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Atypical antipsychotics are now the most commonly prescribed antipsychotics in young patients. These drugs are increasingly being used because of better tolerance and safety as seen in the adult populations. Youth with more severe psychopathology who are treated in the inpatient setting have been overlooked in much of the published research, and the extent of use and rationale in this population is unknown. This naturalistic retrospective study examined a population of adolescents in an inpatient state hospital setting with regard to their use of atypical antipsychotics. All patients who received an inpatient prescription for atypical antipsychotics between January 1, 1997 and June 1, 2000 and were ages 18 or younger at the time of medication initiation were included in the study. Twenty-three percent (88/380) of patients received an atypical antipsychotic: 68% (60/88) risperidone, 27% (24/88) olanzapine, and 5% (4/88) quetiapine. Psychotic disorders were considered as the primary diagnosis in only 17% of patients treated with atypical antipsychotics, and no particular diagnosis was predictive of monotherapy with an atypical antipsychotic. In the adolescent populations, atypical antipsychotics are being used for a wide variety of diagnoses and are commonly used adjunctively (more than 80%) with many concomitant psychotropic medications. More research is needed to develop useful and specific practice guidelines in children and adolescents for these commonly used medications.

Auditory gating deficits observed in patients with schizophrenia have been modeled in animals administered the indirect-acting monoaminergic agonist, d-amphetamine (AMPH). The atypical antipsychotic drug clozapine (CLOZ) reverses the disruption of auditory gating in schizophrenic patients. However, its effects on psychostimulant-induced deficits in animals have yet to be assessed. In the present series of experiments, an auditory evoked potential paradigm was used to: (a) confirm the ability of AMPH to alter auditory gating in the anesthetized rat, (b) specify the nature of the accompanying change(s) in evoked potential waveforms and (c) determine the effects of CLOZ administration on AMPH-induced alterations in auditory gating. We compared the effects of acute (5 mg/kg, i.p.) and chronic (28 days, 0.5 mg/ml in drinking water) CLOZ on AMPH-induced (1.8 mg/kg, i.p.) alterations in evoked potentials recorded in the hippocampus of anesthetized rats during presentation of a pair of identical tones. Gating was assessed by comparing the amplitude of conditioning and test responses in CLOZ and AMPH-treated rats. The ratio of test to conditioning response amplitude (T/C ratio) was not altered by vehicle or CLOZ alone. However, T/C ratio was significantly increased following AMPH due to suppression of the conditioning response. Acute but not chronic CLOZ attenuated but did not prevent the increase in T/C ratio. Qualitative differences between the idiopathic gating deficits observed in schizophrenic patients and AMPH-induced increases in T/C ratio in animals limit this models utility as a means of evaluating the ability of atypical antipsychotic drugs to restore normal sensory gating.

There is considerable evidence that schizophrenia spectrum personality (SSP) disorders mark genetic risk for schizophrenia. Use of the spectrum phenotype in genetic and neurophysiological studies may prove informative. However, the degree to which the current diagnostic criteria correspond with genetic risk is unclear. This can be assessed by observing how measures of liability among SSP subjects change as a function of diagnostic criteria. In this study the generalized estimating equation method was used to assess changes in eye-tracking performance among SSP and non-SSP family and community groups employing various diagnostic criteria. Eye-tracking deficits among SSP relatives remained statistically higher compared with the other groups across progressively more liberal SSP criteria. The results suggest that fewer traits than are used in clinical diagnoses can effectively identify the spectrum phenotype among relatives of schizophrenia patients. Thus, reduced criteria may be used in research to increase "high risk" sample size and power to detect neurophysiological and genetic differences. Our results provide suggestive evidence that the use of clinical criteria in research may, in fact, underidentify at-risk individuals--potentially distorting genetic and neurophysiological findings.

Decreasing hospital admissions is important for improving outcomes for people with schizophrenia. Second-generation antipsychotics (SGAs) are better tolerated for long-term therapy than traditional medications and may contribute to a lower rehospitalization risk, but have not been compared to depot forms with regard to long-term outcomes. This study evaluates the risk of readmission in patients discharged from six State of Maryland inpatient mental health facilities between Jan. 1, 1997 and Dec. 31, 1997 on clozapine (N = 41), risperidone (N = 149), and olanzapine (N = 103). These patients were compared with those discharged from the two largest state facilities during the same time period on fluphenazine decanoate (N = 59) or haloperidol decanoate (N = 59). One-year readmission risk (measured by Kaplan-Meier survival analysis with Holm's adjustment for multiple comparison on Log Rank tests) were 10% for clozapine, 12% for risperidone, and 13% for olanzapine. These risks were not significantly lower than the readmission risk for fluphenazine decanoate (21%) but were significantly lower than haloperidol decanoate (35%) for all three SGAs. Demographic and clinical variables did not predict readmission for any of the medications. In patients with similar demographic and clinical characteristics, 1-year risk of readmission for patients treated with SGAs were at least comparable to the 1-year risk for patients receiving fluphenazine decanoate and lower than the risk for patients treated with haloperidol decanoate. SGAs may provide better long-term prognoses and outcomes for patients with schizophrenia.

