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Adult health status of women HMO members with posttraumatic stress disorder symptoms.

Posttraumatic stress disorder (PTSD) is associated with high numbers of self-reported physical symptoms and functional disability in clinical samples, but little is known about the magnitude of these associations in population samples and using actual physician-coded diagnoses. We administered a 22-page survey to 1225 female HMO enrollees randomly selected from the current membership of a large, staff model HMO in Seattle, Washington. Using the PTSD Checklist (internally validated against a subset of clinical interviews) we compared women with low, moderate, and high scores with respect to differences in self-reported physical health status, functional disability (36-item short form health survey), numbers and types of self-reported health risk behaviors, common physical symptoms, and physician-coded ICD-9 diagnoses. Compared to women with low PTSD symptom severity, those with moderate or high severity reported significantly higher functional disability (P<.001), rates of abuse and neglect (P<.01 to P<.001), health risk behavior scores (P<0.05), as well as higher mean numbers of common physical symptoms (P<.05). Compared to women with low PTSD symptom severity those with moderate or high severity had significantly higher adjusted odds ratios for aversive physical symptoms (range, 1.7-10.1). The mean number of physician-coded ICD-9 diagnoses was also significantly higher in the both the moderate and high severity groups. Among female HMO members, PTSD symptoms are associated with a wide range of both self-reported and physician-coded adverse physical health outcomes.

Adolescent↗

PubMed2000

Patients in Europe evaluate general practice care: an international comparison.

BACKGROUND: Patients' evaluations can be used to improve health care and compare general practice in different health systems. AIM: To identify aspects of general practice that are generally evaluated positively by patients and to compare opinions of patients in different European countries on actual care provision. METHOD: An internationally-validated questionnaire was distributed to and completed by patients in 10 European countries. A stratified sample of 36 practices per country, with at least 1080 patients per country, was included. A set of 23 validated questions on evaluations of different aspects of care was used, as well as questions on age, sex, overall health status, and frequency of visiting the GP. RESULTS: The patient sample included 17,391 patients in 10 different countries; the average response rate was 79% (range = 67% to 89%). In general, patients visiting their general practitioner (GP) were very positive about the care provided. For most of the 23 selected aspects of care more than 80% viewed care as good or excellent; in particular, keeping records confidential, GP listening to patients, time during consultations, and quick services in case of urgent problems were evaluated positively. Patients were relatively negative about organisational aspects of care. The evaluations in different countries were largely similar, with some interesting differences; for instance, service and organisational aspects were evaluated more positively in fee-for-service health systems. CONCLUSIONS: Patients in Europe are positive about general practice but improvements in practice management in some countries are requested. More research is needed to study the complex field of differences in expectations and evaluations between countries with different health systems.

Culture↗

PubMed2003

Exploring and enhancing engagement to the psychosocial intervention 'Preparing for Parenthood'.

BACKGROUND: Poor compliance by participants consenting to be randomised to receive both physical and mental health promotion interventions represents a potentially serious threat to external and internal validity of those interventions. Quantitative and qualitative investigation of possible predictors of engagement forms an appropriate basis for efforts to enhance it. METHODS: Eight 'Preparing for Parenthood' intervention courses of a randomized controlled trial (RCT) underpinned a quantitative study. One 'Preparing for Parenthood' (PFP) intervention course, run upon completion of the RCT, formed a qualitative study. All nine courses followed identical procedures to enable clear comparisons. The three factors quantitatively explored with respect to engagement in health promoting behaviours were: locus of control (LOC), psychosocial support, and life events. The qualitative study utilised grounded theory analysis, the participants reflecting upon their experiences of the intervention and/or their reasons for not attending the course; nine interviews were completed. RESULTS: Participants in the quantitative and qualitative studies were divided into three sub-groups: compliant, non-compliant, and refusers. None of the three health promoting variables predicted compliance to a statistically significant degree. However, a variable from the trial analysis was found to reach significance; those women who had had less contact with the National Health Service in the 12 months prior to the baseline assessment were more likely to refuse the invitation to PFP. The qualitative study produced nine main themes that had influenced participant engagement at both the initial recruitment stage and during the course itself. CONCLUSIONS: In combination these findings may contribute to the future design of both effective and acceptable interventions to prevent postnatal depression. One such modified intervention is described and its impact on engagement outlined.

