Showing papers by "Emory University published in 1994"
TL;DR: The ability of Ang II to stimulate superoxide anion formation is examined and the identity of the oxidases responsible for its production is investigated to suggest that Ang II specifically activates enzyme systems that promote superoxide generation and raise the possibility that these pathways function as second messengers for long-term responses, such as hypertrophy or hyperplasia.
Abstract: The signaling pathways involved in the long-term metabolic effects of angiotensin II (Ang II) in vascular smooth muscle cells are incompletely understood but include the generation of molecules likely to affect oxidase activity. We examined the ability of Ang II to stimulate superoxide anion formation and investigated the identity of the oxidases responsible for its production. Treatment of vascular smooth muscle cells with Ang II for 4 to 6 hours caused a 2.7 +/- 0.4-fold increase in intracellular superoxide anion formation as detected by lucigenin assay. This superoxide appeared to result from activation of both the NADPH and NADH oxidases. NADPH oxidase activity increased from 3.23 +/- 0.61 to 11.80 +/- 1.72 nmol O2-/min per milligram protein after 4 hours of Ang II, whereas NADH oxidase activity increased from 16.76 +/- 2.13 to 45.00 +/- 4.57 nmol O2-/min per milligram protein. The NADPH oxidase activity was stimulated by exogenous phosphatidic and arachidonic acids and was partially inhibited by the specific inhibitor diphenylene iodinium. NADH oxidase activity was increased by arachidonic and linoleic acids, was insensitive to exogenous phosphatidic acid, and was inhibited by high concentrations of quinacrine. Both of these oxidases appear to reside in the plasma membrane, on the basis of migration of the activity after cellular fractionation and their apparent insensitivity to the mitochondrial poison KCN. These observations suggest that Ang II specifically activates enzyme systems that promote superoxide generation and raise the possibility that these pathways function as second messengers for long-term responses, such as hypertrophy or hyperplasia.
2,716 citations
TL;DR: The cellular and subcellular distributions of the glutamate transporter subtypes EAAC1, GLT-1, and GLAST in the rat CNS were demonstrated using anti-peptide antibodies that recognize the C-terminal domains of each transporter.
1,684 citations
TL;DR: In this paper, the authors show that cumulative victories in certification contests extend the life chances of winning organizations but there is no evidence that new startup organizations benefit more than lateral entries and point to the need for an institutionally informed theory of competences.
Abstract: Despite widespread agreement among organizational researchers that intangible resources underlie performance differences among organizations, little empirical evidence exists in the literature. Building on the idea that reputation is socially constructed, this paper depicts reputation as the outcome of the process of legitimation. It observes that organizational researchers have overlooked how certification contests legitimate organizations, generate status orderings, and create favorable reputations. This paper suggests that victories in certification contests are credentials that enable firms to acquire a reputation for competence. It predicts that cumulative victories improve the survival of organizations and better the life chances of startup organizations more than those of lateral entries. These predictions are analyzed in the American auto industry during 1895–1912 when special-purpose product rating agencies were absent and reliability and speed contests served as credentialing devices. The results show that cumulative victories in contests extend the life chances of winning organizations but there is no evidence that new startup organizations benefit more than lateral entries. These findings underscore the significance of intangible assets and point to the need for an institutionally informed theory of competences.
1,371 citations
TL;DR: Patients randomly assigned to the high-dose regimen of adjuvant chemotherapy had significantly longer disease-free and overall survival if their tumors had c-erbB-2 overexpression, a useful marker to identify a subgroup of patients more likely than others to benefit from high doses of chemotherapy.
Abstract: Background The role of molecular markers in predicting the response to treatment of breast cancer is poorly defined. The Cancer and Leukemia Group B (CALGB) conducted a randomized adjuvant-chemotherapy trial (CALGB 8541) comparing three doses (high, moderate, and low) of cyclophosphamide, doxorubicin, and fluorouracil in 1572 women with node-positive breast cancer. This study (CALGB 8869) was designed to determine whether the DNA index, the S-phase fraction, c-erbB-2 expression, or p53 accumulation could be used as a marker to identify a subgroup of patients more likely than others to benefit from high doses of chemotherapy. Methods Tissue blocks were obtained from 442 patients randomly selected from the larger CALGB trial. Paraffin sections from the primary lesions were analyzed for DNA content, S-phase fraction, c-erbB-2 expression, and p53 accumulation. Results Patients randomly assigned to the high-dose regimen of adjuvant chemotherapy had significantly longer disease-free and overall survival if thei...
