Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis.

Multiple sclerosis (MS) is an enigmatic disease of the central nervous system resulting in sclerotic plaques with the pathological hallmarks of demyelination and axonal damage, which can be directly or indirectly orchestrated by cells from the peripheral circulation. The majority of patients with MS follow a relapsing-remitting course in the early stages of the disease (RRMS) but most ultimately enter a secondary progressive phase (SPMS). About 10% of patients follow a primary progressive course from the onset (PPMS). We measured gene expression in whole blood of people with and without chronic progressive MS (CPMS), PPMS and SPMS, to discover genes which may be differentially expressed in peripheral blood in active disease, and so identify pathologically significant genes and pathways; and we investigated genetic differences in the promoters of dysregulated genes encoded in genomic regions associated with MS. If SPMS and PPMS were independently compared to the controls, there was little overlap in the set of most dysregulated genes. Ribosomal protein genes, whose expression is usually associated with cell proliferation and activation, were dramatically over-represented in the set of most down-regulated genes in PPMS compared to SPMS (P < 10(-4), chi(2)). The T cell proliferation gene IL7R (CD127) was also underexpressed in PPMS, but was up-regulated in SPMS compared to the controls. One interleukin 7 receptor (IL7R) promoter single nucleotide polymorphism (SNP), -504 C, was undertransmitted in PPMS trios (P = 0.05, TDT), and carriers of this allele were under-represented in PPMS cases from two independent patient cohorts (combined P = 0.006, FE). The four known IL7R promoter haplotypes were shown to have similar expression levels in healthy controls, but not in CPMS (P < 0.01, t test). These data support the hypothesis that PPMS has significant pathogenetic differences from SPMS, and that IL7R may be a useful therapeutic target in PPMS.

Priorities among recommended clinical preventive services.

BACKGROUND: Many recommended clinical preventive services are delivered at low rates. Decision-makers who wish to improve delivery rates, but face competing demands for finite resources, need information on the relative value of these services. This article describes the results of a systematic assessment of the value of clinical preventive services recommended for average-risk patients by the U.S. Preventive Services Task Force. METHODS: The assessment of services' value for the U.S. population was based on two dimensions: burden of disease prevented by each service and cost effectiveness. Methods were developed for measuring these criteria consistently across different types of services. A companion article describes the methods in greater detail. Each service received 1 to 5 points on each of the two dimensions, for total scores ranging from 2 to 10. Priority opportunities for improving delivery rates were determined by comparing the ranking of services with what is known of current delivery rates nationally. RESULTS: The highest ranked services (scores of 7+) with the lowest delivery rates (< or =50% nationally) are providing tobacco cessation counseling to adults, screening older adults for undetected vision impairments, offering adolescents an anti-tobacco message or advice to quit, counseling adolescents on alcohol and drug abstinence, screening adults for colorectal cancer, screening young women for chlamydial infection, screening adults for problem drinking, and vaccinating older adults against pneumococcal disease. CONCLUSIONS: Decision-makers can use the results to set their own priorities for increasing delivery of clinical preventive services. The methods provide a basis for future priority-setting efforts.

Methods for priority setting among clinical preventive services.

Methods used to compare the value of clinical preventive services based on two criteria-clinically preventable burden (CPB) and cost effectiveness (CE)-are described. A companion article provides rankings of clinical preventive services and discusses its uses for decision-makers; this article focuses on the methods, challenges faced, and solutions. The authors considered all types of data essential to measuring CPB and CE for services recommended by the U.S. Preventive Services Task Force and developed methods essential to ensuring valid comparisons of different services' relative value.

Multiple risk factors and population attributable risk for ischemic heart disease mortality in the United States, 1971-1992.

The objective of this study was to assess the associations and population attributable risks (PAR) of risk factor combinations and ischemic heart disease (IHD) mortality in the United States. We used logistic regression models to assess the association of risk factors with IHD in the First National Health and Nutrition Examination Survey (1971-1974) and Epidemiologic Follow-up Study (1982-1992) among white and black men and women. We examined eight modifiable risk factors: hypertension, elevated serum cholesterol, diabetes, overweight, current smoking, physical inactivity, depression, and nonuse of replacement hormones. Risk factors associated with IHD mortality were the same among white and black men (i.e., age, education, smoking, diabetes, hypertension, and serum cholesterol). Age, education, smoking, diabetes, and hypertension were the risk factors among white and black women. Physical inactivity, nonuse of replacement hormones, serum cholesterol, and overweight were the additional risk factors among white women. Adjusted for demographic risk factors, overall PARs for study risk factors were 41.2% for white men, 60.5% for white women (with five risk factors only), 49.2% for black men, and 71.2% for black women. Much IHD mortality attributable to individual risk factors is caused by those factors in combination with other risk factors; relatively little mortality is attributable to each risk factor in isolation. Analysis that does not examine risk factor combinations may greatly overestimate PARs associated with individual risk factors.

