Screening for Vitamin D Deficiency in Black Americans: Comparison of Total, Free, Bioavailable 25 Hydroxy Vitamin D Levels with Parathyroid Hormone Levels and Bone Mineral Density.

OBJECTIVES: There is debate surrounding the adequacy of total and free 25 hydroxy vitamin D [25(OH)D] levels in black Americans who have inherently high bone mineral density [BMD] and low serum concentration of vitamin D binding proteins [VDBP]. DESIGN: Retrospective analysis of serum samples and BMD analyses from the African American Health Study [AAHS] cohort. SETTING: The AAHS is a population-based longitudinal study initiated to examine issues of disability and frailty among urban-dwelling black Americans in the city of Saint Louis, Missouri. PARTICIPANTS: 122 men and 206 women, age 60.2 ± 4.3 years. INTERVENTION: Retrospective analysis. MEASUREMENTS: Total 25(OH)D, VDBP, PTH, and BMD of the lumbar spine and hip by dual energy x-ray photometry (DXA). Free and bioavailable vitamin D levels were calculated using serum concentrations and affinity constants for the VDBP (Gc1F and Gc1S) phenotypes. RESULTS: Serum total 25(OH)D levels were 14.6 ± 8.9 ng/mL (36 ± 22 nmol/L). Vitamin D insufficiency was estimated by compensatory elevations of PTH above the normal range (> 65 pg/mL). PTH levels were within the normal reference range in > 95% of the samples at total 25(OH)D levels ≥ 20 ng/mL (≥50 nmol/L). There was no difference in the correlation of the reciprocal relationship of vitamin D vs parathyroid hormone between the VDBP phenotypes. Receiver operating characteristic curve analyses indicated that serum total 25(OH)D discriminated sufficiency from insufficiency at least as well as the calculated levels of the free and bioavailable vitamin D. Very low levels of total 25(OH)D (≤ 8 ng/mL, ≤20 nmol/L) were associated with decreased BMD (p=0.02), but higher levels of 25(OH)D did not show statistical differences in BMD. CONCLUSION: Total 25(OH)D levels of ≤ 8ng/mL (≤20 nmol/L) are associated with clinically significant changes in BMD, whereas total 25(OH)D levels ≥ 20 ng/mL (≥50 nmol/L) suppressed PTH and were not associated with deficiencies in BMD. Lower levels of 25(OH)D may be acceptable for bone health in black than in white Americans.

Higher C-reactive protein and soluble tumor necrosis factor receptor levels are associated with poor physical function and disability: a cross-sectional analysis of a cohort of late middle-aged African Americans.

BACKGROUND: This cohort of "late middle-aged" African Americans has an excess of disability. We aimed to determine associations of circulating cytokine receptors (sTNFR1, sTNFR2, and sIL-6R) and C-reactive protein (CRP) with disability, physical function, and body composition. METHODS: Stratified sampling of two socioeconomically diverse strata of St Louis, Missouri, occurred in 2000-2001. Inclusion criteria were self-reported black or African American race, born 1936-1950 inclusive, and Mini-Mental State Examination score of 16 or greater. In-home evaluations of handgrip strength, lean body mass percentage (LBM%), physical performance, upper and lower body functional limitations (UBFLs and LBFLs), and basic and instrumental activities of daily living (BADLs and IADLs) were collected. Of the 998 participants, 368 had blood sampled at baseline. Serum was stored and assayed in 2006. RESULTS: Absolute risks were LBFLs of 2 or more, 46%; UBFLs of 1 or more, 23.5%; BADLs of 2 or more, 20.6%; and IADLs of 2 or more, 22.5%. Independent of age, sex, and underlying comorbid conditions, higher CRP and sTNFR were associated with poorer physical performance (beta = -1.462, p < .001 and beta = -0.618, p = .003), UBFLs (odds ratio [OR] 2.26, 95% confidence interval [CI] 1.1-4.64 and OR 1.39, 95% CI 0.96-2.02), LBFLs (OR 2.30, 95% CI 1.19-4.45 and OR 1.91, 95% CI 1.26-2.91), BADLs (OR 2.79, 95% CI 1.03-5.96 and OR 1.66, 95% CI 1.11-2.46), and IADLs (OR 2.13, 95% CI 1.03-4.41 and OR 1.43, 95% CI 0.99-2.08). Higher CRP (beta = -3.251, p <.001), sIL-6R (beta = -6.152, p = .013), and lower adiponectin (beta = 2.947, p = .052) were associated with lower LBM%. CONCLUSIONS: Higher CRP and sTNFR are independently associated with disability and physical dysfunction. Higher sIL-6R, CRP, and lower adiponectin associate with lower LBM%.