971 citations
TL;DR: Findings support the hypothesis that alterations in 5-HT neurons play a role in the pathophysiology of depression.
Abstract: Considerable evidence has accrued in the last two decades to support the hypothesis that alterations in serotonergic neuronal function in the central nervous system occur in patients with major depression. These findings include the following: (a) reduced cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin (5-HT) in drug-free depressed patients; (b) reduced concentrations of 5-HT and 5-HIAA in postmortem brain tissue of depressed and (or) suicidal patients; (c) decreased plasma tryptophan concentrations in depressed patients and a profound relapse in remitted depressed patients who have responded to a serotonergic antidepressant when brain tryptophan availability is reduced; (d) in general, all clinically efficacious antidepressants augment 5-HT neurotransmission following chronic treatment; (e) clinically efficacious antidepressant action by all inhibitors of 5-HT uptake; (f) increases in the density of 5-HT2 binding sites in postmortem brain tissue of depressed patients and suicide victims, as well as in platelets of drug-free depressed patients; (g) decreased number of 5-HT transporter (determined with [3H]imipramine or [3H]paroxetine) binding sites in postmortem brain tissue of suicide victims and depressed patients and in platelets of drug-free depressed patients. In our studies, this reduction in platelet 5-HT transporter binding is not due to prior antidepressant treatment of hypercortisolemia and is not observed in mania, Alzheimer disease, schizophrenia, panic disorder, fibromyalgia, or atypical depression. In a pilot study, this deficit predicted treatment response to an experimental antidepressant. These findings support the hypothesis that alterations in 5-HT neurons play a role in the pathophysiology of depression.
902 citations
University of Texas Health Science Center at San Antonio1, Abbott Laboratories2, University of Texas Health Science Center at Houston3, Case Western Reserve University4, University of Illinois at Chicago5, University of Texas Southwestern Medical Center6, Indiana University7, Emory University8, University of Miami9
TL;DR: Divalproex was as effective in rapid-cycling manic patients as in other patients and appears to be independent of prior responsiveness to lithium, while lithium was significantly more effective than placebo in reducing the symptoms of acute mania.
Abstract: Objective. —To compare the effectiveness of divalproex sodium with that of lithium and placebo in patients with acute mania. Design. —Randomized, double-blind, parallel-group study of treatment outcomes in patients with manic-depressive illness. Patients. —A total of 179 hospitalized, acutely manic patients meeting the Research Diagnostic Criteria for manic disorder, approximately half of whom had been nonresponsive to lithium previously, were studied at nine university-affiliated hospitals. Interventions. —After a minimum 3-day washout period, random assignment for 21 days to divalproex, lithium, or placebo in a 2:1:2 ratio. Dosage of divalproex and lithium was increased if tolerated to a target concentration of 1041 μmol/L (150 μg/ mL) or 1.5 mmol/L (conventionally expressed as milliequivalents per liter), respectively. Main Outcome Measures. —Primary outcome measures were changes in the Mania Rating scale derived from the Schedule for Affective Disorders and Schizophrenia. Results. —Intent-to-treat analysis for efficacy was based on data from 68, 35, and 73 patients in the divalproex, lithium, and placebo groups, respectively. Groups were initially comparable except that all eight patients with four or more manic episodes in the previous year were in the divalproex group. In 30%, 33%, and 51% of the above groups, treatment was prematurely terminated due to lack of efficacy, with fewer premature terminations from divalproex than placebo (P=.017). The proportions of patients improving at least 50% were higher for divalproex and lithium groups than for the placebo group: 48% for divalproex (P=.004) and 49% for lithium (P=.025) vs 25% for placebo. Divalproex was as effective in rapid-cycling manic patients as in other patients. Conclusions. —Both divalproex and lithium were significantly more effective than placebo in reducing the symptoms of acute mania. The efficacy of divalproex appears to be independent of prior responsiveness to lithium. (JAMA. 1994;271:918-924)
855 citations
TL;DR: The Diagnostic Analysis of Nonverbal Accuracy (DANVA) as mentioned in this paper was designed to measure individual differences in the accurate sending and receiving of nonverbal social information in children from 6 to 10 years of age.