Depression, Postpartum↗

PubMed2003

Evaluating non-randomised intervention studies.

OBJECTIVES: To consider methods and related evidence for evaluating bias in non-randomised intervention studies. DATA SOURCES: Systematic reviews and methodological papers were identified from a search of electronic databases; handsearches of key medical journals and contact with experts working in the field. New empirical studies were conducted using data from two large randomised clinical trials. METHODS: Three systematic reviews and new empirical investigations were conducted. The reviews considered, in regard to non-randomised studies, (1) the existing evidence of bias, (2) the content of quality assessment tools, (3) the ways that study quality has been assessed and addressed. (4) The empirical investigations were conducted generating non-randomised studies from two large, multicentre randomised controlled trials (RCTs) and selectively resampling trial participants according to allocated treatment, centre and period. RESULTS: In the systematic reviews, eight studies compared results of randomised and non-randomised studies across multiple interventions using meta-epidemiological techniques. A total of 194 tools were identified that could be or had been used to assess non-randomised studies. Sixty tools covered at least five of six pre-specified internal validity domains. Fourteen tools covered three of four core items of particular importance for non-randomised studies. Six tools were thought suitable for use in systematic reviews. Of 511 systematic reviews that included non-randomised studies, only 169 (33%) assessed study quality. Sixty-nine reviews investigated the impact of quality on study results in a quantitative manner. The new empirical studies estimated the bias associated with non-random allocation and found that the bias could lead to consistent over- or underestimations of treatment effects, also the bias increased variation in results for both historical and concurrent controls, owing to haphazard differences in case-mix between groups. The biases were large enough to lead studies falsely to conclude significant findings of benefit or harm. Four strategies for case-mix adjustment were evaluated: none adequately adjusted for bias in historically and concurrently controlled studies. Logistic regression on average increased bias. Propensity score methods performed better, but were not satisfactory in most situations. Detailed investigation revealed that adequate adjustment can only be achieved in the unrealistic situation when selection depends on a single factor. CONCLUSIONS: Results of non-randomised studies sometimes, but not always, differ from results of randomised studies of the same intervention. Non-randomised studies may still give seriously misleading results when treated and control groups appear similar in key prognostic factors. Standard methods of case-mix adjustment do not guarantee removal of bias. Residual confounding may be high even when good prognostic data are available, and in some situations adjusted results may appear more biased than unadjusted results. Although many quality assessment tools exist and have been used for appraising non-randomised studies, most omit key quality domains. Healthcare policies based upon non-randomised studies or systematic reviews of non-randomised studies may need re-evaluation if the uncertainty in the true evidence base was not fully appreciated when policies were made. The inability of case-mix adjustment methods to compensate for selection bias and our inability to identify non-randomised studies that are free of selection bias indicate that non-randomised studies should only be undertaken when RCTs are infeasible or unethical. Recommendations for further research include: applying the resampling methodology in other clinical areas to ascertain whether the biases described are typical; developing or refining existing quality assessment tools for non-randomised studies; investigating how quality assessments of non-randomised studies can be incorporated into reviews and the implications of individual quality features for interpretation of a review's results; examination of the reasons for the apparent failure of case-mix adjustment methods; and further evaluation of the role of the propensity score.

Bias↗

PubMed2003

Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project.