The visual working memory (WM) storage capacity of patients with schizophrenia was investigated using a change detection paradigm. Participants were presented with 2, 3, 4, or 6 colored bars with testing of both single feature (color, orientation) and feature conjunction conditions. Patients performed significantly worse than controls at all set sizes but demonstrated normal feature binding. Unlike controls, patient WM capacity declined at set size 6 relative to set size 4. Impairments with subcapacity arrays suggest a deficit in task set maintenance: Greater impairment for supercapacity set sizes suggests a deficit in the ability to selectively encode information for WM storage. Thus, the WM impairment in schizophrenia appears to be a consequence of attentional deficits rather than a reduction in storage capacity.

The inability to modulate processing time in conjunction with varying difficulty levels may be a core component of schizophrenia's cognitive deficit. In this study we used a parametric design to demonstrate this group's inability to increase and decrease response times in association with varying levels of task demand during auditory and visual recognition tasks. Unlike participants with schizophrenia, healthy volunteers responded to increasing levels of difficulty and high error by robustly increasing their average response times. In the group with schizophrenia, the greater the correlation between a subject's Response-Time and error rate the better was the subject in his/her overall discrimination accuracy. The higher their correlations the better they performed across all levels of difficulty in both modalities. The schizophrenia group's tendency to process high and low error conditions with similar behavioral resources may reflect a relatively static, non-dynamic cognitive repertoire.

Background: Results of several studies have suggested that diet during adolescence may influence the risk of breast cancer in adulthood. We evaluated whether an intervention to lower fat intake among adolescent girls altered their serum concentrations of sex hormones that, in adults, are related to breast cancer development. Methods: We conducted an ancillary hormone study among 286 of the 301 girls who participated between 1988 and 1997 in the Dietary Intervention Study in Children, in which healthy, prepubertal, 8- to 10year-olds with elevated low-density lipoprotein cholesterol were randomly assigned to usual care or to a behavioral intervention that promoted a low-fat diet. Median time on the intervention was 7 years. Blood samples collected before randomization and at the year 1, year 3, year 5, and last visits were assayed to determine the girls’ serum levels of sex hormones. All P values are two-sided. Results: At the year 5 visit, girls in the intervention group had 29.8% (95% confidence interval [CI] = 5.4% to 47.9%; P = .02) lower estradiol, 30.2% (95% CI = 7.0% to 47.7%; P = .02) lower nonsex hormone binding globulin-bound estradiol, 20.7% (95% CI = 4.7% to 34.0%; P = .02) lower estrone, and 28.7% (95% CI = 5.1% to 46.5%; P = .02) lower estrone sulfate levels during the follicular phase of the menstrual cycle and 27.2% (95% CI = 5.7% to 53.1%; P = .01) higher testosterone levels during the luteal phase of the menstrual cycle than did girls in the usual care group. At the last visit, the luteal phase progesterone level was 52.9% (95% CI = 20.0% to 72.3%) lower for girls in the intervention group than for girls in the usual care group (P = .007). Conclusion: Modest reductions in fat intake during puberty are associated with changes in sex hormone concentrations that are consistent with alterations in the function of the hypothalamic–pituitary–ovarian axis. Whether these changes influence breast cancer risk is currently unknown. [J Natl Cancer Inst 2003;95:132–41]

Objective. The National Heart, Lung, and Blood Institute Growth and Health Study (NGHS) is a 10-year study to investigate the development of obesity in black and white girls during adolescence and its en- vironmental and psychosocial correlates. The purpose of this report was to examine changes in the annual preva- lence rates of overweight and obesity in the NGHS co- hort from ages 9 to 19 years. Participants and Setting. A total of 2379 black and white girls, aged 9 to 10 years, were recruited from schools in Richmond, California, and Cincinnati, Ohio, and from families enrolled in a health maintenance or- ganization in the Washington, DC area. Participant eligi- bility was limited to girls and their parents who declared themselves as being either black or white and who lived in racially concordant households. Design and Statistical Analysis. The NGHS is a mul- ticenter prospective study of a biracial cohort followed annually from ages 9 to 10 years through 18 to 19 years. The prevalence of overweight and obesity was based on age-specific >85th and >95th percentile values, respec- tively, for body mass index based on the 1960 -1965 Na- tional Health Examination Survey reference population. Main Outcome Measures. The main outcome mea- sures were body mass index (weight in kilograms di- vided by height in meters, squared) and proportions of girls who were "overweight" and "obese" by age and race. Results. The prevalence of overweight was 37% higher in blacks as compared with whites (30.6% vs 22.4%) even by age 9. The rate of overweight almost doubled in both groups during the 10-year period. By age 19, the rate of overweight was 56.9% in black and 41.3%, in white girls. The prevalence of obesity was 17.7% in black and 7.7% in white girls at 9 years old, and the rates also doubled during the study period. Conclusions. The doubling in the prevalence of over- weight and obesity during adolescence in black and white NGHS girls was surprising. By age 19, more than half of black girls were overweight and more than one third were obese. Almost half of white girls were over- weight and almost 1 of 5 girls were obese. These findings should sound an alarm for all primary care physicians and public health professionals to take heed of what is happening to our youth. Pediatrics 2002;110(5). URL: http://www.pediatrics.org/cgi/content/full/110/5/e54; race, adolescence, body mass index, obesity, overweight, preva- lence rates, females.