Comparison of screening questionnaires for the diagnosis of hypogonadism.

Three questionnaires, the St. Louis University Androgen Deficiency in Aging Male (ADAM), the Aging Male Survey (AMS) and the Massachusetts Male Aging Study (MMAS), have been developed as potential screening tools for hypogonadism in older males. We compared these questionnaires in 148 males aged 23-80 years using bioavailable testosterone as the "biochemical gold standard" for diagnosis of hypogonadism. The sensitivity for the ADAM was 97%, for the AMS 83% and the MMAS 60%. Specificity was 30% for the ADAM, 59% for the MMAS and 39% for AMS. Both bioavailable testosterone and the calculated free testosterone correlated significantly with a number of the individual questions. Total testosterone correlated poorly with most of the questions. In conclusion, the ADAM and AMS may be useful screening tools for hypogonadism across the adult lifespan, but both are relatively nonspecific.

Testosterone, aging and quality of life.

Testosterone levels decline over the lifespan. Many symptoms of hypogonadism are similar to age-related changes in older males. A small number of studies have suggested that some of these symptoms may be reversed by testosterone. Among them, one trial has suggested that decline in bioavailable testosterone may be related to the development of functional decline. Testosterone replacement during rehabilitation may improve functional outcomes and plays an important role in the maintenance of sexual related quality of life. The overall improvement in well-being and/or health-related quality of life in older males needs to be determined with large placebo-controlled trials. This is particularly important in view of the substantial placebo effect on aging symptomatology.

Androgen treatment of male hypogonadism in older males.

The treatment of primary and secondary hypogonadism with testosterone is well established. Recently, there has been increased awareness that low testosterone levels also occur in chronically ill persons and aging males. Because of sex hormone binding globulin changes, it is more appropriate to make the diagnosis using either free or bioavailable testosterone. A small number of controlled studies have suggested that testosterone replacement in older men improves libido, quality of erections, some aspects of cognition, muscle mass, muscles strength, and bone mineral density. It also decreases fat mass and leptin levels. A number of screening questionnaires for the andropause have been developed. Insufficient numbers of older men have been treated with testosterone to characterize the true incidence of side effects. There is a desperate need for well designed, large controlled trials to establish the value or otherwise of testosterone treatment in older males.

Evaluation of assays available to measure free testosterone.

