Biomedical subjects

D D Savage

Publications and source records attributed to D D Savage.

At least 19 recordsLinked to original sources

PubMed1992

Evidence of altered T-lymphocyte number and proliferative responses in genetically epilepsy-prone rats.

Genetically epilepsy-prone (GEPR-9) rats exhibit decreased antibody plaque-forming cell responses following immunization. We examined the hypothesis that this immunosuppression was due to deficits in the number or proliferative responses of T-lymphocytes. Splenocyte responses to concanavalin A and pokeweed mitogen were significantly greater in GEPR-9 rats than controls. Flow cytometric analysis indicated that GEPR-9 rats possess an increase in T-cells associated with the T-helper phenotype. The increased proportion of T-helper cells in GEPR-9 rats may underlie their enhanced proliferative responses to T-cell mitogens. These results clearly indicate that the failure of the GEPR-9 rat to respond to a T-dependent antigen in vivo is not due to a lack of T-helper activity.

Animals↗

PubMed1992

Effects of prenatal ethanol exposure on hippocampal ionotropic-quisqualate and kainate receptors.

Previous studies from our laboratories have shown that the consumption of moderate quantities of ethanol by rat dams during pregnancy reduces N-methyl-D-aspartate (NMDA) agonist receptor binding and NMDA-mediated electrophysiological responses in the hippocampal formation of adult offspring. We hypothesized that prenatal ethanol exposure would produce similar effects on receptor number and agonist-mediated responses of two so-called "non-NMDA" subtypes of glutamate receptors, the ionotropic-quisqualate (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-sensitive and the kainate-sensitive receptors. Sprague-Dawley rats were fed either a liquid diet containing 3.35% ethanol, an isocalorically matched liquid diet, or lab chow ad libitum throughout gestation. No significant differences between offspring from these three groups in the agonist concentration-response curves for either AMPA-induced or kainate-induced depolarization of hippocampal CA1 pyramidal neurons were observed. Furthermore, no significant differences in the density of [3H]-AMPA or [3H]-vinylidene kainic acid binding sites in any of the apical dendritic field regions of dorsal or ventral hippocampal formation were observed between the groups. These results indicate that the ionotropic quisqualate and kainate receptors, located in the apical dendritic field regions of the principal hippocampal neurons, are not affected by the same degree of prenatal ethanol exposure, which is known to reduce NMDA receptor binding and function in these same regions.

Animals↗

PubMed1992

Perinatal hypothyroidism decreases hippocampal mossy fiber zinc density in rats.

The effect of perinatal hypothyroidism on hippocampal mossy fiber zinc density was examined in rats. Timed pregnant Sprague-Dawley rat dams were given water containing either 0.02% propylthiouracil (PTU) or vehicle from gestational day 18 until their litters were weaned on postnatal day 31. Hippocampal mossy fiber zinc density was reduced by 75% in both the dorsal and ventral hippocampal formation CA3 stratum lucidum region of 31-day-old PTU-treated rats compared to untreated controls. Perinatal hypothyroidism did not alter hippocampal tissue zinc concentration, indicating that the PTU-induced reduction in mossy fiber zinc was not a consequence of reduced hippocampal zinc concentration. At 120 days of age, 3 months after discontinuation of PTU treatment, hippocampal mossy fiber zinc density remained significantly reduced by 33-45% in PTU-treated rats compared to control. These data indicate that perinatal hypothyroidism causes a long-lasting reduction in hippocampal mossy fiber zinc density.

Animals↗

PubMed1991

Hippocampal mossy fiber zinc deficit in mice genetically selected for ethanol withdrawal seizure susceptibility.