We examined the effects of long-term clozapine treatment, concurrent treatment with beta-adrenergic antagonists, and clozapine-induced weight gain on serum glucose and lipid measures. Fifty subjects met the DSM-III-R criteria for schizophrenia or schizoaffective disorder, participated in a 10-week, double-blind comparison of haloperidol and clozapine and a 1-year, open-label clozapine trial, and had available serum glucose and lipid levels. Weight and glucose, and lipid laboratory values were measured at the baseline and throughout the double-blind and year-long study. There were significant increases in serum triglyceride, total cholesterol, and glucose levels during the course of clozapine treatment. There were no significant changes in high-density lipoprotein (HDL) or low-density lipoprotein (LDL). Propranolol and atenolol had additive effects on changes in the total cholesterol and triglycerides, with propranolol having the most pronounced effects. Propranolol and atenolol had no significant effect on the serum glucose levels. There were significant correlations between the triglyceride and HDL level changes and clozapine-associated weight gain during the study. There were no significant correlations between the change in serum total cholesterol, LDL, or glucose and weight gain. Clozapine therapy has adverse effects on glucose and lipid homeostasis, with clozapine-induced changes in serum glucose likely due to the inherent pharmacological properties of clozapine. Concurrent beta-adrenergic receptor antagonist treatment may have an additive effect on serum lipids, and clozapine-associated weight gain also plays a modest role in triglyceride increases.

Concern has been raised about the adequacy of radioimmunoassays to measure steroid sex hormones in population studies. We compared steroid sex hormone measurements in serum by radioimmunoassay with mass spectrometry. Four male and four female serum pools with known relative concentrations of steroid sex hormones were measured multiple times by both methods. Because measurements are expected to increase linearly with concentration for each sex, we examined whether the linear regressions of hormone measurements on concentration were the same for radioimmunoassay and mass spectrometry. Estradiol, estrone, androstenedione, testosterone, and dehydroepiandrosterone sulfate were measured in female pools; testosterone, dihydrotestosterone, androstenedione, and dehydroepiandrosterone sulfate were measured in male pools. Regression slopes for radioimmunoassay and mass spectrometry measurements were comparable for all hormones except androstenedione, which had a steeper slope when measured by mass spectrometry (Por = 0.02). Intercepts for radioimmunoassay and mass spectrometry were similar and close to zero for estradiol, androstenedione, dehydroepiandrosterone sulfate, and in male samples, testosterone. For testosterone in female samples, estrone, and dihydrotestosterone, radioimmunoassay and mass spectrometry intercepts differed significantly. Standard deviations of individual measurements by radioimmunoassay and mass spectrometry differed by hormone and serum concentration; neither method consistently measured hormone concentrations with less variability. Our findings suggest that although absolute concentrations may differ for some hormones, radioimmunoassay and mass spectrometry can yield similar estimates of between subject differences in serum concentrations of most steroid sex hormones commonly measured in population studies. Relative power of studies using radioimmunoassay and mass spectrometry will depend on the hormones measured and their serum concentrations.

This report describes the development and use of two self-report methods and an objective measure to assess longitudinal changes in physical activity in a large biethnic cohort of young girls from childhood through adolescence.The NHLBI Growth and Health Study (NGHS) is a multicenter study of obesity development in 2379 black and white girls followed from ages 9-10 yr to 18-19 yr (NGHS years 1-10). A Caltrac activity monitor was used to objectively quantify activity levels in years 3-5. A 3-d diary (AD) and a habitual patterns questionnaire (HAQ) were administered annually and biannually, respectively, to subjectively quantify physical activity levels. The changing pattern of activities as the girls matured during the 10-yr study period necessitated periodic form changes. Empirical analytic approaches were developed to help distinguish between true longitudinal changes in activity levels from potential numerical artifacts resulting from modifications in forms.The longitudinal activity data indicate a steep decline in the level of reported activity from baseline to year 10 as indicated by AD scores (446.8 to 292.1 MET-min x d(-1), 35%) as well as by HAQ scores (29.3 to 4.9 MET-times x wk(-1), 83%). This parallel trend in the pattern of the decline in activity among the two self-report methods was mirrored by a similar decline using the Caltrac method of physical activity assessment. From years 3 to 5, the AD decreased by 22%, whereas both the HAQ and Caltrac declined by 21%.The longitudinal data on physical activity collected in the NGHS cohort further confirm a dramatic decrease in the overall level of physical activity during the transition from childhood to adolescence. The consistency among the three methods indicate that both the AD and HAQ are useful tools for the assessment of activity levels in adolescent girls.

In a clinical trial in which mortality occurs and a nonfatal outcome is measured after a fixed duration of follow-up, composite rank scores in which deaths (ranked by survival time) are scored below ranks for the nonfatal outcome have been proposed to test for treatment efficacy. This report derives formulae for calculating power for such a rank test under the conservative assumption that the treatment has a beneficial effect on the nonfatal outcome but no effect on mortality.

