Biomedical subjects

S B Manuck

Publications and source records attributed to S B Manuck.

At least 19 recordsLinked to original sources

PubMed2005

A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity.

Recent studies have indicated that a newly identified second isoform of the tryptophan hydroxylase gene (TPH2) is preferentially involved in the rate-limiting synthesis of neuronal serotonin. Genetic variation in the human TPH2 gene (hTPH2) has been associated with altered in vitro enzyme activity as well as increased risk for mood disorders. Here, we provide the first in vivo evidence that a relatively frequent regulatory variant (G(-844)T) of hTPH2 biases the reactivity of the amygdala, a neural structure critical in the generation and regulation of emotional behaviors.

Amygdala↗

PubMed2003

Influence of estradiol on cortisol secretion in ovariectomized cynomolgus macaques (Macaca fascicularis).

In an investigation of cortisol secretion in fully mature, ovariectomized cynomolgus monkeys (Macaca fascicularis), we compared monkeys that were given either placebo (OVX, n = 26) or 17beta estradiol (E(2 )) (EST, n = 26) in a daily oral dose. Serum cortisol concentrations were measured prior to the experimental manipulation and 3, 6, 9, and 12 months following initiation of treatment. Pretreatment cortisol values did not differ between groups. Assessment of the treatment period values revealed that cortisol concentrations were significantly higher ( approximately 10%) in the EST than in the OVX monkeys. Cortisol also varied significantly across periods of sampling. This time-dependent variation was attributable to elevations in months 6 and 9 (when daylight was generally long), relative to months 3 and 12 (when daylight was relatively short). The modest stimulatory effect of estrogen on corticosteroid production observed in this study is consistent with what has been seen in women, and contrasts with the more robust effects observed in New World monkeys. The possible relationship between season and cortisol secretion observed here has not been previously described in monkeys.

Animals↗

PubMed2002

Premenopausal social status and hormone exposure predict postmenopausal atherosclerosis in female monkeys.

OBJECTIVE: To determine whether premenopausal social subordination in female monkeys predicts postmenopausal atherosclerosis, and whether any such effect is altered by chronic exposure to contraceptive steroids or postmenopausal hormone replacement. METHODS: One hundred seventy-seven (177) premenopausal cynomolgus monkeys (Macaca fascicularis) housed in social groups of five or six were fed an atherogenic diet that, for half of the animals, also contained an oral contraceptive (OC). Individuals were judged socially dominant or subordinate based on behavioral observations. After 26 months animals were oophorectomized, biopsied for iliac atherosclerosis, and for the next 36 months were fed one of three atherogenic diets containing soy protein: 1) phytoestrogen-free; 2) phytoestrogens intact; and 3) phytoestrogen-free plus conjugated equine estrogens. Plasma lipids and menstrual cyclicity were also assessed. Finally, all animals were necropsied and the extent of atherosclerosis measured in the coronary and iliac arteries. RESULTS: The interaction of premenopausal social status and OC exposure predicted postmenopausal coronary artery atherosclerosis (P =.02). Subordinate animals not receiving OCs developed twice the coronary atherosclerosis of similarly untreated dominants (P <.01), an outcome mitigated by premenopausal OC exposure (P <.01). These effects occurred across postmenopausal treatment groups and independent of variation in plasma lipids. The same associations were observed in the iliac arteries, and, to a similar extent, both pre- and post-menopausally. Hormone data suggest that untreated premenopausal subordinates may have been estrogen deficient. CONCLUSION: Premenopausal social subordination exacerbates postmenopausal atherosclerosis, an effect possibly mediated by estrogen deficiency and shown here to be prevented by premenopausal OC exposure. These results occur irrespective of postmenopausal treatment.

Animals↗

PubMed2001

Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials.

OBJECTIVE: To investigate the association between cholesterol lowering interventions and risk of death from suicide, accident, or trauma (non-illness mortality). DESIGN: Meta-analysis of the non-illness mortality outcomes of large, randomised clinical trials of cholesterol lowering treatments. STUDIES REVIEWED: 19 out of 21 eligible trials that had data available on non-illness mortality. INTERVENTIONS REVIEWED: Dietary modification, drug treatment, or partial ileal bypass surgery for 1-10 years. MAIN OUTCOME MEASURE: Deaths from suicides, accidents, and violence in treatment groups compared with control groups. RESULTS: Across all trials, the odds ratio of non-illness mortality in the treated groups, relative to control groups, was 1.18 (95% confidence interval 0.91 to 1.52; P=0.20). The odds ratios were 1.28 (0.94 to 1.74; P=0.12) for primary prevention trials and 1.00 (0.65 to 1.55; P=0.98) for secondary prevention trials. Randomised clinical trials using statins did not show a treatment related rise in non-illness mortality (0.84, 0.50 to 1.41; P=0.50), whereas a trend toward increased deaths from suicide and violence was observed in trials of dietary interventions and non-statin drugs (1.32, 0.98 to 1.77; P=0.06). No relation was found between the magnitude of cholesterol reduction and non-illness mortality (P=0.23). CONCLUSION: Currently available evidence does not indicate that non-illness mortality is increased significantly by cholesterol lowering treatments. A modest increase may occur with dietary interventions and non-statin drugs.