This study compared the results of various testosterone assays in a cross-sectional study of 50 male subjects age 28 to 90 years. The purpose of the study was to determine the relationship of the various testosterone assays to one another. In addition, we determined week-to-week variability in testosterone and bioavailable testosterone in 16 subjects. The following assays were undertaken: total testosterone (T), free testosterone by equilibrium dialysis (FT(D)), bioavailable testosterone (BT), free testosterone by ultracentrifugation (FT(U)), and direct estimation of serum free T by an analog ligand radioimmunoassay (FT(A)). In addition, using total T and sex hormone-binding globulin (SHBG), we calculated the free androgen index (FAI = T/SHBG) and the free testosterone index (FTI) using the method of Vermeulen. In a second study, we measured the week-to-week variation in T and BT in a group of older males. Lastly, we demonstrated excellent stability of serum stored at -70 degrees C for up to 7 years for T and BT. Correlations of the various assays to increasing age were significant for all assays except total T (r = -.126). The best correlation was found with BT (r = -.744, P <.001). All measures were statistically significantly correlated with FT. The best correlations were FTI (r =.807, P <.007) and BT (r =.670, P <.001). If T was used to classify hypogonadism in comparison to BT, it resulted in misclassification in 42% of cases. In addition, we demonstrated a marked week-to-week variability in T and BT in older men with the T and BT being in the eugonadal range some weeks and hypogonadal on other occasions. This occurred in 8 of 16 men for T and 10 of 16 men for BT. Based on these data, we suggest that the FTI or BT are the most practical methods to determine hypogonadism. There is a need for increased awareness that marked week-to-week variability within a single individual can occur for measurements of both T and BT.

Osteoporosis in men: are we ready to diagnose and treat?

Because osteoporosis and its attendant fractures are more common in women than in men, most studies have been performed in women. However, age-related osteoporosis and fragility fractures are also a major problem in men. Recent studies suggest that diagnosing men as osteoporotic when they fall more than 2.5 standard deviations below the mean for young men identifies a group at risk for fracture. Data suggest that many men with femoral fractures have age-related hypogonadism. Hypogonadism is associated with decreased lean body mass and bone mass. Most men with femoral fractures are reported to be hypogonadal. Testosterone replacement in hypogonadal older men improves bone mass and lean body mass. A therapeutic intervention to reduce fracture incidence in men with osteoporosis has been reported. No population-based study has examined the incidence or prevalence of hypogonadism with or without osteoporosis in men. Thus, osteoporosis in men probably exists with and without hypogonadism. Therapeutic interventions should be based on treatment of hypogonadism when present with osteoporosis.

Hormone replacement therapy and fractures in older adults.

Estrogen deficiency in women is associated with accelerated bone loss, and estrogen replacement therapy has been proven to be effective in preventing osteoporosis and fractures in postmenopausal women. The introduction of selective estrogen receptor modulators that have an estrogen-like effect on the skeleton but have a different pattern of effects on other tissues may have an important role in the management of osteoporosis in women in the near future. In men, androgen deficiency has been shown to be associated with osteoporosis. Although androgen replacement in hypogonadal men may decrease bone resorption and increase bone mass, long-term placebo-controlled trials are needed to better define the benefits and risks of such therapy before it can be recommended. Sex hormone deficiency is linked to the development of osteoporosis in both women and men. In women, hormonal replacement by estrogen or the newly developed selective estrogen receptor modulators may prevent the development of osteoporosis and its related fractures. In men, there is early evidence that testosterone replacement therapy may enhance bone mass in hypogonadal men.

Polypharmacy and hospitalization among older home care patients.