Current methods of the US Preventive Services Task Force: a review of the process.

The U.S. Preventive Services Task Force (USPSTF/Task Force) represents one of several efforts to take a more evidence-based approach to the development of clinical practice guidelines. As methods have matured for assembling and reviewing evidence and for translating evidence into guidelines, so too have the methods of the USPSTF. This paper summarizes the current methods of the third USPSTF, supported by the Agency for Healthcare Research and Quality (AHRQ) and two of the AHRQ Evidence-based Practice Centers (EPCs). The Task Force limits the topics it reviews to those conditions that cause a large burden of suffering to society and that also have available a potentially effective preventive service. It focuses its reviews on the questions and evidence most critical to making a recommendation. It uses analytic frameworks to specify the linkages and key questions connecting the preventive service with health outcomes. These linkages, together with explicit inclusion criteria, guide the literature searches for admissible evidence. Once assembled, admissible evidence is reviewed at three strata: (1) the individual study, (2) the body of evidence concerning a single linkage in the analytic framework, and (3) the body of evidence concerning the entire preventive service. For each stratum, the Task Force uses explicit criteria as general guidelines to assign one of three grades of evidence: good, fair, or poor. Good or fair quality evidence for the entire preventive service must include studies of sufficient design and quality to provide an unbroken chain of evidence-supported linkages, generalizable to the general primary care population, that connect the preventive service with health outcomes. Poor evidence contains a formidable break in the evidence chain such that the connection between the preventive service and health outcomes is uncertain. For services supported by overall good or fair evidence, the Task Force uses outcomes tables to help categorize the magnitude of benefits, harms, and net benefit from implementation of the preventive service into one of four categories: substantial, moderate, small, or zero/negative. The Task Force uses its assessment of the evidence and magnitude of net benefit to make a recommendation, coded as a letter: from A (strongly recommended) to D (recommend against). It gives an I recommendation in situations in which the evidence is insufficient to determine net benefit. The third Task Force and the EPCs will continue to examine a variety of methodologic issues and document work group progress in future communications.

The art and science of incorporating cost effectiveness into evidence-based recommendations for clinical preventive services.

As medical technology continues to expand and the cost of using all effective clinical services exceeds available resources, decisions about health care delivery may increasingly rely on assessing the cost-effectiveness of medical services. Cost-effectiveness is particularly relevant for decisions about how to implement preventive services, because these decisions typically represent major investments in the future health of large populations. As such, decisions regarding the implementation of preventive services frequently involve, implicitly if not explicitly, consideration of costs. Cost-effectiveness analysis summarizes the expected benefits, harms, and costs of alternative strategies to improve health and has become an important tool for explicitly incorporating economic considerations into clinical decision making. Acknowledging the usefulness of this tool, the third U.S. Preventive Services Task Force (USPSTF) has initiated a process for systematically reviewing cost-effectiveness analyses as an aid in making recommendations about clinical preventive services. In this paper, we provide an overview and examples of roles for using cost-effectiveness analyses to inform preventive services recommendations, discuss limitations of cost-effectiveness data in shaping evidence-based preventive health care policies, outline the USPSTF approach to using cost-effectiveness analyses, and discuss the methods the USPSTF is developing to assess the quality and results of cost-effectiveness studies. While this paper focuses on clinical preventive services (i.e., screening, counseling, immunizations, and chemoprevention), the framework we have developed should be broadly portable to other health care services.

Screening and treating adults for lipid disorders.