Accidents↗

PubMed2001

The nature of the association between diet and serum lipids in the community: a twin study.

Diet is commonly thought to be an environmental influence on serum lipid concentrations. This study evaluated whether total caloric and fat intake predict total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TRIG) concentrations for environmental, as compared with genetic, reasons among 137 monozygotic and 67 dizygotic young adult twins. When genetic influences were controlled by correlating differences between monozygotic co-twins, a significant association remained between diet and TC, LDL, and HDL, suggesting that these dietary and serum lipid measures correlate for environmental reasons. Twin structural equation modeling confirmed these results. Overall, these results provide additional support for the hypothesis that diet is an environmental influence on TC, LDL, and HDL.

Adolescent↗

PubMed2001

Associations between stress, trait negative affect, acute immune reactivity, and antibody response to hepatitis B injection in healthy young adults.

Eighty-four healthy graduate participants were administered the standard course of 3 hepatitis B vaccinations. Five months after the first dose (shortly after the second injection), each participant completed psychosocial measures, and a blood sample was drawn for determination of hepatitis B surface antibody titer. After completion of the vaccination series, participants performed an acute stress protocol, consisting of a 30-min adaptation period and a 5-min evaluative speech task. Blood was drawn at the end of the resting and task periods for assessment of cellular immune measures. Lower antibody response, as assessed after the second hepatitis B injection, was predicted independently by (a) high trait negative affect and (b) diminished T-cell proliferation in response to PHA. These data provide evidence that trait negative affect and the magnitude of stress-induced suppression of immune function may have clinical significance.

Adult↗

PubMed2000

Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults.

The apolipoprotein E genotype (APOE) is an established risk factor for Alzheimer disease, with the age-at-onset occurring earlier in individuals having at least one APOE epsilon 4 allele, relative to the APOE epsilon 3 or APOE epsilon 2 isoforms. Moreover, nondemented older adults with the APOE epsilon 4 allele also show diminished cognitive performance, particularly on tests of learning and memory, and an accelerated decline in memory performance with increasing age. The current investigation extends the study of the APOE epsilon 4 allele and cognitive performance to healthy, middle-aged adults. A community sample of 220 non-Hispanic Caucasian men and women, aged 24-60 (average age = 46), were genotyped for the APOE polymorphism and completed a battery of neuropsychological tests. Multivariate analyses were conducted on measures of verbal learning and memory (e. g., learning a list of words and recalling them 30 min later), visual memory (e.g., reproducing a previously copied figure from memory), and attention span (e.g., repeating long lists of digits), after adjustments for age, and estimated IQ. Results indicated that performance on learning and memory tasks was significantly poorer in adults having any APOE epsilon 4 allele, relative to adults with APOE epsilon 2 and epsilon 3 genotypes (P <.01). Attention span did not differ by genotype. These findings, the first in a sample of middle-aged adults, suggest that the APOE polymorphism is a marker for age-related decline in memory (detectable prior to overt, clinical manifestations of memory loss), and/or a marker for individual differences in memory ability across the life span. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:707-711, 2000.

Adult↗

PubMed2000

Anticipatory blood pressure responses to exercise are associated with left ventricular mass in Finnish men: Kuopio Ischemic Heart Disease Risk Factor Study.

BACKGROUND: Exaggerated cardiovascular reactivity to psychological demands may contribute to the development of left ventricular (LV) hypertrophy. We examined the cross-sectional association between anticipatory blood pressure (BP) responses to bicycle exercise and LV mass in the Kuopio Ischemic Heart Disease Risk Factor Study, a population-based epidemiological sample. METHODS AND RESULTS: Among 876 men from 4 age cohorts (ages 42, 48, 58, and 64 years), we collected echocardiographic assessments of LV mass along with measures of BP response taken before bicycle ergometry testing. Anticipatory BP responses were positively associated with LV mass, with significant associations only among younger (age <50 years) subjects with elevated resting pressures (3-way interactions for anticipatory BP x age x resting pressure for systolic and diastolic BP, all P:<0.05; for younger subjects with elevated systolic BP, P:<0. 01; and for younger subjects with elevated diastolic BP, P:<0.001). Among these subgroups, exaggerated anticipatory BP responses (top quartile) were associated with an incremental increase in LV mass of 10% or greater, corrected for body surface area. Results remained significant after adjusting for age, education, salt consumption, and resting BP, and the pattern of findings was maintained among men with no previous history of cardiovascular disease. CONCLUSIONS: The tendency to show exaggerated pressor responses to psychological demands may be a significant independent correlate of LV mass, especially among young men with high resting pressures. This is the first study to examine such associations in a middle-aged population sample.