BACKGROUND: One of the major goals of home care is the prevention of hospitalization. The objective of this study was to examine the relation between medication use (number, type, and inappropriateness) and hospitalization among home care patients older than 65 years. METHODS: A retrospective chart review of 833 discharged older home care patients was performed. These patients were consecutive discharges from a single home care agency who either (a) returned to independent self-care or care of the family (S/F Care group) or (b) were admitted to the hospital (Hospitalized group). Medication assessment within these two groups included total number of medications (prescription and nonprescription); degree of polypharmacy (percentage of patients taking 5 or more, 7 or more, and 10 or more medications); and prevalence for different types of medications, including different types of inappropriate medications. Inappropriate medications were designated according to a list that was previously developed through a modified Delphi consensus technique by a panel of 13 experts in geriatric pharmacology and has been utilized in other studies. Student's t test was used for continuous variables and chi-square test was used for categorical variables to evaluate for differences between the S/F Care group and the Hospitalized group (p <.05). For comparisons of types of medications, p < .01 was used for significant differences, because of the high number of comparisons made. RESULTS: Of 833 discharges, 644 (77.3%) returned to self-care or care of the Family (S/F Care group) and 189 (22.7%) were hospitalized. The Hospitalized group, compared with the S/F Care group, was taking a higher number of medications (mean +/- SD: 6.6+/-3.9 vs 5.7+/-3.4, p = .004), and had a higher percentage of patients taking 7 or more medications (46% vs 26%, p = .002) and 10 or more medications (21% vs 10%, p = .005), but not 5 or more medications. Only three types of medications were more commonly used among patients in the Hospitalized group than among patients in the S/F Care group: clonidine (4.2% vs 1.1%, p = .004); mineral supplements (23.8% vs 14.8%, p = .003); and metoclopramide (5.8% vs 2.0%, p = .006). The Hospitalized group had a lower percentage of patients taking inappropriate medications than did the S/F Care group (20% vs 27%, p = .040), but none of the types of inappropriate medications was used more often in either group. CONCLUSIONS: This study shows a relationship between high levels of polypharmacy and hospitalization. Although it cannot be determined from this study whether a higher number of medications was an indicator of sicker patients at risk for hospitalization, or whether a higher number of medications might have directly led to hospitalization, polypharmacy should still be considered a marker for older home care patients for whom prevention of hospitalization is the goal.

Validation of a screening questionnaire for androgen deficiency in aging males.

It is now well established that testosterone levels decline with age. What has not been established is whether the decline in testosterone is associated with a symptom complex. This study examined whether certain symptoms are more commonly present in males with low bioavailable testosterone (BT) levels. These were used to evaluate a questionnaire for androgen deficiency in aging males (ADAM). The validity of the ADAM questionnaire to screen for low BT was tested in 316 Canadian physicians aged 40 to 62 years. Low BT levels were present in 25% of this population. None had elevated luteinizing hormone (LH) levels. The ADAM questionnaire had 88% sensitivity and 60% specificity. When the questionnaire was administered twice 2 to 4 weeks apart to 10 men, it was determined that the coefficient of variation was 11.5%. In a second study of 34 ADAM-positive patients, 37% of those with clearly normal BT levels demonstrated some evidence of dysphoria. Finally, in 21 patients who were treated with testosterone, improvement on the ADAM questionnaire was demonstrated in 18 (P = .002). These data support the concept of a symptom complex associated with low BT levels in aging males. In addition, the ADAM questionnaire appears to be a reasonable screening questionnaire to detect androgen deficiency in males over 40 years of age.

Testosterone and leptin in older African-American men: relationship to age, strength, function, and season.

Testosterone (T) and bioavailable testosterone (BT) levels have been shown to decline with aging in Caucasian males. We are unaware of any studies that have examined this in African-American men. Previous studies have suggested a relationship of T to strength and leptin levels, but no such correlation with measured functional tests exists. This study explores these associations in a cross-sectional sample of older African-Americans from the Saint Louis University Inner City Aging Project. The participants were 65 African-American males aged 70 to 102 years. Measurements included T, BT, and leptin levels, isometric muscle strength, and relevant physical impairments. Statistical analysis included a t test and simple and multiple ordinary least-squares regression. Age was inversely related to T and BT. Of these older African-American males, 90.7% had a BT value less than the normal range for young males. T correlated with upper- and lower-limb strength and functional tests. Leptin was correlated with the body mass index (BMI) and inversely with T, but not with BT. Circannual rhythms for T, BT, and leptin were present. This study demonstrates for the first time an age-related decrease in T and BT in African-Americans and a circannual rhythm for leptin. T was correlated with upper- and lower-limb strength and functional status.

Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP).