The National Heart, Lung, and Blood Institute Growth and Health Study (NGHS) is an epidemiologic study of 1,213 Black and 1,166 White girls (ages 9-10) of risk factors for obesity. NGHS used Harter's Self-Perception Profile for Children (SPPC) to measure domain-specific competence and overall self-worth. This report reviews the psychometric properties of the SPPC in this biracial cohort at baseline and Year 3 visits (ages 11-12). Simple structure yielding unique components for each of the SPPC domains was obtained for White but not Black girls, whether analyzed overall or by parental education level. Internal consistency was higher for White girls in both years. The lack of simple structure was reflected in the higher correlations among the subscales for Black girls. The structure and internal consistency improved in Year 3 for Black girls, indicating that the physical appearance and athletic competence domains were not yet fully differentiated at baseline. Readers should be cautious, however, when interpreting the SPPC in young Black girls.

Objective Many patients with coronary artery disease (CAD) develop myocardial ischemia in response to mental stress. This has been documented both in the natural environment and in the laboratory. However, the reproducibility of laboratory mental stress-induced ischemia has not been investigated. Method Sixty patients with documented CAD and a positive exercise stress test discontinued cardiac medications and underwent two standardized mental stress tests (a timed Stroop Color-Word test and a public speaking task) in a nuclear cardiology laboratory (Visit 1), and repeated this procedure between 2 and 8 weeks later (Visit 2). Measurements of cardiovascular function and neurohormonal responses were obtained throughout testing, and mood state was assessed before and after testing. Results Sixty-eight percent of the 56 patients with detailed radionuclide data from both visits had consistent responses (ie, ischemia either present during both sessions or absent during both) to the Stroop task (kappa = .29, p = .03), 61% had consistent responses to the speech task (kappa = .20, p = .12), and 60% had consistent responses when ischemia was considered present if it occurred during either the Stroop test, the speech task, or both, and absent if it did not occur during either task (kappa = .22, p = .07). Hemodynamic and neuroendocrine responses to the tests were moderately reproducible. Conclusions We conclude that two popular laboratory tests for mental stress-induced myocardial ischemia are modestly reproducible. The relatively low reproducibility is probably influenced by uncertainties in detecting relatively small changes in wall motion, habituation of the patient to repeated exposure to psychological stressors, and physiological differences in threshold for ischemia on different days of testing.

Objective This study evaluated physiological, neuroendocrine, and psychological status and functioning of patients with coronary artery disease in order to clarify their role in the expression of symptoms during myocardial ischemia (MI), and to establish repeatability of responses to mental stress. Design and methods of the study are presented. Methods One hundred ninety-six coronary artery disease patients were examined during physical and mental stress tests in four hospitals. Eligibility criteria included narrowing of at least 50% in the diameter of at least one major coronary artery or verified history of myocardial infarction, and evidence of ischemia on an exercise treadmill test. Psychological, biochemical, and autonomic function data were obtained before, during, and after exposure to mental and exercise stressors during 2 or 3 half-days of testing. Ventricular function was assessed by radionuclide ventriculography, and daily ischemia by ambulatory electrocardiography. Sixty patients returned for a short-term mental stress repeatability study. Twenty-nine individuals presumed to be free of coronary disease were also examined to establish reference values for cardiac responses to mental stress. Results Study participants were 41 to 80 years of age; 83 (42%) had a history of MI, 6 (3%) of congestive heart failure, and 163 (83%) of chest pain; 170 (87%) were men; and 90 (46%) had ischemia accompanied by angina during exercise treadmill testing. Ischemia during ambulatory monitoring was found in 35 of 90 (39%) patients with and 48 of 106 (45%) patients without angina during exercise-provoked ischemia. Intraobserver variability of ejection fraction changes during bicycle exercise and two mental stress tests (Speech and Stroop) was good (kappa = 1.0, .90, and .76, respectively; percent agreement = 100, 97.5, and 93.8%, respectively). Variability of assessed wall motion abnormalities during bicycle exercise was better (kappa, agreement = 85%) than during Speech or Stroop kappa and .57, percent agreement = 70% and 82.5%, respectively). Conclusions Study design, quality control data, and baseline characteristics of patients enrolled for a clinical study of symptomatic and asymptomatic myocardial ischemia are described. Lower repeatability of reading wall motion abnormalities during mental stress than during exercise may be due to smaller effects on wall motion and lack of an indicator for peak mental stress.

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), a double-blind randomized clinical trial, compared the frequency of acute vaso-occlusive (painful) crises during 2 yr of follow-up in 299 patients randomly assigned to hydroxyurea or placebo. Most patients had more than one crisis; all crises reported were included in the primary outcome analysis. A total of 7,229 follow-up medical contact reports were classified as crises/not crises by a Crisis Review Committee. Because of the time required to report, document, and classify contacts, interim analyses were prepared with incomplete data. If a stopping boundary were crossed, early termination could be advised only after assessing the potential impact of the incomplete data. In an extension of stochastic curtailment methods, simulation procedures were used to estimate the probability of detecting differences when group crisis rates projected to the end of the study were compared using a rank test. To account for medical contacts not yet reported and the future occurrence of crises, Poisson process models assuming no treatment effect on crisis rates were used for these simulations. The number of unclassified contacts that would be classified as crises was simulated as a binomial random variable. These methods may be useful for interim monitoring in other studies of recurrent events with ongoing event reporting and classification.