CONTEXT: Screening and treatment of lipid disorders in people at high risk for future coronary heart disease (CHD) events has gained wide acceptance, especially for patients with known CHD, but the proper role in people with low to medium risk is controversial. OBJECTIVE: To examine the evidence about the benefits and harms of screening and treatment of lipid disorders in adults without known cardiovascular disease for the U.S. Preventive Services Task Force. DATA SOURCES: We identified English-language articles on drug therapy, diet and exercise therapy, and screening for lipid disorders from comprehensive searches of the MEDLINE database from 1994 through July 1999. We used published systematic reviews, hand searching of relevant articles, the second Guide to Clinical Preventive Services, and extensive peer review to identify important older articles and to ensure completeness. DATA SYNTHESIS: There is strong, direct evidence that drug therapy reduces CHD events, CHD mortality, and possibly total mortality in middle-aged men (35 to 65 years) with abnormal lipids and a potential risk of CHD events greater than 1% to 2% per year. Indirect evidence suggests that drug therapy is also effective in other adults with similar levels of risk. The evidence is insufficient about benefits and harms of treating men younger than 35 years and women younger than 45 years who have abnormal lipids but no other risk factors for heart disease and low risk for CHD events (less than 1% per year). Trials of diet therapy for primary prevention have led to long-term reductions in cholesterol of 3% to 6% but have not demonstrated a reduction in CHD events overall. Exercise programs that maintain or reduce body weight can produce short-term reductions in total cholesterol of 3% to 6%, but longer-term results in unselected populations have found smaller or no effect. To identify accurately people with abnormal lipids, at least two measurements of total cholesterol and high-density lipoprotein cholesterol are required. The role of measuring triglycerides and the optimal screening interval are unclear from the available evidence. CONCLUSIONS: On the basis of the effectiveness of treatment, the availability of accurate and reliable tests, and the likelihood of identifying people with abnormal lipids and increased CHD risk, screening appears to be effective in middle-aged and older adults and in young adults with additional cardiovascular risk factors.

Aspergillosis case-fatality rate: systematic review of the literature.

To update the case-fatality rate (CFR) associated with invasive aspergillosis according to underlying conditions, site of infection, and antifungal therapy, data were systematically reviewed and pooled from clinical trials, cohort or case-control studies, and case series of >/=10 patients with definite or probable aspergillosis. Subjects were 1941 patients described in studies published after 1995 that provided sufficient outcome data; cases included were identified by MEDLINE and EMBASE searches. The main outcome measure was the CFR. Fifty of 222 studies met the inclusion criteria. The overall CFR was 58%, and the CFR was highest for bone marrow transplant recipients (86.7%) and for patients with central nervous system or disseminated aspergillosis (88.1%). Amphotericin B deoxycholate and lipid formulations of amphotericin B failed to prevent death in one-half to two-thirds of patients. Mortality is high despite improvements in diagnosis and despite the advent of newer formulations of amphotericin B. Underlying patient conditions and the site of infection remain important prognostic factors.

Indirect cost of ischemic heart disease to employers.

BACKGROUND: The management of healthcare programs by employers requires accurate information about the indirect and direct costs of important chronic diseases. OBJECTIVE: To determine the indirect costs of ischemic heart disease from the perspective of the employer in private industry in the United States. DESIGN: Indirect cost of illness analysis using the human capital approach, taking the perspective of the employer rather than that of society. METHODS: Ischemic heart disease was identified in a proprietary claims database of 3.1 million insured persons using an algorithm based on administrative codes. Economic data were derived from the Bureau of Labor Statistics, the Employment Management Association, and published sources. Work-loss data were taken from the National Center for Health Statistics' Health Interview Survey. The indirect cost was calculated as the sum of the costs due to morbidity and mortality. From the perspective of the employer, morbidity costs come from lost productivity, idle assets, and nonwage factors resulting from absenteeism and mortality costs are expenditures for replacing and retraining workers. This differs from calculations from the societal perspective, in which indirect costs are the value of an individual's lost income--both current and potential. RESULTS: The total indirect cost of ischemic heart disease to employers in private industry was $182.74 per enrollee. Ninety-five percent of the indirect cost was the consequence of work loss due to morbidity rather than of mortality costs. CONCLUSION: From the perspective of the employer, the indirect cost of ischemic heart disease is overwhelmingly due to morbidity costs.

Preventable smoking and exercise-related hospital admissions. A model based on the NHEFS.