CONTEXT: The Systolic Hypertension in the Elderly Program (SHEP) demonstrated that treating isolated systolic hypertension in older patients decreased incidence of total stroke, but whether all types of stroke were reduced was not evaluated. OBJECTIVE: To investigate antihypertensive drug treatment effects on incidence of stroke by type and subtype, timing of strokes, case-fatality rates, stroke residual effects, and relationship of attained systolic blood pressure to stroke incidence. DESIGN: The SHEP study, a randomized, double-blind, placebo-controlled trial began March 1, 1985, and had an average follow-up of 4.5 years. SETTING AND PARTICIPANTS: A total of 4736 men and women aged 60 years or older with isolated systolic hypertension at 16 clinical centers in the United States. INTERVENTIONS: Patients were randomly assigned to receive treatment with 12.5 mg/d of chlorthalidone (step 1); either 25 mg/d of atenolol or 0.05 mg/d of reserpine (step 2) could be added (n = 2365); or placebo (n = 2371). MAIN OUTCOME MEASURES: Occurrence, type and subtype, and timing of first strokes and stroke fatalities; and change in stroke incidence for participants (whether in active treatment or placebo groups) reaching study-specific systolic blood pressure goal (decrease of at least 20 mm Hg from baseline to below 160 mm Hg) compared with participants not reaching goal. RESULTS: A total of 85 and 132 participants in the active treatment and placebo groups, respectively, had ischemic strokes (adjusted relative risk [RR], 0.63; 95% confidence interval [CI], 0.48-0.82); 9 and 19 had hemorrhagic strokes (adjusted RR, 0.46; 95% CI, 0.21-1.02); and 9 and 8 had strokes of unknown type (adjusted RR, 1.05; 95% CI, 0.40-2. 73), respectively. Four subtypes of ischemic stroke were observed in active treatment and placebo group participants, respectively, as follows: for lacunar, n = 23 and n = 43 (adjusted RR, 0.53; 95% CI, 0.32-0.88); for embolic, n = 9 and n = 16 (adjusted RR, 0.56; 95% CI, 0.25-1.27); for atherosclerotic, n = 13 and n = 13 (adjusted RR, 0. 99; 95% CI, 0.46-2.15); and for unknown subtype, n = 40 and n = 60 (adjusted RR, 0.64; 95% CI, 0.43-0.96). Treatment effect was observed within 1 year for hemorrhagic strokes but was not seen until the second year for ischemic strokes. Stroke incidence significantly decreased in participants attaining study-specific systolic blood pressure goals. CONCLUSIONS: In this study, antihypertensive drug treatment reduced the incidence of both hemorrhagic and ischemic (including lacunar) strokes. Reduction in stroke incidence occurred when specific systolic blood pressure goals were attained. JAMA. 2000;284:465-471

Pretreatment blood pressure as a predictor of 21-year mortality.

Our objective was to evaluate pretreatment predictors of longevity, particularly blood pressure, in a large cohort of hypertensive men. During 1974 to 1976, 10,367 male hypertensive veterans (47% black) were identified at screening and subsequently characterized in 32 special Veterans Administration (VA) hypertension clinics. Their mean age was 52 years and mean blood pressure (BP) 154/100 mm Hg. During an average of 21 years of follow-up, 61% died. Risk ratios for all-cause mortality as functions of BP and other risk factors are presented for each variable alone; for each variable controlling for age, race, and BP; and for a multivariate model. We observed that when the entire cohort was divided into deciles by systolic blood pressure (SBP) and by diastolic blood pressure (DBP), the risk ratios for 21-year mortality increased from lowest to highest decile by 178% for SBP and 16% for DBP. When the deciles were computed separately by age group, increases from lowest to highest decile for those less than 40 years of age were 138% for SBP and 263% for DBP. For those over 60 years, the increases were 154% and -10%, respectively. Although blacks were younger and had more severe diastolic hypertension than whites, the risk ratios were similar within each race group. Risk patterns for mean arterial pressure and pulse pressure resembled those for SBP but had smaller gradients. Survival curves for BP groups suggested constant mortality rates during follow-up. Other significant observations included decreasing mortality with increasing body mass index and increased mortality in the Stroke Belt. We concluded that pretreatment SBP strongly predicted all-cause mortality during 21-year follow-up. For the young, both SBP and DBP were strong predictors; for the elderly, only SBP was predictive.