Abstract Delineating the role that diet plays in blood pressure levels in children is important for guiding dietary recommendations for the prevention of hypertension. The purpose of this study was to investigate relationships between dietary nutrients and blood pressure in children. Data were analyzed from 662 participants in the Dietary Intervention Study in Children who had elevated low-density lipoprotein cholesterol and were aged 8 to 11 years at baseline. Three 24-hour dietary recalls, systolic pressure, diastolic pressure, height, and weight were obtained at baseline, 1 year, and 3 years. Nutrients analyzed were the micronutrients calcium, magnesium, and potassium; the macronutrients protein, carbohydrates, total fat, saturated fat, polyunsaturated fat, and monounsaturated fat; dietary cholesterol; and total dietary fiber. Baseline and 3-year longitudinal relationships were examined through multivariate models on diastolic and systolic pressures separately, controlling for height, weight, sex, and total caloric intake. The following associations were found in longitudinal analyses: analyzing each nutrient separately, for systolic pressure, inverse associations with calcium ( P P P P P P P P P P P P P P

Background The pathophysiology of mental stress–induced myocardial ischemia, which occurs at lower heart rates than during physical stress, is not well understood. Methods and Results The Psychophysiological Investigations of Myocardial Ischemia Study (PIMI) evaluated the physiological and neuroendocrine functioning in unmedicated patients with stable coronary artery disease and exercise-induced ischemia. Hemodynamic and neurohormonal responses to bicycle exercise, public speaking, and the Stroop test were measured by radionuclide ventriculography, ECG, and blood pressure and catecholamine monitoring. With mental stress, there were increases in heart rate, systolic blood pressure, cardiac output, and systemic vascular resistance that were correlated with increases in plasma epinephrine. During exercise, systemic vascular resistance fell, and there was no relationship between the hemodynamic changes and epinephrine levels. The fall in ejection fraction was greater with mental stress than exercise. During mental stress, the changes in ejection fraction were inversely correlated with the changes in systemic vascular resistance. Evidence for myocardial ischemia was present in 92% of patients during bicycle exercise and in 58% of patients during mental stress. Greater increases in plasma epinephrine and norepinephrine occurred with ischemia during exercise, and greater increases in systemic vascular resistance occurred with ischemia during mental stress. Conclusions Mental stress–induced myocardial ischemia is associated with a significant increase in systemic vascular resistance and a relatively minor increase in heart rate and rate-pressure product compared with ischemia induced by exercise. These hemodynamic responses to mental stress can be mediated by the adrenal secretion of epinephrine. The pathophysiological mechanisms involved are important in the understanding of the etiology of myocardial ischemia and perhaps in the selection of appropriate anti-ischemic therapy.

The purpose of this investigation was to determine whether measures of socioeconomic status (SES) are inversely associated with obesity in 9- to 10-year-old black and white girls and their parents. Subjects were participants in the Growth and Health Study (NGHS) of the National Heart, Lung, and Blood Institute. Extensive SES, anthropometric, and dietary data were collected at baseline on 2379 NGHS participants. The prevalence of obesity was examined in the NGHS girls and parents in relation to SES and selected environmental factors. Less obesity was observed at higher levels of household income and parental education in white girls but not in black girls. Among the mothers of the NGHS participants who were seen, lower prevalence of obesity was observed with higher levels of income and education for white mothers, but no consistent patterns were seen in black mothers. Univariate logistic models indicated that the prevalence of obesity was significantly and inversely associated with parental income and education and number of parents in the household in white girls whereas caloric intake and TV viewing were significantly and positively associated with obesity. Among black girls, only TV viewing was significantly and positively associated with the prevalence of obesity. Multivariate logistic regression models revealed that lower parental educational attainment, one-parent household, and increased caloric intake were significantly associated with the prevalence of obesity in white girls; for black girls, only increased hours of TV viewing were significant in these models. It is concluded that socioeconomic status, as measured by education and income, was related to the prevalence of obesity in girls, with racial variation in these associations. A lower prevalence of obesity was seen at higher levels of socioeconomic status in white girls, whereas no clear relationship was detected in black girls. These findings raise new questions regarding the correlates of obesity in black girls.

Background There are few data comparing clinical outcome and potential indications for routine post–myocardial infarction cardiac catheterization and revascularization of patients who sustain a non–Q-wave versus Q-wave infarct after thrombolytic therapy. Methods and Results A secondary analysis of 2634 patients enrolled in the TIMI II trial with a first myocardial infarction was performed to determine 6-week and 1-year cardiac event rates and identify clinical and angiographic differences between the 1867 patients (70.9%) who evolved a Q-wave infarct and the 767 patients (29.1%) who sustained a non–Q-wave infarct after treatment with intravenous thrombolytic therapy. Male sex (85.3% versus 75.6%; P P P =.001) had normalization of initial ST-segment elevation. Infarct-related artery patency (TIMI flow grade 2 or 3) ( P =.02), complete infarct-related artery reperfusion (TIMI 3 flow grade) ( P 55% ( P P P =.76), death ( P =.76), and combined death or reinfarction ( P =.43) were similar in patients assigned to the invasive or conservative postlytic management strategy, regardless of infarct type. One-year mortality was 3.4% versus 4.4% for non–Q-wave versus Q-wave infarct type, respectively ( P =.25). Conclusions Angiographic and clinical differences were observed between patients who present with initial ST-segment elevation and evolve early non–Q-wave versus Q-wave myocardial infarcts after treatment with rTPA, heparin, and aspirin. Early mortality and adverse clinical cardiac events in these patients are not significantly different after a conservative compared with an invasive treatment strategy, regardless of whether the infarct type is non–Q wave or Q wave.