Adult↗

PubMed2000

A regulatory polymorphism of the monoamine oxidase-A gene may be associated with variability in aggression, impulsivity, and central nervous system serotonergic responsivity.

This study presents preliminary evidence of an association between polymorphic variation in the gene for monoamine oxidase-A (MAOA) and interindividual variability in aggressiveness, impulsivity and central nervous system (CNS) serotonergic responsivity. An apparently functional 30-bp VNTR in the promoter region of the X-chromosomal MAOA gene (MAOA-uVNTR), as well as a dinucleotide repeat in intron 2 (MAOA-CAn), was genotyped in a community sample of 110 men. All participants had completed standard interview and questionnaire measures of impulsivity, hostility and lifetime aggression history; in a majority of subjects (n=75), central serotonergic activity was also assessed by neuropsychopharmacologic challenge (prolactin response to fenfluramine hydrochloride). The four repeat variants of the MAOA-uVNTR polymorphism were grouped for analysis (alleles '1+ 4' vs. '2+3') based on prior evidence of enhanced transcriptional activity in MAOA promoter constructs with alleles 2 and 3 (repeats of intermediate length). Men in the 1/4 allele group scored significantly lower on a composite measure of dispositional aggressiveness and impulsivity (P<0.015) and showed more pronounced CNS serotonergic responsivity (P<0.02) than men in the 2/3 allele group. These associations were also significant on comparison of the more prevalent one and three alleles alone (encompassing 93% of subjects). Although in linkage disequilibrium with the MAOA-uVNTR polymorphism, MAOA-CAn repeat length variation did not vary significantly with respect to behavior or fenflluramine challenge in this sample. We conclude that the MAOA-uVNTR regulatory polymorphism may contribute, in part, to individual differences in both CNS serotonergic responsivity and personality traits germane to impulse control and antagonistic behavior.

Adult↗

PubMed2000

White-coat hypertension and carotid artery atherosclerosis: a matching study.

BACKGROUND: Blood pressure (BP) measurements obtained in the clinic have long served as the basis for determining risk of hypertensive vascular disease, yet many patients with high BP in the physician's office are normotensive elsewhere. It remains unclear whether such patients with "white coat" hypertension elude the risk of atherosclerosis. METHODS: Community residents 40 to 70 years of age and not receiving any cardiovascular medications were recruited to participate in a study of cardiovascular risk factors. On the basis of clinic and daytime ambulatory BP and a threshold criterion of 140/90 mm Hg, subjects were classified as having persistent hypertension, white-coat hypertension, or persistent normotension. One-to-one matching was conducted in male participants on the basis of race and BP. Subjects with persistent hypertension and white-coat hypertension were matched on clinic BP, and those with white-coat hypertension and normotension were matched on daytime ambulatory BP. RESULTS: The 3 matched groups of men (n=40 in each group) were similar in age, smoking status, and fasting glucose and lipid levels. Compared with the normotensive subjects, subjects with either persistent or white-coat hypertension had greater mean body mass index, waist-hip ratio, and fasting insulin concentration. On the basis of standardized duplex ultrasound examination of the carotid arteries, mean maximal intimal-medial thickness and plaque index in subjects with white-coat hypertension were greater than among normotensive subjects and equal to that of the subjects with persistent hypertension. CONCLUSION: When compared with unmedicated individuals with comparable elevations in clinic BP, individuals with white-coat hypertension appear not to be protected from the atherosclerotic sequelae of hypertension.

Adult↗

PubMed2000

The stability of and intercorrelations among cardiovascular, immune, endocrine, and psychological reactivity.