Department of Veterans Affairs hypertension meeting : a proposal for improved care.

A major invitational hypertension meeting was hosted by the Department of Veterans Affairs (VA) in Washington, DC, on May 26 to 28, 1999. It followed a report that only 25% of hypertensive veterans had adequate levels of treated blood pressure and focused on how control of hypertension could be improved both immediately and in the future. After the presentation of brief outlines of 5 unresolved basic science questions, 2 general topics were considered: (1) 30 years of change in hypertension and its treatment and (2) current healthcare delivery mechanisms and how to improve them. Since 1970, the severity of hypertension has decreased, malignant hypertension has disappeared, and the prognostic roles of systolic and diastolic blood pressure have been reversed as hypertension became milder. Five VA Cooperative Studies have provided important data: the 1970 Freis Trial report demonstrated the value of treatment, 2 trials showed that some controlled patients can decrease or even discontinue pharmacological treatment without recrudescent hypertension, a blinded trial was performed on the efficacy of different antihypertensive drugs, and an unblinded trial showed that diuretics and beta-blockers are the most effective agents when caregivers choose the agent and dose. Two healthcare models were considered: (1) the patient-friendly VA Hypertension Screening and Treatment Program that was introduced in 1972, which controls 80% of patients at the goal of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure with diuretics and keeps patients in the program an average of 7.5 years, and (2) the newer primary care health maintenance organization-like model in the VA and throughout the United States. Choosing a regimen and monitoring control of blood pressure and compliance with therapy were discussed. The meeting was closed with 6 general recommendations for improving the care of hypertensive patients.

Regional and racial differences in response to antihypertensive medication use in a randomized controlled trial of men with hypertension in the United States. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

BACKGROUND: Stroke incidence and mortality rates are higher in the southeastern region of the United States, which is called the "Stroke Belt." We compared the response to antihypertensive medication use in patients from different US regions. METHODS: The short-term and 1-year efficacy of the antihypertensive medications hydrochlorothiazide, atenolol, diltiazem hydrochloride (sustained release), captopril, prazosin hydrochloride, and clonidine was compared by US region in a randomized controlled trial of 1,105 men with hypertension from 15 US Veterans Affairs medical centers. RESULTS: Compared with patients outside the Stroke Belt, patients inside the Stroke Belt achieved significantly lower treatment success rates of diastolic blood pressure control at 1 year with hydrochlorothiazide (63% vs 41%), atenolol (62% vs 46%), captopril (60% vs 30%), and clonidine (69% vs 43%); there were no differences in treatment success rates with diltiazem (70% vs 71%) or prazosin (54% vs 53%). When controlling for race, patients inside the Stroke Belt had significantly lower treatment success rates with hydrochlorothiazide (P = .003) and clonidine (P = .003), and the lower success rate with atenolol approached significance (P = .15). Regardless of region, blacks were less likely than whites to achieve treatment success with atenolol (P = .02) or prazosin (P = .03) and more likely with diltiazem (P = .05). There was a trend for blacks residing inside the Stroke Belt to have a lower treatment success rate than other race-region groups when treated with captopril (P = .07). Many regional and racial differences in diet, lifestyle, and other characteristics were observed. After adjustment for these characteristics by regression analysis, the effect of residing inside the Stroke Belt remained for captopril (P = .01) and clonidine (P = .01) and approached significance for hydrochlorothiazide (P = .10). CONCLUSIONS: Hypertension in patients residing inside the Stroke Belt responded less to the use of several antihypertensive medications and important differences were shown in a number of characteristics that may affect the control of blood pressure, compared with patients residing outside the Stroke Belt.

The Washington University-EPRI Veterans' Cohort Mortality Study: preliminary results.