BACKGROUND Few thrombolytic studies have assessed whether patient age is an indication for routine postlytic cardiac catheterization and revascularization or evaluated the impact of age on 1-year outcome differences after acute myocardial infarction. METHODS AND RESULTS A secondary analysis of 3339 patients enrolled in the TIMI II trial was performed to identify differences in clinical and coronary angiographic findings and 1-year cardiac event rates among 841 patients < 50 years old, 1639 patients 50 to 64 years old, and 859 patients 65 to 75 years old. Differences in 1-year clinical outcome were assessed among patients randomly assigned to an invasive or a conservative postlytic strategy within each age group. The percentages of patients with a prior history of myocardial infarction, angina, congestive heart failure, hypertension, or diabetes mellitus or an infarction complicated at the time of study entry by shock, pulmonary edema, hypotension, rales more than one third of lung fields, or atrial fibrillation as well as the percentage of female patients (all P < .001) increased with age. Fewer older patients (65 to 75 years) received early (ie, < or = within 2 hours after symptom onset) treatment with recombinant tissue-type plasminogen activator (rTPA), and fewer were eligible for random assignment to immediate or deferred beta-blocker therapy (P = .01). The location of the infarct-related artery and the percentage of patients with patent (ie, TIMI flow grade 2 or 3) or "complete" (ie, TIMI flow grade 3) infarct-related artery flow did not vary with age. The percentage of patients with multivessel disease was greatest in the older patients (P = .001). Cumulative 1-year mortality was low in the youngest patients (2.8%; 99% confidence interval [CI], 1.6% to 4.7%) regardless of whether the infarct location was anterior (3.7%) or nonanterior (1.6%). The highest 1-year mortality occurred in the older patients (13.6%; 99% CI, 10.9% to 16.9%), particularly when the infarct location was anterior (18%). The 42-day rates of reinfarction (P = .85), death (P = .95), or death or reinfarction (P = .99) were similar in patients assigned to the invasive or conservative postlytic treatment strategy, regardless of age group. CONCLUSIONS Among patients with acute myocardial infarction treated with intravenous rTPA, heparin, and aspirin, there were age-related differences in time to treatment with thrombolytic therapy, use of beta-blockers, extent of coronary artery disease, and 1-year cardiac event rates. Routine use of cardiac catheterization and coronary revascularization does not improve immediate or 1-year outcome in terms of mortality or reinfarction compared with a more conservative strategy in young, middle-aged, or elderly patients similar to those enrolled in TIMI II.

Context The administration of nicotine transiently improves many neurobiological and cognitive functions in schizophrenia and schizoaffective disorder. It is not yet clear which nicotinic acetylcholine receptor (nAChR) subtype or subtypes are responsible for these seemingly pervasive nicotinic effects in schizophrenia and schizoaffective disorder. Objective Becauseα4β2 is a key nAChR subtype for nicotinic actions, we investigated the effect of varenicline tartrate, a relatively specificα4β2 partial agonist and antagonist, on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans. Design A double-blind, parallel, randomized, placebo-controlled trial of patients with schizophrenia or schizoaffective disorder to examine the effects of varenicline on biomarkers at 2 weeks (short-term treatment) and 8 weeks (long-term treatment), using a slow titration and moderate dosing strategy for retainingα4β2-specific effects while minimizing adverse effects. Setting Outpatient clinics. Participants A total of 69 smoking and nonsmoking patients; 64 patients completed week 2, and 59 patients completed week 8. Intervention Varenicline. Main Outcome Measures Prepulse inhibition, sensory gating, antisaccade, spatial working memory, eye tracking, processing speed, and sustained attention. Results A moderate dose of varenicline (1) significantly reduced the P50 sensory gating deficit in nonsmokers after long-term treatment (P = .006), (2) reduced startle reactivity (P = .02) regardless of baseline smoking status, and (3) improved executive function by reducing the antisaccadic error rate (P = .03) regardless of smoking status. A moderate dose of varenicline had no significant effect on spatial working memory, predictive and maintenance pursuit measures, processing speed, or sustained attention by Conners' Continuous Performance Test. Clinically, there was no evidence of exacerbation of psychiatric symptoms, psychosis, depression, or suicidality using a gradual titration (1-mg daily dose). Conclusions Moderate-dose treatment with varenicline has a unique treatment profile on core schizophrenia-related biomarkers. Further development is warranted for specific nAChR compounds and dosing and duration strategies to target subgroups of schizophrenic patients with specific biological deficits. Trial Registration clinicaltrials.gov Identifier: NCT00492349