Abstract: The Diagnostic Analysis of Nonverbal Accuracy (DANVA) was designed to measure individual differences in the accurate sending and receiving of nonverbal social information. The DANVA consists of four receptive and three expressive subtests that measure nonverbal processing accuracy in children from 6 to 10 years of age. Four propositions were offered to guide the gathering of construct validity data for the DANVA. In support of the propositions, researchers found that DANVA accuracy scores increased with age, were internally consistent and reliable over time, and snowed significant relationships with indices of personal and social adjustment and academic achievement but were not related to IQ. Evidence for construct validity was stronger for receptive, as compared to expressive, subtests. Future research should include additional populations of subjects and study of the impact of intensity of emotion being sent or received.
757 citations
TL;DR: A three-year prospective, randomized trial comparing the outcomes of percutaneous transluminal coronary angioplasty as compared with coronary-artery bypass grafting for patients with multivessel coronary artery disease.
Abstract: Background The clinical benefit of percutaneous transluminal coronary angioplasty (PTCA) as compared with coronary-artery bypass grafting (CABG) for patients with multivessel coronary artery disease has not been established. To determine the outcomes of these treatments in patients referred for the first time for coronary revascularization, we conducted a three-year prospective, randomized trial comparing the two procedures. Methods Revascularization was performed by accepted methods. Follow-up clinical information was collected every six months, and coronary arteriography and thallium stress scanning were performed at one and three years. The primary end point was a composite of death, Q-wave myocardial infarction, and a large ischemic defect identified on thallium scanning at three years. Secondary end points included clinical and angiographic status and the need for additional revascularization procedures. Data were analyzed according to the intention-to-treat principle. Results Of the 5118 patients sc...
729 citations
TL;DR: The doses of chemotherapy used to treat breast cancers, especially early breast cancer, should not be reduced if the maximal benefit is to be achieved, according to either a dose-response effect or a threshold level of the dose or dose intensity.
Abstract: Background Adjuvant chemotherapy is widely used for breast cancer and is known to extend survival. Some clinicians seek a greater survival benefit by increasing the intensity of the dose, whereas others lower it to diminish toxicity. Methods The Cancer and Leukemia Group B (CALGB) conducted a randomized trial of different levels of doses and dose intensity (dose per unit of time) of adjuvant chemotherapy in 1572 women with node-positive, stage II breast cancer who were assigned to three treatment groups. One group received 400 mg of cyclophosphamide per square meter of body-surface area and 40 mg of doxorubicin per square meter once every 28 days and 400 mg of fluorouracil per square meter twice every 28 days, for six cycles. Another group received 50 percent higher doses of the three drugs (600 mg, 60 mg, and 600 mg, respectively) but for only four cycles, so that the total dose was identical in these two groups but the dose intensity was higher in the second. The third group of women received half the t...
678 citations
TL;DR: Tumor cell lines with elevated fatty acid synthase showed commensurate increases in incorporation of [U-14C]acetate into acylglycerols demonstrating that fatty acids synthase increases occur in the context of overall increases in endogenous fatty acid synthesis.