One hundred fifteen college students were exposed to an evaluative speech task twice, separated by 2 weeks. At both sessions, we assessed cardiovascular, endocrine, immune, and psychological response at baseline and during the task. We found stability across sessions for stress-induced increases in anxiety and task engagement, heart rate, blood pressure, norepinephrine (but not epinephrine), cortisol, natural killer cell cytotoxicity, and numbers of circulating CD3+, CD8+, and CD56+ (but not CD4+ or CD19+) lymphocytes. The stable cardiovascular, immune, and endocrine reactivities were intercorrelated, providing evidence of a unified physiological stress response across these outcomes. Although stable stress-induced increases in task engagement were associated with the physiological stress responses, stress-induced anxiety was not.

Adolescent↗

PubMed2000

Effects of lovastatin on cognitive function and psychological well-being.

PURPOSE: Animal research and cross-sectional studies suggest that serum lipid concentrations may influence cognitive function, mood, and behavior, but few clinical trials have studied these effects. SUBJECTS AND METHODS: In this double-blind investigation, 209 generally healthy adults with a serum low-density-lipoprotein (LDL) cholesterol level of 160 mg/dL or higher were randomly assigned to 6-month treatment with lovastatin (20 mg) or placebo. Assessments of neuropsychological performance, depression, hostility, and quality of life were conducted at baseline and at the end of the treatment period. Summary effect sizes were estimated as z scores on a standard deviation (SD) scale. RESULTS: Placebo-treated subjects improved between baseline and posttreatment periods on neuropsychological tests in all five performance domains, consistent with the effects of practice on test performance (all P <0.04), whereas those treated with lovastatin improved only on tests of memory recall (P = 0.03). Comparisons of the changes in performance between placebo- and lovastatin-treated subjects revealed small, but statistically significant, differences for tests of attention (z score = 0.18; 95% confidence interval (CI), 0.06 to 0.31; P = 0.005) and psychomotor speed (z score = 0.17; 95% CI, 0.05 to 0.28; P = 0. 004) that were consistent with greater improvement in the placebo group. Psychological well-being, as measured several ways, was not affected by lovastatin. CONCLUSION: Treatment of hypercholesterolemia with lovastatin did not cause psychological distress or substantially alter cognitive function. Treatment did result in small performance decrements on neuropsychological tests of attention and psychomotor speed, the clinical importance of which is uncertain.

Adult↗

PubMed2000

Behaviorally-evoked plasma catecholamine response and 24-hour excretion of urinary catecholamines among cardiac and vascular reactors.

Individuals differ in the cardiac and vascular processes that underlie blood pressure elevations evoked by environmental stimuli; such differences may reflect variability in sympathoadrenal response. We separated 108 healthy, young-adult males into those with predominant elevations in either cardiac output or peripheral resistance when exposed to psychological challenges. We then asked if they differed on other measures of cardiovascular response, concomitant plasma catecholamine reactions or 24-h urinary excretion of catecholamines. Cardiac reactors, relative to vascular reactors, showed reduced cardiac pre-ejection period, a smaller reduction in stroke volume, and elevated plasma epinephrine response and 24-h urinary epinephrine excretion. Vascular reactors, relative to cardiac reactors, responded to mental stress with more elevated diastolic blood pressure, a rise in peripheral resistance and pulse wave velocity, and a greater reduction in stroke volume. Vascular reactors, however, did not show plasma norepinephrine response or 24-h urinary norepinephrine excretion that was greater than cardiac reactors. The results provide partial support for the hypothesis that variability in sympathoadrenal activity contributes to individual differences in cardiac and vascular reactivity, and extend prior observations by demonstrating covariation of behaviorally-elicited cardiac reactivity with the 24-h excretion of epinephrine.

Adolescent↗

PubMed2000

Enhancing the laboratory-to-life generalizability of cardiovascular reactivity using multiple occasions of measurement.

Studies examining the association between laboratory measures of stress-related cardiovascular (CV) reactivity and responses to psychological challenges in the natural environment have yielded mixed results. Frequently, single laboratory tasks have been used to predict responses to natural stressors on a single occasion of measurement. Because aggregation broadens the range of stimuli sampled and reduces measurement error, laboratory-to-life generalizability should be more easily detected when multiple predictor and criterion observations are used. Sixty students in a public speaking course were administered multitask assessments of CV reactivity during two laboratory sessions and during two in-class public speech assignments. CV responses to the classroom speeches were greater among those who showed larger responses in the laboratory, and these associations became stronger as measures were aggregated across multiple samples of behavior. These results support the generalizability of CV reactivity as a measure of individual difference, and they help to shed light on previous inconsistent findings in this area.

Adolescent↗

PubMed1999

Aggression and anger-related traits associated with a polymorphism of the tryptophan hydroxylase gene.

