In vivo maintenance of human regulatory T cells during CD25 blockade.

Regulatory T cells (Tregs) mediate immune tolerance to self and depend on IL-2 for homeostasis. Treg deficiency, dysfunction, and instability are implicated in the pathogenesis of numerous autoimmune diseases. There is considerable interest in therapeutic modulation of the IL-2 pathway to treat autoimmunity, facilitate transplantation tolerance, or potentiate tumor immunotherapy. Daclizumab is a humanized mAb that binds the IL-2 receptor a subunit (IL-2R a or CD25) and prevents IL-2 binding. In this study, we investigated the effect of daclizumab-mediated CD25 blockade on Treg homeostasis in patients with relapsing-remitting multiple sclerosis. We report that daclizumab therapy caused an ~50% decrease in Tregs over a 52-wk period. Remaining FOXP3+ cells retained a demethylated Treg-specific demethylated region in the FOXP3 promoter, maintained active cell cycling, and had minimal production of IL-2, IFN- g, and IL-17. In the presence of daclizumab, IL-2 serum concentrations increased and IL-2R bg signaling induced STAT5 phosphorylation and sustained FOXP3 expression. Treg declines were not associated with daclizumab-related clinical benefit or cutaneous adverse events. These results demonstrate that Treg phenotype and lineage stability can be maintained in the face of CD25 blockade.

Intermediate-affinity interleukin-2 receptor expression predicts CD56(bright) natural killer cell expansion after daclizumab treatment in the CHOICE study of patients with multiple sclerosis.

OBJECTIVE: The objective of this study was to evaluate whether interleukin-2 (IL-2) receptor expression on CD56(bright) natural killer (NK) cells predicted CD56(bright) NK cell expansion and therapeutic response to daclizumab (DAC) in multiple sclerosis (MS). METHODS: DAC exposure, CD56(bright) NK cell counts, IL-2 receptor alpha (CD25) and beta (CD122) subunits, and new or enlarged lesions on brain MRI were measured in 64 subjects in a pharmacokinetic/pharmacodynamic substudy of the phase 2 CHOICE trial at multiple time points. Peripheral blood mononuclear cell (PBMC) samples were obtained from healthy subjects to assess the relationship among DAC treatment, intermediate affinity IL-2 signaling, and CD56(bright) NK cell expansion. RESULTS: Increased CD56(bright) NK cell counts in DAC/interferon beta (IFNß)-treated subjects were observed by day 14, the first post-dosing time point (mean [SD] ln{CD56(bright) NK cell count}: DAC high/IFNß, 2.01 [1.25]; DAC low/IFNß, 2.29 [1.06]; placebo/IFNß, 1.01 [1.03]; adjusted p = 0.003), and persisted throughout the treatment period. Higher DAC dose predicted a faster rate of CD56(bright) NK cell expansion (p < 0.001), but individual subjects' increases in CD56(bright) NK cells from baseline levels were only weakly correlated with DAC exposure (r(2) = 0.167). Higher expression of the intermediate-affinity IL-2 receptor subunit (CD122) on CD56(bright) NK cells at baseline predicted fewer new gadolinium-enhanced (Gd+) lesions during the treatment period (1.77 vs. 0.62 adjusted mean new Gd+ lesions during weeks 8-24, lowest vs. highest quartile of percentage CD122(+) CD56(bright) NK cells; p = 0.033) and a greater increase in CD56(bright) NK cell counts at the end of DAC dosing (p = 0.029). CONCLUSION: CD56(bright) NK cell expansion after DAC treatment appears to reflect individual differences in the capacity for intermediate-affinity IL-2 signaling and could provide a basis for predicting clinical response to DAC in MS.

Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack.