BACKGROUND: International interest in clinical practice guidelines has never been greater but many published guidelines do not meet the basic quality requirements. There have been renewed calls for validated criteria to assess the quality of guidelines. OBJECTIVE: To develop and validate an international instrument for assessing the quality of the process and reporting of clinical practice guideline development. METHODS: The instrument was developed through a multi-staged process of item generation, selection and scaling, field testing, and refinement procedures. 100 guidelines selected from 11 participating countries were evaluated independently by 194 appraisers with the instrument. Following refinement the instrument was further field tested on three guidelines per country by a new set of 70 appraisers. RESULTS: The final version of the instrument contained 23 items grouped into six quality domains with a 4 point Likert scale to score each item (scope and purpose, stakeholder involvement, rigour of development, clarity and presentation, applicability, editorial independence). 95% of appraisers found the instrument useful for assessing guidelines. Reliability was acceptable for most domains (Cronbach's alpha 0.64-0.88). Guidelines produced as part of an established guideline programme had significantly higher scores on editorial independence and, after the publication of a national policy, had significantly higher quality scores on rigour of development (p<0.005). Guidelines with technical documentation had higher scores on that domain (p<0.0001). CONCLUSIONS: This is the first time an appraisal instrument for clinical practice guidelines has been developed and tested internationally. The instrument is sensitive to differences in important aspects of guidelines and can be used consistently and easily by a wide range of professionals from different backgrounds. The adoption of common standards should improve the consistency and quality of the reporting of guideline development worldwide and provide a framework to encourage international comparison of clinical practice guidelines.

Europe↗

PubMed2001

Evidence- and consensus-based practice guidelines for the diagnosis of irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) presents a significant diagnostic and management challenge for primary care practitioners. Improving the accuracy and timeliness of diagnosis may result in improved quality and efficiency of care. OBJECTIVE: To systematically appraise the existing diagnostic criteria and combine the evidence with expert opinion to derive evidence- and consensus-based guidelines for a diagnostic approach to patients with suspected IBS. METHODS: We performed a systematic literature review (January 1966-April 2000) of computerized bibliographic databases. Articles meeting explicit inclusion criteria for diagnostic studies in IBS were subjected to critical appraisal, which formed the basis of guideline statements presented to an expert panel. To develop a diagnostic algorithm, an expert panel of specialists and primary care physicians was used to fill in gaps in the literature. Consensus was developed using a modified Delphi technique. RESULTS: The systematic literature review identified only 13 published studies regarding the effectiveness of competing diagnostic approaches for IBS, the accuracy of diagnostic tests, and the internal validity of current diagnostic symptom criteria. Few studies met accepted methodological criteria. While symptom criteria have been validated, the utility of endoscopic and other diagnostic interventions remains unknown. An analysis of the literature, combined with consensus from experienced clinicians, resulted in the development of a diagnostic algorithm relevant to primary care that emphasizes a symptom-based diagnostic approach, refers patients with alarm symptoms to subspecialists, and reserves radiographic, endoscopic, and other tests for referral cases. The resulting algorithm highlights the reliance on symptom criteria and comprises a primary module, 3 submodules based on the predominant symptom pattern (constipation, diarrhea, and pain) and severity level, and a subspecialist referral module. CONCLUSIONS: The dearth of available evidence highlights the need for more rigorous scientific validation to identify the most accurate methods of diagnosing IBS. Until such time, the diagnostic algorithm presented herein could inform decision making for a range of providers caring for primary care patients with abdominal discomfort or pain and altered bowel function suggestive of IBS.

Algorithms↗

PubMed2003

A clinical prediction rule to identify patients with atrial fibrillation and a low risk for stroke while taking aspirin.