BACKGROUND: Central nervous system (CNS) serotonergic activity correlates inversely with human aggressive behavior, and individual differences in aggressive disposition are at least partially heritable. This study was conducted to evaluate the possible association between measures of antagonistic behavior and an intronic polymorphism of the gene coding for tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis. METHODS: Locally recruited men and women (n = 251) were genotyped for the A218C polymorphism located in intron 7 of the TPH gene. All subjects were administered standard interview and questionnaire indices of aggression and anger-related traits of personality; in a portion of subjects, CNS serotonergic activity was assessed by neuropsychopharmacologic challenge (prolactin response to fenfluramine hydrochloride). RESULTS: Persons having any TPH U allele scored significantly higher on measures of aggression and tendency to experience unprovoked anger and were more likely to report expressing their anger outwardly than individuals homozygous for the alternate L allele. In men, but not women, peak prolactin response to fenfluramine was also attenuated among subjects having any U allele, relative to LL homozygotes. CONCLUSIONS: Individual differences in aggressive disposition are associated with an intronic polymorphism of the TPH gene in a nonpatient sample of community-derived volunteers.

Aggression↗

PubMed1999

Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism.

A deletion/insertion polymorphism in the transcriptional control region of the serotonin transporter gene (5-HTTLPR) was reported to be associated with dimensional measures of neuroticism, although subsequent replication attempts have failed. These replication attempts, however, have been dissimilar to the initial study in sample size, distribution of allelic frequency and/or assessment of neuroticism. The current study was conducted in a further attempt to replicate the initial finding using: (a) a sample that was more comparable to each of the individual samples in the initial report; and (b) identical psychometric methodology to assess neuroticism. Two hundred and twenty-five Caucasian adults were genotyped for the 5-HTTLPR polymorphism and completed the NEO Personality Inventory. Results did not replicate the association between the 5-HTTLPR polymorphism and neuroticism; individuals with the short form of this variant did not report higher NEO Neuroticism. Indeed, men with the short form reported lower Anxiety, a finding that is directionally opposite to the initial results. These findings, combined with other failures to replicate, indicate that the reproducibility of the association between the 5-HTTLPR polymorphism and neuroticism must be regarded as questionable. The contradictory findings suggest the need for a replication attempt in a large, normative sample that is stratified by ethnicity and sex.

Adult↗

PubMed1999

Genetic and environmental causes of covariation among blood pressure, body mass and serum lipids during young adulthood: a twin study.

OBJECTIVE: To determine the extent to which the correlation of systolic blood pressure, diastolic blood pressure, body mass, fasting total cholesterol and fasting triglycerides in young adulthood reflects common genetic or environmental influences. DESIGN: Cardiovascular risk factors were measured in a community sample of 129 monozygotic and 67 dizygotic twin pairs, ages 18-30 years. METHODS: Multivariate twin structural equation modelling allows estimation of the extent to which the covariation of two or more variables is attributable to common genetic and environmental factors and was used to analyse the correlation among systolic blood pressure, diastolic blood pressure, body mass index, fasting total cholesterol and triglycerides. RESULTS: The covariation of risk factors was partially attributable to a single common genetic factor, while the covariation of systolic blood pressure, body mass index and triglycerides was also, in part, attributable to a common non-shared environmental factor. CONCLUSIONS: Genetic and, to a lesser extent, non-shared environmental factors contribute to the covariation of cardiovascular risk factors in young adult twins. Nonetheless, it should be noted that these common influences account for a relatively small percentage of the variance in each risk factor compared to genetic and environmental factors that are risk factor-specific.

Adolescent↗

PubMed1999

Status, stress, and atherosclerosis: the role of environment and individual behavior.

Atherosclerosis induced by moderate hyperlipoproteinemia in group-housed cynomolgus monkeys differs significantly between animals of dominant and subordinate social status. The nature of this association also varies by sex, and in males, by stability of the social environment. Dominant males develop more extensive atherosclerosis than subordinates when housed in unstable, but not stable, social groups; in contrast, subordinate females develop greater atherosclerosis than dominants, and do so irrespective of the conditions of social housing. Experimental investigations reveal that the first of these associations (males) is mediated by concomitant sympathoadrenal activation and the second (females) by ovarian impairment associated with the stress of social subordination. We believe our findings offer clues to the neuroendocrine mediation of behavioral influences on coronary artery disease in humans. This is particularly true where these influences reflect asymmetries in the power or status relationships among individuals within similar social environments, or when dimensions of temperament or disposition give rise to such relationships. We propose that these data also may be informative regarding the pathophysiological sequelae of social stratification (in which disease incidence varies by class membership within populations), but only where social environments engendered by class inequalities exacerbate status-dependent behavioral differences among individuals within communities of associates.

Animals↗