BACKGROUND: The NHANES I Epidemiologic Follow-Up Study (NHEFS), a longitudinal study of a representative sample of U.S. adults, makes it possible for the first time to develop a simulation model relating hospital admissions to baseline clinical risk factors for the general adult population. The model is presented here and used to project the impact on hospital admissions of changes in smoking behavior and sedentary lifestyle. METHODS: Three kinds of projections were calculated for the cohort of adults aged 45 to 74 at baseline: projections of hospital admissions in the absence of the risk factor; projections that reflect a 10-year lag between behavior change and full health benefit; and projections that reflect both lag and incomplete adherence to behavior change. For incomplete adherence we assumed that only 10% of the at-risk population changed their behavior. RESULTS: Tests of the simulation model showed that it agreed with a Cox analysis of the hospital data and accurately projected observed hospital admissions over the study period. The projections showed that eliminating smoking would reduce annual rates of all-cause hospitalization among older adults by 8.9% 20 years after baseline. Eliminating inactivity would reduce them 4.6%. Introducing a lag of 10 years between behavior modification and full benefit delayed the impact on hospitalization rates but the effect at 20 years was the same. When only 10% of the population at risk stopped smoking or became physically active, a percentage that reflects the effectiveness of current interventions, annual hospitalization rates at 20 years fell by 0.9% and 0.5%, respectively. CONCLUSIONS: Substantial reductions in hospital admissions can be achieved by interventions to prevent smoking, help smokers quit, or encourage inactive persons to become active. Improving adherence can markedly improve the impact on hospitalizations. The costs of these efforts would be rewarded not only by better health, but by lower expenditures for hospitalization.

Motor-vehicle occupant injury: strategies for increasing use of child safety seats, increasing use of safety belts, and reducing alcohol-impaired driving.

The Task Force on Community Preventive Services has conducted systematic reviews of interventions designed to increase use of child safety seats, increase use of safety belts, and reduce alcohol-impaired driving. The Task Force strongly recommends the following interventions: laws requiring use of child safety seats, distribution and education programs for child safety seats, laws requiring use of safety belts, both primary and enhanced enforcement of safety belt use laws, laws that lower the legal blood alcohol concentration (BAC) limit for adult drivers to 0.08%, laws that maintain the minimum legal drinking age at 21 years, and use of sobriety checkpoints. The Task Force recommends communitywide information and enforcement campaigns for use of child safety seats, incentive and education programs for use of child safety seats, and a lower legal BAC for young drivers (in the United States, those under the minimum legal drinking age). This report provides additional information regarding these recommendations, briefly describes how the reviews were conducted, and provides information to help apply the interventions locally.

Burden of aspergillosis-related hospitalizations in the United States.

In the United States in 1996, there were an estimated 10,190 aspergillosis-related hospitalizations (95% confidence interval [CI], 9000-11,380); these resulted in 1970 deaths (95% CI, 1659-2280), 176,272 hospital days (95% CI, 147,163-206,275), and $633.1 million in costs (95% CI, $492.0-$780.2 million). The average hospitalization lasted 17.3 days (95% CI, 16.1-18.6) and cost $62,426 (95% CI, $52,670-$72,181). Although aspergillosis-related hospitalizations account for a small percentage of hospitalizations in the United States, patients hospitalized with the condition have lengthy hospital stays and high mortality rates.

Use of simvastatin treatment in patients with combined hyperlipidemia in clinical practice. For the Simvastatin Combined Hyperlipidemia Registry Group.

OBJECTIVE: To describe and understand current care of simvastatin-treated patients with combined hyperlipidemia in routine clinical practice. DESIGN: A 6-month prospective observational study. Demographics, simvastatin dosage, cardiac risk factors, and lipid profile were collected from August 1997 to December 1998 at 20 sites (230 patients) across the United States. RESULTS: Overall mean percentage of reduction in total cholesterol levels was 27% (P<.001), low-density lipoprotein cholesterol (LDL-C) was 35% (P<.001), and triglyceride values was 28% (P<.001). Among those patients with low baseline high-density lipoprotein cholesterol (HDL-C) values (<0.91 mmol/L [<35 mg/dL]) (N = 49), there was a 17% increase in HDL-C (P< or =.001); 35% of these patients achieved National Cholesterol Education Program HDL-C goal (ie, < or =0.91 mmol/L [> or =35 mg/dL]). Coronary heart disease (CHD) patients were given significantly higher initial doses (mean, 15.1 mg) compared with non-CHD patients (mean, 11.5 mg) (P< or =.001). Overall, 74% of patients achieved LDL-C goal (52% on starting dose, 22% after 1 titration). Among those patients who were not at goal and had a follow-up lipid profile result available, only 1 patient (2%) was at the maximum dose (80 mg); 69% were receiving 20 mg or less. Approximately 63% of patients with CHD, 80% of patients with 2 or more risk factors, and 91% of patients with fewer than 2 risk factors achieved LDL-C goal. CONCLUSIONS: Multiple factors contribute to LDL-C goal achievement in a usual care setting. A significant opportunity exists to increase the number of patients who achieve LDL-C goal by appropriate dose titration and/or give patients a higher initial dose of simvastatin.

Diabetes mellitus, impaired fasting glucose, atherosclerotic risk factors, and prevalence of coronary heart disease.

