancer cells to 5-fluorouracil and methotrexate.

BACKGROUND: Folylpoly-gamma-glutamate synthetase (FPGS) converts intracellular folates and antifolates (for example, methotrexate (MTX)) to polyglutamates. Polyglutamylated folates and antifolates are retained in cells longer and are better substrates than their monoglutamate counterparts for enzymes involved in one carbon transfer. Polyglutamylation of intracellular 5,10-methylenetetrahydrofolate may also enhance the cytotoxicity of 5-fluorouracil (5-FU) by allowing more efficient formation and stabilisation of the inhibitory ternary complex involving thymidylate synthase and a 5-FU metabolite. AIM: We investigated the effects of FPGS modulation on the chemosensitivity of colon cancer cells to 5-FU and MTX. METHODS: Human HCT116 colon cancer cells were stably transfected with the sense or antisense FPGS cDNA or blank (control). FPGS protein expression and enzyme activity, growth rate, intracellular folate content and composition, and in vitro chemosensitivity to 5-FU and MTX were determined. RESULTS: Compared with cells expressing endogenous FPGS, those overexpressing FPGS had significantly faster growth rates and higher concentrations of total folate and long chain folate polyglutamates while antisense FPGS inhibition produced opposite results. FPGS overexpression significantly enhanced, whereas FPGS inhibition decreased, chemosensitivity to 5-FU. No significant difference in chemosensitivity to MTX was observed. CONCLUSIONS: These data provide functional evidence that FPGS overexpression and inhibition modulate chemosensitivity of colon cancer cells to 5-FU by altering intracellular folate polyglutamylation, providing proof of principle. Thus FPGS status may be an important predictor of chemosensitivity of colon cancer cells to 5-FU based chemotherapy, and FPGS gene transfer may increase the sensitivity of colon cancer cells to 5-FU-based chemotherapy.

Diagnostic misclassification reduces the ability to detect linkage in inflammatory bowel disease genetic studies.

BACKGROUND: Linkage data have now identified several inflammatory bowel disease (IBD) susceptibility loci but these data have not been consistently replicated in independent studies. One potential explanation for this is the possibility that patients enrolled in such studies may have been erroneously classified with respect to their diagnosis. AIMS: To determine the rate and type of misclassification in a large population of individuals referred for participation in an IBD genetics study and to examine the effect of diagnostic misclassification on the power to detect linkage. METHODS: The medical records of 1096 patients entered into an IBD genetics programme were reviewed using standardised diagnostic criteria. The original patient reported diagnoses were changed, if necessary, based on review, and the reasons for the change in diagnosis were recorded. To evaluate the effect of misclassification on linkage results, simulations were created with Gensim and analysed using Genehunter to evaluate a model for IBD inheritance. RESULTS: Sixty eight of 1096 (6.2%) individuals had a change in diagnosis from that originally reported. The majority of changes were patients with either Crohn's disease or ulcerative colitis who were determined not to have IBD at all. The principal reasons for changes to the original diagnosis were discordance between the patients' subjective reports of diagnosis and actual clinical history, endoscopic, or pathological results; a change in disease pattern over time; and insufficient information available to confirm the original diagnosis. A 10% misclassification rate resulted in 28.4% and 40.2% loss of power to detect a true linkage when using a statistical model for a presumed IBD locus with lambda(s) values of 1.8 and 1.3, respectively. CONCLUSIONS: Diagnostic misclassification occurs in patients enrolled in IBD genetic studies and frequently involves assigning the diagnosis of IBD to non-affected individuals. Even low rates of diagnostic misclassification can lead to significant loss of power to detect a true linkage, particularly for loci with modest effects as are likely to be found in IBD.

What guides a search for food that has disappeared? Experiments on cotton-top tamarins (Saguinus oedipus).

When food is launched down a vertically positioned S-shaped opaque tube, cotton-top tamarins (Saguinus oedipus) search for the food in the position directly beneath the release point, even though over several trials it never appears in this position (B. M. Hood et al., 1999). Experiment 1 showed that when the trajectory of the food shifts from the vertical to the horizontal plane, tamarins no longer show systematic perseverative errors and, in general, perform better on this invisible displacement task. Experiment 2 showed that tamarins with experience on the horizontal task show less of a bias when tested on the vertical task but nonetheless fail overall to solve this invisible displacement problem; their performance is substantially worse than it was on the horizontal task. Experiment 3 revealed that when the vertically positioned tube is replaced by an occluded ramp, tamarins consistently search in the compartment below the release point, even though most of the tamarins had experience in Experiments 1 and 2. Overall, results indicate that tamarins have a significant gravity bias when searching for food that has disappeared along the vertical plane but also have more general problems finding food that has moved out of sight.

Coping behavior and social support contribute independently to quality of life after surgery for inflammatory bowel disease.