Hippocampal mossy fiber zinc was examined in mice selectively bred for differences in susceptibility to handling-induced convulsions during ethanol withdrawal. The density of mossy fiber zinc in the CA3 stratum lucidum was significantly decreased in the duplicate lines of untreated withdrawal seizure prone (WSP) mice compared to untreated withdrawal seizure resistant (WSR) mice. Mossy fiber zinc densities in randomly bred control lines of mice (WSC) were intermediate to WSP and WSR mice. Serum, whole brain and whole hippocampal zinc were not significantly different between WSP and WSR mice, indicating that the reduction in the chelatable pool of hippocampal mossy fiber zinc was not a consequence of deficits in brain or whole body zinc nutrition. A highly significant correlation between hippocampal mossy fiber zinc density and handling-induced convulsion indices suggests that a reduction in mossy fiber zinc may be one contributing factor in the expression of seizure susceptibility in WSP mice.

Animals↗

PubMed1991

Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension.

OBJECTIVE: To assess the prognostic significance of left ventricular mass and geometry in initially healthy persons with essential hypertension. DESIGN: An observational study of a prospectively identified cohort. SETTING: University medical center. PATIENTS: Two hundred and eighty patients with essential hypertension and no pre-existing cardiac disease were evaluated using echocardiography between 1976 and 1981. Two hundred and fifty-three subjects or their family members (90%) were contacted for a follow-up interview an average of 10.2 years after the initial echocardiogram was obtained; the survival status of 27 patients lost to follow-up was ascertained using National Death Index data. MEASUREMENTS AND MAIN RESULTS: Left ventricular mass exceeded 125 g/m2 in 69 of 253 patients (27%). Cardiovascular events occurred in a higher proportion of patients with than without left ventricular hypertrophy (26% compared with 12%; P = 0.006). Patients with increased ventricular mass were also at higher risk for cardiovascular death (14% compared with 0.5%; P less than 0.001) and all-cause mortality (16% compared with 2%; P = 0.001). Electrocardiographic left ventricular hypertrophy did not predict risk. Patients with normal left ventricular geometry had the fewest adverse outcomes (no cardiac deaths; morbid events in 11%), and those with concentric hypertrophy had the most (death in 21%; morbid events in 31%). In a multivariate analysis, only age and left ventricular mass--but not gender, blood pressure, or serum cholesterol level--independently predicted all three outcome measures. CONCLUSIONS: Echocardiographically determined left ventricular mass and geometry stratify risk in patients with essential hypertension independently of and more strongly than blood pressure or other potentially reversible risk factors and may help to stratify the need for intensive treatment.

Adult↗

PubMed1991

Evidence of immunosuppression in the genetically epilepsy-prone rat.

Immune system function was examined in the genetically epilepsy prone (GEPR-9) rat and non-epileptic Sprague-Dawley control rats. Significant decreases in direct and indirect plaque-forming cell responses were observed in GEPR-9 rats immunized with sheep erythrocytes. Serum levels of IgM were also decreased in non-immunized GEPR-9 rats, providing additional evidence of immunosuppression. However, total serum levels of IgG were three-fold greater in GEPR-9 rats compared to control. These results suggest that the nature of the immune system deficit in the GEPR-9 is complex and may involve an active T-cell population stimulating an overproduction of IgG leading to a diminished capacity to respond to new antigen challenges. This immunological defect may underlie the enhanced susceptibility of GEPR-9 rats to infectious agents. The specific cause of this immune dysfunction is not known. Possible etiological factors include a breakdown in the communication between cells within the immune system or an alteration of neuroendocrine modulation of immune responses.

Animals↗

PubMed1991

Hypertensive heart disease in African-Americans.

Hypertensive heart disease is a frequent complication in hypertensive African-Americans because of inadequate high blood pressure control. Moreover, African-Americans may be predisposed to develop LVH earlier in life and more readily than Caucasians, and it may be more malignant. The appearance of both LVH and congestive heart failure are ominous developments in individual patients, and early detection of LVH is mandatory for adequate management and reversal of this complication, if possible. Additional research is needed, and new, sensitive tools for detecting LVH will accelerate such studies. Further investigations are also needed on the reversibility of LVH, preferred antihypertensive agents for accomplishing reversal, and whether expected benefits result.

Black People↗

PubMed1990

Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study.