BACKGROUND: We sought to derive and internally validate a simple and easily applied clinical prediction rule to identify patients with nonvalvular atrial fibrillation (AF) whose stroke risk while taking aspirin is, irrespective of age, low enough that oral anticoagulation therapy is unnecessary. METHODS: We included 2501 patients with AF treated with aspirin during participation in 6 clinical trials. Patients were randomly divided into derivation and validation sets. Recursive partitioning was used to identify patients in the derivation set whose risk for stroke (ischemic or hemorrhagic) or transient ischemic attack was comparable to that observed in an age- and sex-matched cohort from the Framingham Heart Study. The derived prediction rules were tested on the validation set. RESULTS: Overall, 166 patients (6.6%) had an event during 4688.6 person-years (PYs) of observation for an incident rate of 3.5 events per 100 PYs. Patients in the derivation set classified as low risk (no previous stroke or transient ischemic attack, no treated hypertension or systolic blood pressure equal to or exceeding 140 mm Hg, no symptomatic coronary artery disease, and no diabetes) experienced 1.0 events per 100 PYs, compared with an age- and sex-matched rate of 1.2 events per 100 PYs. In the validation set, low-risk patients experienced 1.1 events per 100 PYs (expected rate of 1.2 events per 100 PYs). Low-risk patients made up 24% of the cohort and 16% of patients older than 75 years. Low-risk patients who were randomized to therapeutic oral anticoagulation therapy experienced 1.5 events per 100 PYs. CONCLUSION: Irrespective of age, patients with AF and none of these 4 clinical features and who take aspirin have stroke rates comparable to those of age-matched community cohorts and would not benefit substantially from anticoagulation.

Aspirin↗

PubMed2001

The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, II: characteristics of patients enrolled and not enrolled. COMS Report No. 17.

OBJECTIVES: To describe characteristics of patients evaluated for the Collaborative Ocular Melanoma Study (COMS) randomized clinical trial of iodine 125 brachytherapy for choroidal melanoma by enrollment status, and to compare characteristics of patients enrolled with those of patients with tumors of eligible size who did not enroll in order to assess the extent to which findings from the clinical trial can be generalized to future patients. METHODS: For all patients diagnosed with choroidal melanoma and evaluated for the clinical trial at COMS centers from November 1986 through July 31, 1998, selected data were transmitted to the COMS Coordinating Center, Baltimore, Md, where they were integrated and analyzed. Data included ophthalmic and medical history, examination findings, and visual acuity measurements recorded prior to enrollment; standardized A- and B-scan echographic examination findings; and wide-angle fundus photographs and fluorescein angiograms. RESULTS: Of 8712 patients with choroidal melanoma, 5046 had tumors of eligible size; of these, 2882 (57%) were eligible for enrollment, and 1317 (46% of eligible patients, 26% of patients with tumors of eligible size) enrolled. Most differences between eligible and ineligible patients corresponded to eligibility and exclusion criteria. However, ineligible patients were older and had thicker tumors than eligible patients. Eligible patients who enrolled were slightly older and had larger tumors than those who did not enroll. Nearly half (48%) of enrolled patients had choroidal melanoma with the apex located temporal to the fovea, compared with 40% of eligible patients not enrolled and 29% of ineligible patients. CONCLUSIONS: This trial was designed to yield internally valid treatment comparisons through random assignment to treatment at time of enrollment. Information from this and other studies document that enrolled patients were similar to other patients with choroidal melanoma who were treated with 125I brachytherapy. These findings support the external validity of the trial and applicability of treatment findings to all patients who meet the criteria used to judge eligibility for the trial.

Adult↗

PubMed2003

Impact of patching and atropine treatment on the child and family in the amblyopia treatment study.

OBJECTIVE: To assess the psychosocial impact on the child and family of patching and atropine as treatments for moderate amblyopia in children younger than 7 years. METHODS: In a randomized, controlled clinical trial, 419 children younger than 7 years with amblyopic eye visual acuity in the range of 20/40 to 20/100 were assigned to receive treatment with either patching or atropine at 47 clinical sites. After 5 weeks of treatment, a parental quality-of-life questionnaire was completed for 364 (87%) of the 419 patients. Main Outcome Measure Overall and subscale scores on the Amblyopia Treatment Index. RESULTS: High internal validity and reliability were demonstrated for the Amblyopia Treatment Index questionnaire. The overall Amblyopia Treatment Index scores and the 3 subscale scores were consistently higher (worse) in the patching group compared with the atropine-treated group (overall mean, 2.52 vs 2.02, P<.001; adverse effects of treatment: mean, 2.35 vs 2.11, P =.002; difficulty with compliance: mean, 2.46 vs 1.99, P<.001; and social stigma: mean, 3.09 vs 1.84, P<.001, respectively). CONCLUSION: Although the Amblyopia Treatment Index questionnaire results indicated that both atropine and patching treatments were well tolerated by the child and family, atropine received more favorable scores overall and on all 3 questionnaire subscales.