Predischarge supine bicycle ergometry was used to assess persistent myocardial ischemia in postinfarction patients who received thrombolytic therapy and were randomized to an invasive versus conservative strategy in the Thrombolysis in Myocardial Infarction (TIMI) II trial. The frequency of ischemic responses in both strategies, and the 1-year prognostic importance of the different exercise test outcomes were examined. At 14 days, the percentage of patients with any adverse outcome (including death, presence of exercise-induced ST-segment depression, or inability to perform the exercise test) was 33.7% of 1,681 randomly assigned to the invasive strategy compared with 34.6% of 1,658 randomly assigned to the conservative strategy (p = 0.57). The 1-year mortality was greater in patients who did not perform the predischarge exercise test (7.7%) than in those who did (1.8%) (p0.001); the former were older, and a greater proportion were women, had a more frequent history of myocardial infarction, and more extensive coronary artery disease (p0.01 for each comparison). The 1-year mortality in patients with exercise-induced ST-segment depression or chest pain was only 1.4% (3 of 22) among those randomly assigned to the conservative strategy where coronary angiography and revascularization were recommended if the test result was abnormal (relative risk compared with those without ST-segment depression or chest pain 0.6; 99% confidence interval 0.1 to 2.9).(ABSTRACT TRUNCATED AT 250 WORDS)

The increased mortality rate of persons with schizophrenia has been ot" concern for several decades and is known to be 2-3 times higher than the general population. The relative risk of developing cardiovascular disease may be approximately 5 times higher than the general population. This risk may be rising, possibly due to newer medications. While second-generation antipsychotics (SGAs) offer many advantages over conventional antipsychotics, some may have serious long-term health consequences associated with use. All patients with medical or pharmacy assistance treated with clozapine in the State of Maryland (inpatients and outpatients) and N1 patients treated with risperidone as inpatients prior to December 31, 2000 were examined for date and cause of death by the Social Security Death Index and death record acquisition. During this time period 3,095 people with schizophrenia were included of which 152 (~5%) were found to be deceased. The mean age of death was significantly younger in patients who have been treated with clozapine vs. risperidone (59.2 vs. 72.9 years; p

Background Impairments in working memory have been proposed to underlie a broad range of cognitive deficits seen in schizophrenia. Visual working memory impairments are frequently reported in schizophrenia. Investigations of visual working memory generally assume intact visual information processing, despite evidence of visual perceptual impairments in schizophrenia. In this study, we evaluated the integrity of the perceptual system for object and spatial visual information and the relevant working memory system, after adjusting for individual perceptual performance differences. Methods Thirty patients with schizophrenia and 20 healthy control subjects underwent testing using a task of perceptual discrimination of spatial and object visual stimuli. For testing visual working memory, a delay was introduced to the perceptual discrimination task. A thresholding procedure was used so that each subject adequately perceived the information during the working memory test. Results Subjects with schizophrenia exhibited impaired performance relative to controls for object and spatial visual perceptual discrimination. The extent of impairment was greater for the object than for the spatial test. After controlling for perceptual impairments, the subjects with schizophrenia exhibited impaired performance relative to controls for the spatial working memory test but not the object working memory test. Conclusions Findings implicate dysfunction of posterior brain areas that mediate visual perceptual processing and the prefrontal areas involved in the active maintenance of information during delay intervals. However, the systems that govern object and spatial visual perception and working memory appear to be affected differentially by schizophrenia.