A pattern of left ventricular hypertrophy evident on the electrocardiogram is a harbinger of morbidity and mortality from cardiovascular disease. Echocardiography permits the noninvasive determination of left ventricular mass and the examination of its role as a precursor of morbidity and mortality. We examined the relation of left ventricular mass to the incidence of cardiovascular disease, mortality from cardiovascular disease, and mortality from all causes in 3220 subjects enrolled in the Framingham Heart Study who were 40 years of age or older and free of clinically apparent cardiovascular disease, in whom left ventricular mass was determined echocardiographically. During a four-year follow-up period, there were 208 incident cardiovascular events, 37 deaths from cardiovascular disease, and 124 deaths from all causes. Left ventricular mass, determined echocardiographically, was associated with all outcome events. This relation persisted after we adjusted for age, diastolic blood pressure, pulse pressure, treatment for hypertension, cigarette smoking, diabetes, obesity, the ratio of total cholesterol to high-density lipoprotein cholesterol, and electrocardiographic evidence of left ventricular hypertrophy. In men, the risk factor-adjusted relative risk of cardiovascular disease was 1.49 for each increment of 50 g per meter in left ventricular mass corrected for the subject's height (95 percent confidence interval, 1.20 to 1.85); in women, it was 1.57 (95 percent confidence interval, 1.20 to 2.04). Left ventricular mass (corrected for height) was also associated with the incidence of death from cardiovascular disease (relative risk, 1.73 [95 percent confidence interval, 1.19 to 2.52] in men and 2.12 [95 percent confidence interval, 1.28 to 3.49] in women). Left ventricular mass (corrected for height) was associated with death from all causes (relative risk, 1.49 [95 percent confidence interval, 1.14 to 1.94] in men and 2.01 [95 percent confidence interval, 1.44 to 2.81] in women). We conclude that the estimation of left ventricular mass by echocardiography offers prognostic information beyond that provided by the evaluation of traditional cardiovascular risk factors. An increase in left ventricular mass predicts a higher incidence of clinical events, including death, attributable to cardiovascular disease.

Blood Pressure↗

PubMed1990

Association of echocardiographic left ventricular mass with body size, blood pressure and physical activity (the Framingham Study).

Left ventricular (LV) hypertrophy has been found to predispose to increased cardiovascular morbidity and mortality. To assess the clinical correlates and potential determinants of LV mass, the relation of echocardiographically determined LV mass to a variety of clinical parameters was examined in a general population. From 1979 to 1983 Framingham Heart Study participants underwent routine evaluation including medical history, physical examination and M-mode echocardiography. LV mass was determined using an anatomically validated formula that incorporates measurements of LV wall thickness and LV internal diameter. The study population consisted of 2,226 men and 2,746 women (mean age 51 years, range 17 to 90). Age, height, systolic blood pressure and body mass index (a measure of obesity) were statistically significant and independent correlates of LV mass in both sexes (p less than 0.001). In men under age 50, leisure-time physical activity was associated with LV mass (p less than 0.05), but this was not observed in women. Results from multivariate analyses in which body mass index and subscapular skinfold thickness were included suggest that lean body mass is correlated with LV mass. Maintenance of ideal body weight and normal blood pressure, weight reduction in obese persons and blood pressure control in hypertensive patients may contribute to the primary and secondary prevention of LV hypertrophy and its sequelae. Clinical interpretation of echocardiograms should include consideration of the correlates of LV mass to gain better insight into the pathogenesis of LV hypertrophy.

Age Factors↗

PubMed1990

Decrease in hippocampal [3H]vinylidene kainic acid binding in genetically epilepsy-prone rats.