Adult↗

PubMed1986

Hypochondriasis. An evaluation of the DSM-III criteria in medical outpatients.

We attempted to integrate the DSM-III criteria for hypochondriasis with the clinical literature and derived six positive and two negative diagnostic criteria. Seven of these were assessed in a random sample of 92 medical outpatients by means of a self-report questionnaire, structured interview, and medical record audit. The results are in accord with previous work: there appears to be considerable internal validity and consistency in the syndrome in that disease conviction, disease fear, bodily preoccupation, and somatic symptoms are significantly intercorrelated. The three hypochondriacal attitudes (conviction, fear, and preoccupation) were not statistically related to the number of medical diagnoses in the patients' medical records. Depressive symptoms, as measured by the Beck Depression Inventory, were highly correlated with the other hypochondriacal symptoms. The hypochondriacal syndrome in these patients appears to be consistent with the clinical disorder described in DSM-III.

Adult↗

PubMed2006

Two-year randomized controlled trial and follow-up of dialectical behavior therapy vs therapy by experts for suicidal behaviors and borderline personality disorder.

CONTEXT: Dialectical behavior therapy (DBT) is a treatment for suicidal behavior and borderline personality disorder with well-documented efficacy. OBJECTIVE: To evaluate the hypothesis that unique aspects of DBT are more efficacious compared with treatment offered by non-behavioral psychotherapy experts. DESIGN: One-year randomized controlled trial, plus 1 year of posttreatment follow-up. SETTING: University outpatient clinic and community practice. PARTICIPANTS: One hundred one clinically referred women with recent suicidal and self-injurious behaviors meeting DSM-IV criteria, matched to condition on age, suicide attempt history, negative prognostic indication, and number of lifetime intentional self-injuries and psychiatric hospitalizations. INTERVENTION: One year of DBT or 1 year of community treatment by experts (developed to maximize internal validity by controlling for therapist sex, availability, expertise, allegiance, training and experience, consultation availability, and institutional prestige). MAIN OUTCOME MEASURES: Trimester assessments of suicidal behaviors, emergency services use, and general psychological functioning. Measures were selected based on previous outcome studies of DBT. Outcome variables were evaluated by blinded assessors. RESULTS: Dialectical behavior therapy was associated with better outcomes in the intent-to-treat analysis than community treatment by experts in most target areas during the 2-year treatment and follow-up period. Subjects receiving DBT were half as likely to make a suicide attempt (hazard ratio, 2.66; P = .005), required less hospitalization for suicide ideation (F(1,92) = 7.3; P = .004), and had lower medical risk (F(1,50) = 3.2; P = .04) across all suicide attempts and self-injurious acts combined. Subjects receiving DBT were less likely to drop out of treatment (hazard ratio, 3.2; P < .001) and had fewer psychiatric hospitalizations (F(1,92) = 6.0; P = .007) and psychiatric emergency department visits (F(1,92) = 2.9; P = .04). CONCLUSIONS: Our findings replicate those of previous studies of DBT and suggest that the effectiveness of DBT cannot reasonably be attributed to general factors associated with expert psychotherapy. Dialectical behavior therapy appears to be uniquely effective in reducing suicide attempts.

Adaptation, Psychological↗

PubMed2003

Interventions for violence against women: scientific review.