Background. Black women are particularly vulnerable to obesity, with a prevalence rate of >50%. The higher mortality and morbidity from cardiovascular disease, stroke, and diabetes have been attributed, in part, to their obesity. In recent years, a particular public health concern is the increasing secular trend in obesity with an even greater racial disparity, especially in girls and women. Between the early 1960s and late 1980s, the prevalence of obesity tripled in young black girls 6 to 11 years of age, while it doubled in white girls. Similarly, both overweight and obesity in adolescent girls 12 to 17 years of age also increased, with a greater increase again seen in adolescent black girls. This secular trend in obesity with a greater increase in black girls signals a potentially grave future chronic disease burden on black women, which is already higher than in white women. The increasing occurrence in children and adolescents of noninsulin-dependent diabetes, traditionally viewed as an adult-onset condition, may be a consequence of the currently high prevalence of obesity in American youth. Not surprisingly, this condition is seen more frequently among black youths. Prepubescent black girls are generally leaner than age-comparable white girls, but by 20 years of age, black women are considerably heavier than are white women. Thus, it is assumed that the racial disparity in adiposity evolves during adolescence. However, the specific age at which this occurs and underlying factors are yet to be identified because of the current paucity of longitudinal cohort data. Objectives. In 1985, the National Heart, Lung, and Blood Institute (NHLBI) initiated a 10-year longitudinal multicenter study (the NHLBI Growth and Health Study [NGHS]) to investigate the development of obesity in black and white girls during adolescence and its environmental, psychosocial, and cardiovascular disease risk factor correlates. The purpose of this report is to examine the natural history of adiposity and weight accretion during adolescence in a biracial cohort of girls to investigate the evolution of the racial divergence in adiposity and to examine the relationships between increases in adiposity and pubertal maturation, energy intake, and physical activity. Participants and Setting. A total of 2379 black (51%) and white (49%) girls, 9 to 10 years of age, were recruited from public and parochial schools in Richmond, California, and Cincinnati, Ohio, and from families enrolled in a large health maintenance organization in the Washington, DC area. Participant eligibility was limited to girls and their parents who declared themselves as being either black or white and who lived in racially concordant households. Design and Statistical Analysis. The NGHS is a multicenter prospective study of black and white girls with annual visits from 9 to 10 years of age through 18 to 19 years of age. The follow-up rate was 89% at the 10th annual visit. Skinfold measurements were obtained at the triceps, suprailiac, and subscapular sites with Holtain calipers. Sexual maturation was assessed by trained registered nurses. The onset of menarche was ascertained annually by questionnaire. All clinical assessments were conducted using a common protocol by centrally trained staff. Longitudinal regression (generalized estimating equations) models were used to examine the relationship between adiposity and race, age, pubertal maturation, daily energy intake, and physical activity. Main Outcome Measures. The main outcome measure was the sum of skinfolds (SSF) at the triceps, subscapular, and suprailiac sites as an index of adiposity for comparison between the 2 racial groups. Body mass index (BMI; weight in kilograms divided by height in meters, squared) distributions were examined by age and race. Results. Racial differences in SSF, unadjusted for maturation, were evident at 10 years of age. For each chronological age, there was a higher proportion of black girls with more advanced pubertal maturation than white girls. The 15th percentiles for SSF were similar and remained thus throughout the study. The median for SSF for black girls, although similar to the median SSF of white girls at 9 years of age, became greater for black girls at 12 years of age (36 mm vs 32.5 mm) and at age 19 years the difference was 6 mm (49.5 mm vs 43.5 mm). In contrast, the difference in the 85th as well as the 95th percentile values for SSF were substantially higher in black girls at all ages (9 mm and 10 mm, or 18% and 15%, respectively, at age 9 years) and these racial differences widened with age (20 mm and 26 mm, or 25% and 24%, respectively, by age 19 years). The racial difference in the median BMI increased from 0.4 to 2.3 kg/m2 between ages 9 and 19 years. Unlike SSF at the 15th percentile, the BMI for lean 9-year-old black girls was ∼3% higher than whites. As with SSF, for heavier girls, BMI at the 85th percentile even at age 9 years was 11% greater in black girls and became 23% greater by age 19 years. Differences in BMI at the 95th percentile also increased from 3.6 to 8.1 kg/m2 between ages 10 and 18 years. After adjusting for stages of maturation in multivariate longitudinal regression models, adiposity for black girls became significantly greater at age 12 years compared with white girls. The largest gain in adiposity for both groups was seen at the time of pubescence, an approximate increase of 8.0 mm in SSF for white girls and 10.8 mm for black girls. The next milestone for a gain in adiposity occurred around menarche with an increase in SSF of 5.0 mm for white girls and 3.4 mm for black girls. Additionally, there was a significantly greater accrual of adiposity with earlier achievement of menarche, ie, a gain of 3.7 mm for white girls and 3.0 mm for black girls for each year. Although the effect of puberty on the gain in adiposity was similar for both races, for each chronological age, there was a greater accrual of adiposity in black girls because they matured earlier than white girls. Energy intake was significantly and inversely associated with increasing adiposity but not with levels of physical activity. Conclusion. The time of the largest accrual of body fat occurred around the 2 major pubertal milestones, the onsets of puberty and menarche. Even after adjusting for pubertal maturation, after age 12 years, black girls were significantly fatter than were white girls. Earlier menarche conferred an additional risk for greater gain in adiposity for both racial groups. Primary prevention of obesity, therefore, should commence with fostering the maintenance of normal growth in young girls before the initiation of pubertal maturation because increased adiposity is associated with earlier menarche. Next, and more importantly, pediatricians should be particularly vigilant with growth monitoring during the critical milestones of pubertal development, a vulnerable time for a large accrual of adiposity. Greater emphasis needs to be placed on preventive efforts in black girls to minimize their risk for developing obesity during adolescence.

Objective. —To assess the efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol to decrease low-density lipoprotein cholesterol (LDL-C) levels in children. Design. —Six-center randomized controlled clinical trial. Participants. —Prepubertal boys (n=362) and girls (n=301) aged 8 to 10 years with LDL-C levels greater than or equal to the 80th and less than the 98th percentiles for age and sex were randomized into an intervention group (n=334) and a usual care group (n=329). Intervention. —Behavioral intervention to promote adherence to a diet providing 28% of energy from total fat, less than 8% from saturated fat, up to 9% from polyunsaturated fat, and less than 75 mg/4200 kJ (1000 kcal) per day of cholesterol (not to exceed 150 mg/d). Main Outcome Measures. —The primary efficacy measure was the mean LDL-C level at 3 years. Primary safety measures were mean height and serum ferritin levels at 3 years. Secondary efficacy outcomes were mean LDL-C levels at 1 year and mean total cholesterol levels at 1 and 3 years. Secondary safety outcomes included red blood cell folate values; serum zinc, retinol, and albumin levels; serum high-density lipoprotein cholesterol (HDL-C) values, LDL-C:HDL-C ratio, and total triglyceride levels; sexual maturation; and psychosocial health. Results. —At 3 years, dietary total fat, saturated fat, and cholesterol levels decreased significantly in the intervention group compared with the usual care group (allP .05) or other safety outcomes. Conclusions. —The dietary intervention achieved modest lowering of LDL-C levels over 3 years while maintaining adequate growth, iron stores, nutritional adequacy, and psychological well-being during the critical growth period of adolescence. (JAMA. 1995;273:1429-1435)