BACKGROUND: We aimed to validate two similar existing prognostic scores for early risk of stroke after transient ischaemic attack (TIA) and to derive and validate a unified score optimised for prediction of 2-day stroke risk to inform emergency management. METHODS: The California and ABCD scores were validated in four independent groups of patients (n=2893) diagnosed with TIA in emergency departments and clinics in defined populations in the USA and UK. Prognostic value was quantified with c statistics. The two groups used to derive the original scores (n=1916) were used to derive a new unified score based on logistic regression. FINDINGS: The two existing scores predicted the risk of stroke similarly in each of the four validation cohorts, for stroke risks at 2 days, 7 days, and 90 days (c statistics 0.60-0.81). In both derivation groups, c statistics were improved for a unified score based on five factors (age >or=60 years [1 point]; blood pressure >or=140/90 mm Hg [1]; clinical features: unilateral weakness [2], speech impairment without weakness [1]; duration >or=60 min [2] or 10-59 min [1]; and diabetes [1]). This score, ABCD(2), validated well (c statistics 0.62-0.83); overall, 1012 (21%) of patients were classified as high risk (score 6-7, 8.1% 2-day risk), 2169 (45%) as moderate risk (score 4-5, 4.1%), and 1628 (34%) as low risk (score 0-3, 1.0%). IMPLICATIONS: Existing prognostic scores for stroke risk after TIA validate well on multiple independent cohorts, but the unified ABCD(2) score is likely to be most predictive. Patients at high risk need immediate evaluation to optimise stroke prevention.

Effect of a US National Institutes of Health programme of clinical trials on public health and costs.

BACKGROUND: Few attempts have been made to estimate the public return on investment in medical research. The total costs and benefits to society of a clinical trial, the final step in testing an intervention, can be estimated by evaluating the effect of trial results on medical care and health. METHODS: All phase III randomised trials funded by the US National Institute of Neurological Disorders and Stroke before Jan 1, 2000, were included. Pertinent publications on use, cost to society, and health effects for each studied intervention were identified by systematic review, supplemented with data from other public and proprietary sources. Regardless of whether a trial was positive or negative, information on use of tested therapies was integrated with published per-use data on costs and health effect (converted to 2004 US dollars) to generate 10-year projections for the US population. FINDINGS: 28 trials with a total cost of 335 million dollars were included. Six trials (21%) resulted in measurable improvements in health, and four (14%) resulted in cost savings to society. At 10 years, the programme of trials resulted in an estimated additional 470,000 quality-adjusted life years at a total cost of 3.6 billion dollars (including costs of all trials and additional health-care and other expenditures). Valuing a quality-adjusted life year at per-head gross domestic product, the projected net benefit to society at 10-years was 15.2 billion dollars. 95% CIs did not include a net loss at 10 years. IMPLICATIONS: For this institute, the public return on investment in clinical trials has been substantial. Although results led to increases in health-care expenditures, health gains were large and valuable.

Recruiting subjects for acute stroke trials: a meta-analysis.

BACKGROUND AND PURPOSE: Recruitment rate is a major determinant of the duration, cost, and feasibility of acute stroke trials. METHODS: We performed a meta-analysis of all randomized, controlled trials of > or =300 subjects that were designed to evaluate the efficacy of a medical intervention for the treatment of acute ischemic stroke. Data about trial recruitment, organization, and inclusion/exclusion criteria were abstracted independently by 2 reviewers who applied predefined criteria. Recruitment efficiency was defined as the number of subjects enrolled per study center per month of recruitment. RESULTS: Of 32 trials meeting inclusion criteria, the average recruitment efficiency was 0.79 subjects per center per month (range 0.08 to 3.7). Recruitment efficiency did not vary by geographic region (P=0.36), but trials conducted in 1 country had more efficient recruitment than international studies (P=0.03), and recruitment efficiency declined with each percentage increase in the total number of study centers (P=0.002). The primary study entry criteria that predicted reduced recruitment efficiency were the maximum allowable time from stroke to study enrollment (P=0.002) and the exclusion of mild strokes (P=0.009). Trials with a treatment window >6 hours had approximately double the recruitment rates of trials that used treatment windows < or =6 hours (1.03 versus 0.52 patients per center per month). CONCLUSIONS: Recruitment rates for acute stroke trials are influenced by organizational structure and study entry criteria. Characterizing predictors of recruitment may help optimize future trial design.

Regionalization of treatment for subarachnoid hemorrhage: a cost-utility analysis.