CONTEXT: Intimate partner violence is prevalent and is associated with significant impairment, yet it remains unclear which interventions, if any, reduce rates of abuse and reabuse. OBJECTIVE: To systematically review, from the perspective of primary health care, the available evidence on interventions aimed at preventing abuse or reabuse of women. DATA SOURCES: MEDLINE, PsycINFO, CINAHL, HealthStar, and Sociological Abstracts were searched from the database start dates to March 2001 using database-specific key words such as domestic violence, spouse abuse, partner abuse, shelters, and battered women. References of key articles were hand searched. The search was updated in December 2002. STUDY SELECTION: Both authors reviewed all titles and abstracts using established inclusion/exclusion criteria. Twenty-two articles met the inclusion criteria for critical appraisal. DATA EXTRACTION: Following the evidence-based methods of the Canadian Task Force on Preventive Health Care, both authors independently reviewed the 22 included studies using an established hierarchy of study designs and criteria for rating internal validity. Quality ratings of individual studies--good, fair, or poor--were determined based on a set of operational parameters specific to each design category developed with the US Preventive Services Task Force. DATA SYNTHESIS: Screening instruments exist that can identify women who are experiencing intimate partner violence. No study has examined, in a comparative design, the effectiveness of screening when the end point is improved outcomes for women (as opposed to identification of abuse). No high-quality evidence exists to evaluate the effectiveness of shelter stays to reduce violence. Among women who have spent at least 1 night in a shelter, there is fair evidence that those who received a specific program of advocacy and counseling services reported a decreased rate of reabuse and an improved quality of life. The benefits of several other intervention strategies in treating both women and men are unclear, primarily because of a lack of suitably designed research measuring appropriate outcomes. In most cases, the potential harms of interventions are not assessed within the studies reviewed. CONCLUSIONS: Much has been learned in recent years about the epidemiology of violence against women, yet information about evidence-based approaches in the primary care setting for preventing intimate partner violence is seriously lacking. The evaluation of interventions to improve the health and well-being of abused women remains a key research priority.

Behavior Therapy↗

PubMed1996

Randomized and non-randomized patients in clinical trials: experiences with comprehensive cohort studies.

In clinical research, randomized trials are widely accepted as the definitive method of evaluating the efficacy of therapies. Random assignment of patients to treatment ensures internal validity of the comparison of new treatments with controls. An assessment of external validity can best be achieved by comparing the randomized study sample to the population of patients who met the eligibility criteria but did not consent to randomization. The Comprehensive Cohort Study (CCS) is designed to recruit all patients fulfilling the clinical eligibility criteria regardless of their consent to randomization. The CCS concept was adopted in the major clinical trials of the German Breast Cancer Study Group (GBSG) conducted between 1983 and 1989. In this period 124 centres recruited 2084 patients in three clinical trials. 734 (35 per cent) of these patients accepted being randomized, while 1350 (65 per cent) chose one of the treatments under study; the randomization rates differed remarkably between trials. In this paper we examine the representativeness of the randomized patients in the three trials. Based on a median follow-up of about 5 years we present results on the external validity of the treatment effects estimated in the randomized patients by means of Cox's proportional hazards model and compare them between trials. We discuss advantages and disadvantages of the CCS design and conclude that its use is only justified under extraordinary circumstances.

Breast Neoplasms↗

PubMed2000

Pros and cons of permutation tests in clinical trials.

Hypothesis testing, in which the null hypothesis specifies no difference between treatment groups, is an important tool in the assessment of new medical interventions. For randomized clinical trials, permutation tests that reflect the actual randomization are design-based analyses for such hypotheses. This means that only such design-based permutation tests can ensure internal validity, without which external validity is irrelevant. However, because of the conservatism of permutation tests, the virtues of permutation tests continue to be debated in the literature, and conclusions are generally of the type that permutation tests should always be used or permutation tests should never be used. A better conclusion might be that there are situations in which permutation tests should be used, and other situations in which permutation tests should not be used. This approach opens the door to broader agreement, but begs the obvious question of when to use permutation tests. We consider this issue from a variety of perspectives, and conclude that permutation tests are ideal to study efficacy in a randomized clinical trial which compares, in a heterogeneous patient population, two or more treatments, each of which may be most effective in some patients, when the primary analysis does not adjust for covariates. We propose the p-value interval as a novel measure of the conservatism of a permutation test that can be defined independently of the significance level. This p-value interval can be used to ensure that the permutation test have both good global power and an acceptable degree of conservatism.