Patients with diabetes mellitus (DM), both diagnosed (history of) and undiagnosed (by fasting glucose [FG] only), as well as impaired FG have an increased risk of coronary heart disease (CHD), compared with those with normal FG. Elevations in FG levels, even in normoglycemic subjects (<110 mg/dl), may be significantly related to CHD morbidity and mortality. Improving lipid profiles and blood pressure can decrease both CHD morbidity and mortality in these patients. We evaluated the relation of glucose status to lipid levels, other risk factors, and prevalence of CHD using the 1997 American Diabetes Association diagnostic criteria in a representative sample of United States adults studied in the Third National Health and Nutrition Examination Survey from 1988 to 1994. Impaired FG, diagnosed DM, and undiagnosed DM were more prevalent in older age groups; those > or =65 years had increased prevalence compared with those <50 years old (rate ratios for IFG, DM-FG, and history of DM were 3.5, 4.8, and 10.8, respectively). Glycosylated hemoglobin levels were increased by glucose status. The frequency of known CHD risk factors also increased with worsening glucose status. Age-adjusted CHD prevalence was increased with impaired FG (rate ratio 1.47), DM-FG (rate ratio 1.56), and history of DM (rate ratio 1.72), compared with normal FG. Adjusting for age and other CHD risk factors, hyperglycemia was no longer significantly associated with CHD prevalence. Lipid values, especially high-density lipoprotein cholesterol, hypertension, and other CHD risk factors were more strongly associated with CHD than glucose status. Thus, patients with impaired FG, DM-FG, and history of DM should be considered at higher risk for CHD morbidity and mortality. However, hyperglycemia, per se, does not explain the excess risk. In addition to glucose, lipid profiles and blood pressure should be periodically monitored and appropriate treatment provided to reduce morbidity and mortality from CHD.

State maternal and child expenditures and low birthweight infants: a descriptive analysis.

This study examines the relationship over time between state public health spending for maternal and child health and rates of low birthweight infants. Using expenditure data from the Public Health Foundation and National Center for Health Statistics, we compare the 10 states with the highest and lowest rates of low birthweight infants in 1980 and the 10 states with the most improved and least improved low birthweight rates over a 10-year period. We hypothesize that the 10 states with the best low birthweight rates and 10 states with the most improvement in low birthweight rates will be the states with the highest levels of maternal and child health expenditures per birth. We find no support for the hypothesis in either group of states. At the state level, maternal and child public health expenditures do not appear correlated with states that are the most successful or are making the most improvement in low birthweight infants.

Developing an evidence-based Guide to Community Preventive Services--methods. The Task Force on Community Preventive Services.

Systematic reviews and evidence-based recommendations are increasingly important for decision making in health and medicine. Over the past 20 years, information on the science of synthesizing research results has exploded. However, some approaches to systematic reviews of the effectiveness of clinical preventive services and medical care may be less appropriate for evaluating population-based interventions. Furthermore, methods for linking evidence to recommendations are less well developed than methods for synthesizing evidence. The Guide to Community Preventive Services: Systematic Reviews and Evidence-Based Recommendations (the Guide) will evaluate and make recommendations on population-based and public health interventions. This paper provides an overview of the Guide's process to systematically review evidence and translate that evidence into recommendations. The Guide reviews evidence on effectiveness, the applicability of effectiveness data, (i.e., the extent to which available effectiveness data is thought to apply to additional populations and settings), the intervention's other effects (i.e., important side effects), economic impact, and barriers to implementation of interventions. The steps for obtaining and evaluating evidence into recommendations involve: (1) forming multidisciplinary chapter development teams, (2) developing a conceptual approach to organizing, grouping, selecting and evaluating the interventions in each chapter; (3) selecting interventions to be evaluated; (4) searching for and retrieving evidence; (5) assessing the quality of and summarizing the body of evidence of effectiveness; (6) translating the body of evidence of effectiveness into recommendations; (7) considering information on evidence other than effectiveness; and (8) identifying and summarizing research gaps. Systematic reviews of and evidence-based recommendations for population-health interventions are challenging and methods will continue to evolve. However, using an evidence-based approach to identify and recommend effective interventions directed at specific public health goals may reduce errors in how information is collected and interpreted, identify important gaps in current knowledge thus guiding further research, and enhance the Guide users' ability to assess whether recommendations are valid and prudent from their own perspectives. Over time, all of these advantages could help to increase agreement regarding appropriate community health strategies and help to increase their implementation.