BACKGROUND: Previous studies have shown that for the treatment of subarachnoid hemorrhage (SAH), outcomes are improved but costs are higher at hospitals with a high volume of admissions for SAH. Whether regionalization of care for SAH is cost-effective is unknown. METHODS AND RESULTS: In a cost-utility analysis, health outcomes for patients with SAH were modeled for 2 scenarios: 1 representing the current practice in California in which most patients with SAH are treated at the closest hospital and 1 representing the regionalization of care in which patients at hospitals with <20 SAH admissions annually (low volume) would be transferred to hospitals with > or =20 SAH admissions annually (high volume). Using a Markov model, we compared net quality-adjusted life-years (QALYs) and cost per QALY. Inputs were chosen from the literature and derived from a cohort study in California. Transferring a patient with SAH from a low- to a high-volume hospital would result in a gain of 1.60 QALYs at a cost of 10,548 dollars/QALY. For transfer to result in only borderline cost-effectiveness (50,000 dollars/QALY), differences in case fatality rates between low- and high-volume hospitals would have to be one fifth as large (2.2%) or risk of death during transfer would have to be 5 times greater (9.8%) than estimated in the base case. CONCLUSIONS: Transfer of patients with SAH from low- to high-volume hospitals appears to be cost-effective, and regionalization of care may be justified. However, current estimates of the impact of hospital volume on outcome require confirmation in more detailed cohort studies.

Thirty-year projections for deaths from ischemic stroke in the United States.

BACKGROUND AND PURPOSE: The age adjustment of stroke mortality rates may obscure the impact of population changes on the total burden of disease. Deaths from ischemic stroke may rise unless future declines in stroke death rates offset the projected growth in high-risk populations. METHODS: Using data on ischemic stroke mortality from the National Center of Health Statistics for 1979 to 1998, we fit a logistic model to predict changes in stroke death rates as a function of time for each of 42 sex-race-age groups. Using population projections from the US Census Bureau, we then calculated the expected number of deaths in the United States from ischemic stroke over the next 30 years on the basis of age, sex, and race. RESULTS: Models generally fit historical data well (median R2=0.81; interquartile range, 0.43 to 0.97) and consistently predicted small declines in future death rates. The total predicted number of stroke deaths increased by 98% from 139,000 in 2002 to 275,000 in 2032, whereas the total US population was projected to increase by only 27% in the same period. The largest percentage increases in stroke deaths were predicted to occur in blacks (134%) and nonwhite, nonblack races (221%). CONCLUSIONS: If recent trends in ischemic stroke mortality continue, increases in US stroke deaths will outpace overall population growth, with a doubling in deaths over the next 30 years.

Pediatric Stroke Belt: geographic variation in stroke mortality in US children.

BACKGROUND AND PURPOSE: Numerous studies have demonstrated higher stroke mortality rates in adults residing in the Southeastern United States (the "Stroke Belt"). If the Stroke Belt is solely caused by regional differences in atherosclerotic stroke risk factors, it should not apply to children. METHODS: For the years 1979 to 1998, we determined rates of death from stroke in children <20 years of age based on death certificates, and compared age-adjusted stroke mortality rates in 11 Stroke Belt states versus other US states. For comparison, the same methods were applied to adults. RESULTS: Children in Stroke Belt states have an increased risk of death from stroke compared with children in other states (relative risk [RR], 1.21; 95% CI, 1.12 to 1.29). The greater risk in Stroke Belt states was apparent for ischemic and hemorrhagic stroke, for all age groups and both sexes, and persisted after adjustment for ethnicity. The geographic disparity in children was similar in magnitude to that in adults. CONCLUSIONS: Similar to adults, children in Stroke Belt states have a higher risk of death from stroke than children in other US states. Stroke risk factors that are applicable to both children and adults should be considered in attempts to explain this geographic variation.

Electrocardiographic findings predict short-term cardiac morbidity after transient ischemic attack.