Humans↗

PubMed1997

Disordered eating patterns, body image, self-esteem, and physical activity in preadolescent school children.

OBJECTIVE: Eating disorders have been typically defined as an "adolescent problem." As a result of emerging evidence which indicated this health problem to be evident in the prepubescent age range, this study aimed to establish prevalence and factors associated with eating/dieting, physical activity, and body image among a nonclinical, naturalistically-derived sample of preadolescent (aged 10 and 11) school children (n = 61). METHOD: This cohort of children, which represented the entire grade 6 class of a suburban Elementary school, was measured for body image satisfaction [silhouettes], a participation in activity index, a self-worth scale and a measure of eating attitudes & behavior [Eating and Me scale [E & M]]. RESULTS: The longitudinal assessment of body image [3 measures over 9 months] indicated signs of stability of "actual" assessments of body image for males, but marked changes for females who preferred to be ideally "chunkier" in stature over time. Physical activity was only implicated with bulimia for the male sub-group. The E & M scale reported a Cronbach's alpha of .76, with two factors [bulimia; drive for thinness/anorexia] representing 65% of the total variance. Moderate internal validity [r .58] between body dissatisfaction on the E & M scale and the silhouette measure was observed. DISCUSSION: These results demonstrated that body image views and concerns appeared before puberty, that gender differences prevailed with respect to eating/dieting, activity and body image, and that the E & M scale has emerged as a promising research tool. The longitudinal nature of this study of eating disorders also promotes the need for qualitative research methodology and attention to pre-pubertal cognitive/perceptual processes.

Anorexia↗

PubMed2000

Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing.

Atthe International Workshop on Genotoxicity Test Procedures (IWGTP) held in Washington, DC, March 25-26, 1999, an expert panel met to develop guidelines for the use of the single-cell gel (SCG)/Comet assay in genetic toxicology. The expert panel reached a consensus that the optimal version of the Comet assay for identifying agents with genotoxic activity was the alkaline (pH > 13) version of the assay developed by Singh et al. [1988]. The pH > 13 version is capable of detecting DNA single-strand breaks (SSB), alkali-labile sites (ALS), DNA-DNA/DNA-protein cross-linking, and SSB associated with incomplete excision repair sites. Relative to other genotoxicity tests, the advantages of the SCG assay include its demonstrated sensitivity for detecting low levels of DNA damage, the requirement for small numbers of cells per sample, its flexibility, its low costs, its ease of application, and the short time needed to complete a study. The expert panel decided that no single version of the alkaline (pH > 13) Comet assay was clearly superior. However, critical technical steps within the assay were discussed and guidelines developed for preparing slides with agarose gels, lysing cells to liberate DNA, exposing the liberated DNA to alkali to produce single-stranded DNA and to express ALS as SSB, electrophoresing the DNA using pH > 13 alkaline conditions, alkali neutralization, DNA staining, comet visualization, and data collection. Based on the current state of knowledge, the expert panel developed guidelines for conducting in vitro or in vivo Comet assays. The goal of the expert panel was to identify minimal standards for obtaining reproducible and reliable Comet data deemed suitable for regulatory submission. The expert panel used the current Organization for Economic Co-operation and Development (OECD) guidelines for in vitro and in vivo genetic toxicological studies as guides during the development of the corresponding in vitro and in vivo SCG assay guidelines. Guideline topics considered included initial considerations, principles of the test method, description of the test method, procedure, results, data analysis and reporting. Special consideration was given by the expert panel to the potential adverse effect of DNA degradation associated with cytotoxicity on the interpretation of Comet assay results. The expert panel also discussed related SCG methodologies that might be useful in the interpretation of positive Comet data. The related methodologies discussed included: (1) the use of different pH conditions during electrophoreses to discriminate between DNA strand breaks and ALS; (2) the use of repair enzymes or antibodies to detect specific classes of DNA damage; (3) the use of a neutral diffusion assay to identify apoptotic/necrotic cells; and (4) the use of the acellular SCG assay to evaluate the ability of a test substance to interact directly with DNA. The alkaline (pH > 13) Comet assay guidelines developed by the expert panel represent a work in progress. Additional information is needed before the assay can be critically evaluated for its utility in genetic toxicology. The information needed includes comprehensive data on the different sources of variability (e.g., cell to cell, gel to gel, run to run, culture to culture, animal to animal, experiment to experiment) intrinsic to the alkaline (pH > 3) SCG assay, the generation of a large database based on in vitro and in vivo testing using these guidelines, and the results of appropriately designed multilaboratory international validation studies.