This article presents the design of and some results from a new prospective mortality study of a national cohort of about 50,000 U.S. veterans who were diagnosed as hypertensive in the mid 1970s, based on approximately 21 yr of follow-up. This national cohort is male with an average age at recruitment of 51 +/- 12 yr; 35% were black and 81% had been smokers at one time. Because the subjects have been receiving care at various U.S. Veterans Administration (VA) hospitals, access to and quality of medical care are relatively homogeneous. The health endpoints available for analysis include all-cause mortality and specific diagnoses for morbidity during VA hospitalizations; only the mortality results are discussed here. Nonpollution predictor variables in the baseline model include race, smoking (ever or at recruitment), age, systolic and diastolic blood pressure (BP), and body mass index (BMI). Interactions of BP and BMI with age were also considered. Although this study essentially controls for socioeconomic status by design because of the homogeneity of the cohort, selected ecological variables were also considered at the ZIP code and county levels, some of which were found to be significant predictors. Pollutants were averaged by year and county for TSP, PM10, CO, O3, and NO2; SO2 and Pb were considered less thoroughly. Both mean and peak levels were considered for gases. SO(4)2- data from the AIRS database and PM2.5, coarse particles, PM15, and SO(4)2- from the U.S. EPA Inhalable Particulate (IP) Network were also considered. Four relevant exposure periods were defined: 1974 and earlier (back to 1953 for TSP), 1975-1981, 1982-1988, and 1989-1996. Deaths during each of the three most recent exposure periods were considered separately, yielding up to 12 combinations of exposure and mortality periods for each pollutant. Associations between concurrent air quality and mortality periods were considered to relate to acute responses; delayed associations with prior exposures were considered to be emblematic of initiation of chronic disease. Preexposure mortality associations were considered to be indirect (noncausal). The implied mortality risks of long-term exposure to air pollution were found to be sensitive to the details of the regression model, the time period of exposure, the locations included, and the inclusion of ecological as well as personal variables. Both positive and negative statistically significant mortality responses were found. Fine particles as measured in the 1979-1984 U.S. EPA Inhalable Particulate Network indicated no significant (positive) excess mortality risk for this cohort in any of the models considered. Among the positive responses, indications of concurrent mortality risks were seen for NO2 and peak O3, with a similar indication of delayed risks only for NO2. The mean levels of these excess risks were in the range of 5-9%. Peak O3 was dominant in two-pollutant models and there was some indication of a threshold in response. However, it is likely that standard errors of the regression coefficients may have been underestimated because of spatial autocorrelation among the model residuals. The significant variability of responses by period of death cohort suggests that aggregation over the entire period of follow-up obscures important aspects of the implied pollution-mortality relationships, such as early depletion of the available pool of those subjects who may be most susceptible to air pollution effects.

Language dominance in neurologically normal and epilepsy subjects: a functional MRI study.

Language dominance and factors that influence language lateralization were investigated in right-handed, neurologically normal subjects (n = 100) and right-handed epilepsy patients (n = 50) using functional MRI. Increases in blood oxygenation-dependent signal during a semantic language activation task relative to a non-linguistic, auditory discrimination task provided an index of language system lateralization. As expected, the majority of both groups showed left hemisphere dominance, although a continuum of activation asymmetry was evident, with nearly all subjects showing some degree of right hemisphere activation. Using a categorical dominance classification, 94% of the normal subjects were considered left hemisphere dominant and 6% had bilateral, roughly symmetric language representation. None of the normal subjects had rightward dominance. There was greater variability of language dominance in the epilepsy group, with 78% showing left hemisphere dominance, 16% showing a symmetric pattern and 6% showing right hemisphere dominance. Atypical language dominance in the epilepsy group was associated with an earlier age of brain injury and with weaker right hand dominance. Language lateralization in the normal group was weakly related to age, but was not significantly related to sex, education, task performance or familial left-handedness.