BACKGROUND: Current guidelines recommend the use of electrocardiography (ECG) in the evaluation of transient ischemic attack (TIA), but the data supporting its value in acute management are sparse. OBJECTIVE: To determine whether ECG findings are useful as independent predictors of short-term cardiac or neurologic complications after TIA. METHODS: We included patients who presented to 1 of 16 emergency departments of a health maintenance organization in northern California and received a diagnosis of TIA from March 1, 1997, through February 28, 1998, for a 90-day follow-up. A cardiac event was defined as a hospitalization or a death due to myocardial infarction, ventricular arrhythmia, heart failure, or unstable angina. RESULTS: Among the 1327 patients with TIA for whom ECG findings were available for diagnostic coding, cardiac events occurred in 2.9%, strokes in 10.9%, recurrent TIAs in 13.7%, and deaths in 2.6% during 90-day follow-up. The ECG findings disclosed a new diagnosis of atrial fibrillation in 28 (2.3%) of the 1200 patients with no history of this condition. The 90-day risk for a cardiac event was greater in those who had any abnormal ECG findings (4.2% vs 0.6%; P<.001). This association remained significant after adjustment for medical history and examination findings (odds ratio, 6.9; 95% confidence interval, 1.6-29.5; P =.009). Left ventricular hypertrophy, atrial fibrillation, and atrioventricular conduction abnormalities were each independently associated with more than doubling of the risk. The ECG abnormalities were not associated with risk for stroke or death. CONCLUSIONS: Short-term cardiac morbidity is substantial after TIA. Electrocardiographic findings disclose new atrial fibrillation in a significant portion of patients with TIA and can identify a group of patients at a substantially higher risk for short-term cardiac events.

Methylenetetrahydrofolate reductase C677T polymorphism and cognitive function in older women.

Homocysteine may play a causal role in cognitive decline. The authors analyzed the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T genotype, a correlate of plasma homocysteine levels, among 6,653 participants in the Study of Osteoporotic Fractures, a community-based, prospective cohort study of older women in four US states. During the years 1986-1998, the authors assessed whether the distribution of MTHFR C677T genotypes was independent of potential confounders and whether persons with the TT genotype had lower baseline performance or showed greater longitudinal declines on standard cognitive tests. Although ethnicity was associated with MTHFR genotype distribution within the entire cohort (p < 0.001), all measured confounders appeared independent of MTHFR genotype within the largest ethnically homogenous subgroup, persons of Northern and/or Central European ancestry (n = 5,668) (Kolmogorov-Smirnov p = 0.97). In this subgroup, the TT genotype was associated with lower scores on the Digit Symbol Substitution Test (p = 0.034) and the Trails B test (p = 0.020) and with a small excess annual decline on a modified version of the Mini-Mental State Examination (p = 0.035). Although the strength of the observed associations was modest, these results lend some support to the theory that an elevated homocysteine level contributes to cognitive decline.

Midlife obesity and long-term risk of nursing home admission.

OBJECTIVE: Obesity is a growing problem among middle-aged individuals. We investigated whether obesity in middle-aged individuals influences the need for future nursing home care and whether the risk of nursing home admission associated with obesity is greater in whites than in blacks. RESEARCH METHODS AND PROCEDURES: The study population (N = 8804) consisted of long-term members of the Kaiser Permanente Medical Care Plan ages 75 to 85 years in 1995 who had completed a standardized, multiphasic health checkup while in their 50s. The multiphasic health checkup examinations were performed as part of routine medical care between the years 1964 and 1973 and included standardized measurements of BMI. We used health plan records to assess incident nursing home admissions from 1995 to 2002. The risk of nursing home admission associated with standard categories of midlife BMI was estimated using Cox proportional hazard analysis. RESULTS: During an average follow-up of 5.1 years, the nursing home admission rate was 6.8 per 100 person-years of observation. After adjustment for comorbidities, midlife obesity predicted incident nursing home admission approximately 25 years later [hazard ratio (HR), 1.30; 95% confidence interval (CI), 1.15 to 1.46; p < 0.001]. Overweight BMI at midlife was not associated with future nursing home admission (HR, 1.05; 95% CI, 0.97 to 1.14; p = 0.23). The risk of nursing home admission associated with midlife obesity was higher in whites (HR, 1.34; 95% CI, 1.17 to 1.54; p < 0.001) than in blacks (HR 1.15; 95% CI, 0.87 to 1.52; p = 0.32), but the difference between races was not significant (p for interaction = 0.65). DISCUSSION: Obesity among middle-aged individuals is associated with an increased risk of nursing home admission in late life and may be an important target for reducing the future societal burden of nursing home care.