Animals↗

PubMed2000

Alterations in the gene expression profile of MCF-7 breast tumor cells in response to c-Jun.

MCF7 breast tumor cells overexpressing human c-Jun exhibit a transformed phenotype characterized not only by increased tumorigenicity but also by enhanced motility and invasion. The cellular phenotypic response to c-Jun overexpression is likely due, at least in part, to altered patterns of gene expression. In order to begin to understand the complexities by which elevated production of c-Jun alters the state of the cell, we have profiled the expression of 588 different genes by comparative hybridization. By using this approach, we have identified a total of 21 upregulated or downregulated gene targets responsive to c-Jun overexpression. Interestingly, 8 of these genes have been previously found associated with c-Jun or AP-1 activity and therefore provide internal validation for this approach to target gene discovery. The remaining 13 genes represent potential new c-Jun regulated target genes. Genomic sequence information was available for 15 of the 21 genes identified in this screen. Analysis of these genomic sequences revealed the presence of AP-1 or AP-1-like sequences in 12 of the 15 genes examined. Consistent with a direct mechanism of target regulation by c-Jun, gel shift analysis of selected AP-1-containing promoter regions revealed elevated and specific binding by proteins present in nuclear extracts of c-Jun expressing MCF7 cells.

ATPases Associated with Diverse Cellular Activitie↗

PubMed2000

Back schools for non-specific low back pain.

BACKGROUND: Since the introduction of the Swedish back school in 1980, the content of back schools has changed and appears to vary widely today. Back schools are frequently used in the treatment of low back pain patients. OBJECTIVES: The objective of this systematic review was to assess the effects of back schools for patients with non-specific low back pain. SEARCH STRATEGY: We searched the Medline and Embase databases up to December 1997 and the Cochrane Controlled Trials Register up to December 1998 if reported in English, Dutch, French or German. We also screened references given in relevant reviews and identified randomised trials. SELECTION CRITERIA: Only randomised trials that reported on any type of back school for non-specific low back pain were included. DATA COLLECTION AND ANALYSIS: Two reviewers blinded with respect to authors, institution and journal independently extracted the data and assessed trial quality. Our preset "high quality" level was 6 or more out of 11 internal validity criteria with positive scores. As data were statistically and clinically too heterogeneous, a qualitative review (best evidence synthesis) was performed. The evidence was classified into 4 levels (strong, moderate, limited or no evidence) taking into account the methodological quality of the studies. MAIN RESULTS: Fifteen RCTs were included in our systematic review. Overall, the methodological quality was low. Only 3 trials were considered high quality. It was not possible to make relevant subgroup analyses for radiation versus no radiation or to have a relevant subgroup of studies reporting on acute low back pain only. The results indicate that there is moderate evidence that back schools have better short-term effects than other treatments for chronic low back pain, and that there is moderate evidence that back schools in an occupational setting are more effective compared to 'placebo' or waiting list controls. REVIEWER'S CONCLUSIONS: Back schools may be effective for patients with recurrent and chronic low back pain in occupational settings, but little is known about the cost-effectiveness of back schools.

Exercise↗