Specific [3H]vinylidene kainic acid binding to the kainate-sensitive subtype of glutamate receptor was studied in brain of 31-day-old non-epileptic Sprague-Dawley control and two colonies of genetically epilepsy-prone rats using in vitro autoradiographic techniques. At 37.5 nM [3H]vinylidene kainic acid, specific [3H]vinylidene kainic acid binding was reduced significantly by 18 and 22% in dorsal and ventral hippocampal formation stratum lucidum of 31-day-old genetically epilepsy-prone-9 rats compared with non-epileptic controls. Hippocampal [3H]vinylidene kainic acid binding was reduced in genetically epilepsy-prone-3 rats by 15 and 18%, but these reductions were not statistically significant. Saturation of [3H]vinylidene kainic acid binding studies indicated that the total number of ventral hippocampal [3H]vinylidene kainic acid binding sites was decreased by 21% in genetically epilepsy-prone-3 rats and 28% in genetically epilepsy-prone-9 rats. The reduction in ventral hippocampal [3H]vinylidene kainic acid binding in genetically epilepsy-prone rats resembles the reduction in ventral hippocampal [3H]vinylidene kainic acid binding sites observed in perinatal hypothyroid rats. As genetically epilepsy-prone rats are hypothyroid during the neonatal period, the reduction in hippocampal [3H]vinylidene kainic acid binding in the genetically epilepsy-prone rats may be a consequence of a hypothyroid-induced defect in the development or maturation of the hippocampal mossy fiber projection in genetically epilepsy-prone rats. An alternative hypothesis is that the putative occurrence of spontaneous limbic seizures in genetically epilepsy-prone rats may lead secondarily to a reduction in hippocampal [3H]vinylidene kainic acid binding sites.

Animals↗

PubMed1990

Transient elevation of amygdala alpha 2 adrenergic receptor binding sites during the early stages of amygdala kindling.

Enhanced noradrenergic neurotransmission retards but does not prevent the development of kindling. We previously reported that locus coeruleus (LC) alpha 2 adrenergic receptor binding sites are transiently elevated during the early stages of kindling development. Since the firing activity of LC noradrenergic neurons is partially regulated via an alpha 2 receptor-mediated recurrent inhibition, the transient elevation in LC alpha 2 receptors could decrease LC activity and consequently facilitate the development of kindling. Transient elevation of alpha 2 receptor binding sites during early stages of kindling may also occur on noradrenergic axon terminals projecting to forebrain sites. Using in vitro neurotransmitter autoradiography techniques, we investigated this hypothesis by measuring specific [3H]idazoxan binding in 5 different areas of rat forebrain at 2 different stages of kindling development. After 2 class 1 kindled seizures, specific [3H]idazoxan binding was elevated significantly in the amygdala, but not in other forebrain regions. No differences in specific [3H]idazoxan binding were observed in any of the 5 brain regions in rats kindled to a single class 5 kindled motor seizure. Saturation of binding experiments indicated that the increase in amygdala [3H]idazoxan binding, following 2 class 1 kindled motor seizures, was due to an increase in the total number of alpha 2 receptor binding sites without a change in the affinity of the binding sites for [3H]idazoxan. Thus, the transient increase in alpha 2 receptors that occurs in the LC in the early stages of kindling also occurs in the forebrain region in which the kindled seizure originates.

Amygdala↗

PubMed1990

Genetic and environmental influences on echocardiographically determined left ventricular mass in black twins.

Genetic and environmental influences on left ventricular mass were examined in normotensive black twins. Left ventricular mass was measured echocardiographically in 7 sets of monozygotic (MZ) and 15 sets of dizygotic (DZ) twins and adjusted for body surface area (LVMI). Regression analyses showed significant effects of gender (R2 = 0.48; P less than .01), systolic blood pressure (R2 = 0.21; P less than .01) and age (R2 = 0.10; P less than .05) on LVMI but did not show an effect for either diastolic blood pressure or caloric expenditure. Monozygotic twins showed smaller within-pair differences (7 +/- 5) than DZ twins (17 +/- 11) for LVMI following adjustment for gender, systolic blood pressure and age (P less than .03). The intraclass correlation for MZ twins was 0.90 (P less than .01) and 0.33 (P = NS) for DZ twins. These results indicate that both genetic and environmental factors are important determinants of left ventricular mass in blacks, independent of gender, blood pressure and age.