Cognitive function predicts first-time stroke and heart disease.

OBJECTIVE: To investigate whether impaired cognitive function is an early manifestation of vascular injury in the brain and therefore predicts risk of subsequent cardiovascular disease. METHODS: The study population consisted of 12,096 middle-aged participants in the Atherosclerosis Risk in Communities (ARIC) Study who had no history of stroke or coronary heart disease (CHD) at the time of cognitive testing. Cognitive function was measured using the Digit-Symbol Substitution Test (DSST), the Word Fluency Test, and the Delayed Word Recall Test. Cognitive test scores were adjusted for demographic factors and then evaluated as predictors of incident cardiovascular events using Cox proportional hazards analysis. RESULTS: Over a median follow-up period of 6.4 years, there were 516 incident cardiovascular events (292 myocardial infarctions, 50 CHD deaths, and 174 strokes), resulting in an average annual incidence rate of 0.7%. Lower adjusted scores on each cognitive test predicted a greater risk of incident cardiovascular events after controlling for established vascular risk factors (highest vs lowest quartile DSST, adjusted hazard ratio 1.56, 95% CI 1.23 to 1.97, p for linear trend by quartile < 0.001). The magnitude of the association was comparable with other commonly used predictors of vascular risk such as left ventricular hypertrophy on EKG and high-density lipoprotein cholesterol level of <35 mg/dL. CONCLUSION: Cognitive test scores below demographic norms predict incident cardiovascular disease in middle-aged subjects independently of established vascular risk factors.

Pre-existing hypertension and the impact of stroke on cognitive function.

Hypertension has been associated with subclinical injury in the brain and may therefore increase the impact of an incident stroke on cognitive function. The Study of Osteoporotic Fractures (SOF) is a prospective, observational study of 9,704 women aged 65 years and older recruited from four U.S. metropolitan areas. Blood pressure was measured at study entry, and cognitive decline was defined by the change from prestroke to poststroke cognitive testing. During an average follow-up of 6.8 years, incident stroke occurred in 260 participants (3.1%) who had previously completed baseline cognitive testing. Among participants with stroke, 119 completed follow-up cognitive testing a median of 1.9 years after the stroke, 80 died before the next study visit, and 61 did not complete further cognitive testing. After adjustment for demographic factors and other confounders, pre-existing hypertension was a strong predictor of cognitive decline when a stroke occurred (odds ratio [OR], 4.07; 95% confidence interval [CI], 1.37-12.1). In contrast, hypertension was only weakly associated with cognitive decline in the absence of stroke (OR, 1.13; 95% CI, 1.04-1.22) (p for interaction = 0.032). Pre-existing hypertension in women is associated with a greater impact of stroke on cognitive function, possibly by influencing the ability to tolerate or recover from brain injury.

Alzheimer disease risk and genetic variation in ACE: a meta-analysis.

BACKGROUND: Numerous studies have tested for associations between common variants of the angiotensin-converting enzyme gene (ACE) and late-onset Alzheimer disease (AD), but results have been inconclusive. METHODS: Relevant studies were systematically identified, and data were abstracted according to predefined criteria. RESULTS: The odds ratio (OR) for AD in individuals with the I allele of the ACE D/I polymorphism compared with those with the DD genotype was 1.27 (95% CI, 1.10 to 1.47; p < 0.001). Heterogeneity between studies was significant (p < 0.001) but not in strata defined by race and age (p > or = 0.10). The risk of AD associated with the I allele appeared to be higher among Asians (OR 2.44; 95% CI, 1.68 to 3.53) when compared with the risk among Caucasians (OR 1.18; 95% CI, 1.02 to 1.37) (p for comparison < 0.001), and in younger cases (mean age 65 to 74 years) (OR 1.54; 95% CI, 1.23 to 1.93) when compared with the risk in older cases (OR 1.13; 95% CI, 0.95 to 1.35) (p for comparison = 0.03). CONCLUSIONS: The I allele of the ACE D/I polymorphism is associated with an increased risk of late-onset AD. Further study of the pathogenetic characteristics of this allele and independent confirmation of the association in larger studies are warranted.