PURPOSE: The purpose of this study was to examine the association between coping behavior at the time of surgery and inflammatory bowel disease-related quality of life after surgery. We also investigated the relationship between perceived social support and both coping style and postsurgical quality of life. Finally, the value of the Medical Outcomes Study Social Support Scale for preoperative screening was assessed. METHODS: Eighty-six subjects who had surgery during a 12-month period completed the Inflammatory Bowel Disease Questionnaire, the Ways of Coping, a measure of inflammatory bowel disease symptom severity, and the Medical Outcomes Study Social Support Scale. Analysis of variance was used to test an association between Ways of Coping score and membership in a high quality of life (Inflammatory Bowel Disease Questionnaire > mean) or low quality of life (Inflammatory Bowel Disease Questionnaire < mean) cohort. Comparison of group means between the high quality of life and low quality of life cohorts identified Ways of Coping behavior scales that differed between the high quality of life and low quality of life cohorts. Stepwise linear regression analysis was then used to determine the independent contribution of 1) current inflammatory bowel disease symptoms, 2) current perceived social support, and 3) identified coping behaviors (self-control, self-blame, and escape, summed as a single index named "maladaptive coping") to postsurgical quality of life. The sensitivity, specificity, and negative predictive value of the Medical Outcomes Study Social Support Scale were assessed. RESULTS: The lower quality of life group distinguished itself by more frequent use of maladaptive coping. Regression analysis revealed that current inflammatory bowel disease-related symptoms, current perceived social support, and maladaptive coping behaviors at the time of surgery each made a highly significant independent contribution to postsurgical quality of life. The sensitivity of the Medical Outcomes Study Social Support Scale in identifying patients with poor postsurgical quality of life was 81 percent, and the specificity was 77 percent. The negative predictive value was 93 percent. CONCLUSIONS: Three coping behaviors which seem to be maladaptive (self-control, self-blame, and escape) are associated with lower quality of life after surgery for inflammatory bowel disease. These coping behaviors make a contribution to postsurgical quality of life independent of the negative effect on quality of life of inflammatory bowel disease symptoms. Perceived social support is a third factor that makes an independent contribution to postsurgical quality of life. The Medical Outcomes Study Social Support Scale has properties associated with an effective screening tool and merits further investigation as an instrument to screen presurgically for individuals at higher risk of poor subjective outcome of inflammatory bowel disease surgery.

Use of community resources before inflammatory bowel disease surgery is associated with postsurgical quality of life.

BACKGROUND: Research in chronic illness shows that community resources can have a lasting influence on the course of the illness; however, little research has been done to evaluate the community agencies that specifically address the needs of inflammatory bowel disease (IBD) patients. OBJECTIVES: To survey awareness of community agency resources among patients who have surgery for IBD, and to analyze the association between using these resources and qualitative postsurgical outcomes. SUBJECTS AND METHODS: Ninety-two subjects who had surgery over a 12-month period completed, in full, the Inflammatory Bowel Disease Questionnaire (IBDQ), and a self-report instrument used to probe awareness and use of local community resources. Community resources were divided into two groups: those involving primarily social and educational participation ('social/ educational') and those involving some individualized attention, usually from a professional or trained lay facilitator ('professional/individual'). The contribution of presurgical participation in each type of resource to postsurgical quality of life was tested using ANOVA, with IBDQ score as the dependent variable. The ANOVA was repeated with postsurgical disease activity as a covariable. IBDQ subscale scores were compared between groups that were found to differ in the ANOVA. RESULTS: Almost all subjects were aware of at least one available resource. Participation in resources before surgery was variable, but 50% of the sample participated in at least one social/educational resource, and 46.9% participated in at least one professional/individual support. For the 92 subjects who completed both the IBDQ and the survey of resources, ANOVA revealed a main effect of professional/individual resource use on postsurgical quality of life but no main effect of social/educational resources and no interaction. DISCUSSION: The association between presurgical participation in professional or individualized community resources and better subjective outcome of IBD surgery may be explained by a positive contribution of participation to coping with surgery for IBD. The data do not support the alternative explanation that subjects with less severe disease (and thus better outcome) have greater ability to participate, although further research is required.

Influence of sex and disease on illness-related concerns in inflammatory bowel disease.

UNLABELLED: Identifying the normal concerns of people with ulcerative colitis and Crohn's disease (CD) facilitates a comprehensive approach to their medical care. Clinically, it can be easily appreciated that the concerns of men and women with inflammatory bowel disease (IBD) may differ and that this may have a substantial impact on both coping and treatment decisions. However, sex differences have received little empirical study. METHODS: Significant differences between the sexes on the 25 items of the Rating Form of IBD Patient Concerns (RFIPC) were determined in 343 subjects by univariate ANOVA with disease type and sex as factors, correcting for multiple comparisons and covarying for IBD symptom severity. RESULTS: Compared with men, women reported higher levels of IBD symptom severity and higher overall RFIPC scores. Women were more concerned than men about feelings related to their bodies, attractiveness, feeling alone and having children. There was an interaction between disease and sex regarding concern about sexual performance and intimacy. In both cases, men with CD reported less concern than each other comparison group. The illness concerns that differ between sexes are not the most intense concerns in either sex. DISCUSSION: These results confirm that sex has a significant influence on a number of illness concerns, particularly concerns related to self-image and relationships. The interaction of disease type and sex with respect to concern over sexual performance and intimacy is open to several potential explanations and requires further research. Sex differences should be considered in the treatment of IBD. Specific inquiry into sex-specific concerns may be useful for the clinician. Further research is required to replicate these retrospective findings.

Operative and environmental risk factors for recurrence of Crohn's disease.

This retrospective study determined whether a hand-sewn or stapled anastomosis leads to a greater recurrence rate in patients undergoing ileocecal resection for terminal ileal Crohn's disease. The effects of oral contraceptive use, smoking, and age at onset of disease were also examined. Ninety-two patients with Crohn's disease of the terminal ileum whose first operation was an ileocecal resection (terminal ileum and right colon up to but not including the hepatic flexure) were studied for symptomatic and operative recurrence. The symptomatic recurrence rates were 15% at 1 year, 31% at 2 years, and 45% at 3 years. The operative recurrence rates were 6% at 1 year, 14% at 2 years, and 22% at 3 years. The type of anastomosis, whether hand-sewn or stapled, did not affect the rates of symptomatic (P = 0.3) or operative (P = 0.6) recurrence. After the initial resection smoking affected both symptomatic (P = 0.03, risk ratio = 2.380) and operative (P = 0.041, risk ratio = 3.13) recurrence, but there was no effect of age at onset of disease or use of the birth control pill.