Adult↗

PubMed1990

Perinatal hypothyroidism decreases hippocampal 3H-vinylidene kainic acid binding in rats.

The effect of perinatal hypothyroidism on the number and distribution of hippocampal kainic acid binding sites was examined in rats. Timed pregnant Sprague-Dawley rat dams were given water containing either 0.02% propylthiouracil (PTU) or untreated water from gestational day 18 until their litters were weaned at postnatal day 31. The offspring were sacrificed at 31 or 120 days of age, blood samples collected and their brains frozen. In the 31-day-old rats, serum thyroxine, serum triiodothyronine, total body weight and whole brain weight all indicated that the PTU-treated rats were hypothyroid. Hippocampal kainic acid binding was analyzed in sections of dorsal and ventral hippocampal formation by in vitro 3H-vinylidene kainic acid (VKA) autoradiography. Compared to the untreated controls, specific 3H-VKA binding was reduced by 43% in the ventral hippocampal formation stratum lucidum of 31-day-old PTU-treated rats. Specific 3H-VKA binding was not different in the dorsal hippocampal formation. Saturation of 3H-VKA binding studies indicated that the decrease-induced by PTU treatment--in ventral hippocampal 3H-VKA binding was due to a reduction in the total number of 3H-VKA binding sites. At 120 days of age, 3 months after the cessation of the PTU treatment, serum thyroid hormone levels were not different than those of controls, indicating a recovery of thyroid hormone function after the perinatal PTU treatment. However, specific 3H-VKA binding remained significantly reduced in the ventral hippocampal formation of 120-day-old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Quantitative histofluorescence of hippocampal mossy fiber zinc.

N-(6-methoxy-8-quinolyl)-p-toluenesulfonamide (TS-Q) is a fluorescent probe for histochemically detecting a chelatable pool of zinc in the hippocampal formation and other brain regions. Utilization of zinc:TS-Q histofluorescence as a quantitative tool required further characterization of zinc:TS-Q fluorescence and the development of appropriate zinc standards. Studies of zinc:TS-Q fluorescence in aqueous solutions were conducted to optimize the reaction conditions for TS-Q chelation with zinc. Possible interference of zinc:TS-Q fluorescence by chelation of other biologically significant cations with zinc:TS-Q was shown to be negligible. Zinc standards were developed using a water soluble plastic embedding medium. Varying the concentration of zinc in the plastic sections yielded a standard curve exhibiting a log-linear relationship between 0.15 and 11 fg zinc/100 microns 2. Zinc:TS-Q histofluorescence was characterized in horizontal sections of rat ventral hippocampal formation using a computerized image analysis system. Section thickness and TS-Q concentration were optimized. The concentration of zinc varied between 1.5 and 17 fg/100 microns 2 in different regions of the mossy fiber projection of the ventral hippocampal formation. The development of this quantitative histofluorescence technique should facilitate our understanding of the functional role of zinc in the mossy fiber projection and can be utilized to investigate changes in mossy fiber zinc in a variety of pathological states.

Aminoquinolines↗

PubMed1989

Transient elevation of locus coeruleus alpha 2-adrenergic receptor binding during the early stages of amygdala kindling.

Enhancement of noradrenergic neurotransmission retards, but does not prevent, the development of kindling. The firing activity of noradrenergic locus coeruleus (LC) neurons is partially regulated by axon collateral recurrent inhibition mediated via alpha 2-adrenergic receptors. We tested the hypothesis that LC autoinhibitory alpha 2-adrenergic receptors may change during the kindling process thereby altering LC excitability. Specific binding of the alpha 2-adrenergic receptor antagonist [3H]RX781094 (idazoxan) was measured in the LC of rats at 3 different stages of kindling development using in vitro neurotransmitter receptor autoradiography techniques. Specific [3H]RX781094 binding was elevated significantly in rats kindled to two Class 1 kindled motor seizures. No differences in binding were observed in animals kindled to Class 3 or Class 5 kindled motor seizures. Saturation of binding experiments indicated that the increase in binding following two Class 1 kindled motor seizures was due to an increase in the total number of alpha 2-receptors without a change in the affinity of the binding site for [3H]RX781094. The transient increase in number of LC alpha 2-adrenergic receptors is consistent with the idea that noradrenergic neurotransmission inhibits the early progress of kindling development, but then subsequently becomes ineffective in maintaining the inhibition during later stages of kindling development.