Data collection instrument and procedure for systematic reviews in the Guide to Community Preventive Services. Task Force on Community Preventive Services.

INTRODUCTION: A standardized abstraction form and procedure was developed to provide consistency, reduce bias, and improve validity and reliability in the Guide to Community Preventive Services: Systematic Reviews and Evidence-Based Recommendations (the Guide). DATA COLLECTION INSTRUMENT: The content of the abstraction form was based on methodologies used in other systematic reviews; reporting standards established by major health and social science journals; the evaluation, statistical and meta-analytic literature; expert opinion and review; and pilot-testing. The form is used to classify and describe key characteristics of the intervention and evaluation (26 questions) and assess the quality of the study's execution (23 questions). Study procedures and results are collected and specific threats to the validity of the study are assessed across six categories (intervention and study descriptions, sampling, measurement, analysis, interpretation of results and other execution issues). DATA COLLECTION PROCEDURES: Each study is abstracted by two independent reviewers and reconciled by the chapter development team. Reviewers are trained and provided with feedback. DISCUSSION: What to abstract and how to summarize the data are discretionary choices that influence conclusions drawn on the quality of execution of the study and its effectiveness. The form balances flexibility for the evaluation of papers with different study designs and intervention types with the need to ask specific questions to maximize validity and reliability. It provides a structured format that researchers and others can use to review the content and quality of papers, conduct systematic reviews, or develop manuscripts. A systematic approach to developing and evaluating manuscripts will help to promote overall improvement of the scientific literature.

Methods for systematic reviews of economic evaluations for the Guide to Community Preventive Services. Task Force on Community Preventive Services.

OBJECTIVES: This paper describes the methods used in the Guide to Community Preventive Services: Systematic Reviews and Evidence-Based Recommendations (the Guide) for conducting systematic reviews of economic evaluations across community health-promotion and disease-prevention interventions. The lack of standardized methods to improve the comparability of results from economic evaluations has hampered the use of data on costs and financial benefits in evidence-based reviews of effectiveness. The methods and instruments developed for the Guide provide an explicit and systematic approach for abstracting economic evaluation data and increase the usefulness of economic information for policy making in health care and public health. METHODS: The following steps were taken for systematic reviews of economic evaluations: (1) systematic searches were conducted; (2) studies using economic analytic methods, such as cost analysis or cost-effectiveness, cost-benefit or cost-utility analysis, were selected according to explicit inclusion criteria; (3) economic data were abstracted and adjusted using a standardized abstraction form; and (4) adjusted summary measures were listed in summary tables. RESULTS: These methods were used in a review of 10 interventions designed to improve vaccination coverage in children, adolescents and adults. Ten average costs and 14 cost-effectiveness ratios were abstracted or calculated from data reported in 24 studies and expressed in 1997 USD. The types of costs included in the analysis and intervention definitions varied extensively. Gaps in data were found for many interventions.

Evaluation of the apo-1/Fas promoter mva I polymorphism in multiple sclerosis.

The pathogenesis of multiple sclerosis is under strong genetic control involving several or more genes each of modest effect. Whilst the mechanisms underlying the pathogenesis of MS remain unknown, it has been hypothesised that either decreased apoptosis of autoreactive T cells in the CNS, or increased apoptosis of oligodendrocytes may play an important role. The Apo-1/Fas antigen (CD95), the gene for which is located in a chromosomal region showing linkage in MS genome screens, is a critical inducer of apoptosis and studies have shown aberrant expression of this molecule in MS, correlating with a decrease in T cell apoptosis or increase in CNS tissue damage. This study investigated an Mva I polymorphism in the Apo-1/Fas promoter region in a group of 124 Australian patients with relapsing-remitting MS and in 183 normal controls. Whilst there were increases in the Mva I*2 allele in MS individuals overall (59% vs 52%, P not corrected=0.08), and in HLA-DRB1*1501 negative MS patients (62% vs 55%), these were not significantly different from controls. Interactions were investigated between the Mva I alleles and T cell receptor beta chain variable region (TCRBV) germline polymorphisms, with a trend in MS individuals towards a decrease of the Mva I*1 allele when combined with the TCRBV3S1*2 allele (Relative Risk=0.25, P=0.067), and with the TCRBV8S1*1 allele (Relative Risk=0.44, P=0.12). Overall, the findings of this study indicate a possible effect of the Apo-1/Fas promoter Mva I polymorphism in MS susceptibility, which needs to be confirmed in further studies. Multiple Sclerosis (2000) 6 14 - 18