Amygdala↗

PubMed1989

Left ventricular mass and incidence of coronary heart disease in an elderly cohort. The Framingham Heart Study.

OBJECTIVE: To examine the association of echocardiographically determined left ventricular mass with incidence of coronary heart disease in an elderly cohort. DESIGN: Cohort study with a follow-up period of 4 years. SETTING: Population-based. SUBJECTS: Elderly original volunteer subjects of the Framingham Heart Study who were free of clinically apparent coronary heart disease. This group included 406 men (mean age, 68 years: range, 60 to 90) and 735 women (mean age, 69 years: range, 59 to 90). MEASUREMENTS AND MAIN RESULTS: During 4 years of follow-up, coronary heart disease events occurred in 37 men and 33 women. Baseline echocardiographically determined left ventricular mass was associated with incidence of coronary disease in both sexes (P less than 0.01). After adjusting for age, systolic blood pressure, smoking, and the ratio of total/high density lipoprotein cholesterol, the relative risk for a coronary event, per 50 g/m increment in left ventricular mass/height, was 1.67 in men (95% CI, 1.24 to 2.23) and 1.60 in women (95% CI, 1.10 to 2.32). CONCLUSIONS: Echocardiographic assessment of left ventricular mass offers prognostic information beyond that provided by traditional risk factors, which can improve our ability to identify individuals at high risk for coronary heart disease. These findings may have widespread implications regarding the applications of echocardiography in clinical practice.

Age Factors↗

PubMed1989

A mechanism for the development of fixed primary (essential) hypertension: insights from population-based studies using echocardiography.

Two recent observations based on echocardiographic studies in large population-based studies may have far-reaching implications: The concentric form of left ventricular hypertrophy emerges prominently in white Framingham (MA) men aged 40-49 years, and ten years later in white Framingham women. This parallels the pattern of emergence of fixed primary hypertension in white Framingham adults. Normotensive black teenage boys in Bogalusa have an echocardiographic profile that parallels more closely the profile of middle-aged white Framingham men and women than white teenage boys and girls. As noted, the former echocardiographic profiles are strongly associated with fixed primary hypertension in older adults and may be the harbingers of the premature development of fixed primary hypertension in the young black boys. These findings fit into a chain of observations that: (1) give new insight into the mechanism for premature development of primary hypertension and that should ultimately lead to closing the loop needed to characterize the cause of such hypertension: (2) may ultimately help to explain the excess of premature cardiovascular, renal, and cerebrovascular morbidity and mortality in the U.S. black population compared with the white population; and (3) may lead to new, more effective strategies for reducing such excess morbidity and mortality.

Adolescent↗

PubMed1989

New perspectives on left ventricular hypertrophy: anatomy, physiology, and significance.

The advent of echocardiography has added an important and sensitive tool for assessment of left ventricular hypertrophy (increased left ventricular mass). Recent echocardiographic studies in large population-based samples suggest an epidemic of left ventricular hypertrophy. Preliminary data suggesting important prognostic importance for such left ventricular hypertrophy (independent of standard risk factors) has fueled interest in the development, determinants, and other features of the hypertrophy. Hemodynamic and neurohumoral factors are the most prominent stimuli to adaptive (physiologic) myocardial hypertrophy, which can progress to maladaptive (pathologic) hypertrophy. The overall blood pressure experience, overweight, the cardiovascular response to recurrent psychosocial stress and physical activity level are four important correlates and potential determinants of left ventricular mass in various urban-suburban populations. Determination of the relative contributions and interrelations of these and other factors (such as heredity) to various forms of left ventricular hypertrophy found in various demographic groups warrants intensive investigation.

Cardiomegaly↗