Abstract: OA-519 is a prognostic molecule found in tumor cells from breast cancer patients with markedly worsened prognosis. We purified OA-519 from human breast carcinoma cells, obtained its peptide sequence, and unambiguously identified it as fatty acid synthase through sequence homology and enzymology. Tumor fatty acid synthase is an approximately 270-kDa polypeptide which specifically abolished immunostaining of human breast cancers by anti-OA-519 antibodies. Tumor fatty acid synthase oxidized NADPH in a malonyl-CoA-dependent fashion and synthesized fatty acids composed of 80% palmitate, 10% myristate, and 10% stearate from acetyl-CoA, malonyl-CoA, and NADPH with a specific activity of 624 nmol of NADPH oxidized per min per mg. Tumor cell lines with elevated fatty acid synthase showed commensurate increases in incorporation of [U-14C]acetate into acylglycerols demonstrating that fatty acid synthase increases occur in the context of overall increases in endogenous fatty acid synthesis. Cerulenin inhibited acylglycerol synthesis in tumor cells and fibroblast controls in a dose-dependent fashion and also caused a growth inhibition which generally paralleled the level of endogenous fatty acid synthesis. Supraphysiologic levels of palmitate, 14 microM in dimethyl sulfoxide, significantly reversed the growth inhibition caused by cerulenin at concentrations of up to 5 micrograms/ml, indicating that cerulenin-mediated growth inhibition was due to fatty acid synthase inhibition.
655 citations
01 Jan 1994
TL;DR: Introduction and General Issues: The Nature and Study of Depression in Children and Adolescents W.F. Reynolds, H.O. Poznanski, and H.M. Johnston.
Abstract: Introduction and General Issues: The Nature and Study of Depression in Children and Adolescents W.M. Reynolds, H.F. Johnston. Phenomenology and Epidemiology of Mood Disorders in Children and Adolescents E.O. Poznanski, H.B. Mokros. Theories and Models of Depression: Dynamic and Interpersonal Theories of Depression J.R. Bemporad. Cognitive and Behavioral Correlates of Childhood Depression: A Developmental Perspective N.J. Kaslow, et al. Approaches to Assessment and Diagnosis: Classification and Diagnostic Criteria of Depression in Children and Adolescents D. Sherak, et al. Evalution of Depression in Children and Adolescents Using Diagnostic Clinical Interviews K. Hodges. Treatment Approaches: Psychological Treatment Approaches for Depression in Children K.D. Stark, et al. Psychological Approaches to the Treatment of Depression in Adolescents P.M. Lewinsohn, et al. Depression in Special Populations: Depression in Infants P.V. Trad. Selected Topics in the Study of Depression in Young People: Maltreatment and Childhood Depression G. Downey, et al. 15 additional articles. Index.
Journal Article•
TL;DR: The loss of genetic information from 19q and 1p as well as the rarity of TP53 mutations in oligodendroglial tumors suggests that the early events in their oncogenesis are distinct from those associated with astrocytic tumors.
Abstract: The molecular genetic alterations of oligodendroglial tumors and mixed gliomas of the central nervous system were studied in a series of 37 cases (8 oligodendrogliomas, 13 anaplastic oligodendrogliomas, 8 oligoastrocytomas, and 8 anaplastic oligoastrocytomas). A total of 180 polymorphic loci and 5 nonpolymorphic gene loci, distributed over all chromosomes, were examined by restriction fragment length polymorphism analysis. Loss of heterozygosity was most frequently observed for loci on 19q with a commonly deleted region at 19q13.2-q13.4 distal to the CYP2a gene and proximal to the D19S22 locus. The incidence of allelic loss on 19q was particularly high (81%) in oligodendroglial tumors and equal to 31% in mixed gliomas. More than 75% of the tumors with allelic deletions on 19q also showed loss of heterozygosity for loci on 1p with one tumor showing only loss of alleles distal to the NGFB gene (1p13-pter). Seven (19%) tumors had lost alleles from 17p with the deleted region including the TP53 tumor suppressor gene in all cases. Sequencing of the TP53 transcripts from exons 2 to 10, however, did not reveal mutations of the remaining allele in any of these tumors. Anaplastic oligodendrogliomas and anaplastic oligoastrocytomas demonstrated an increased incidence of additional allelic losses involving most frequently chromosomes 9p and 10. Gene amplification was detected in two anaplastic tumors, affecting the epidermal growth factor receptor gene in both cases, with additional amplification of the renin gene at 1q32 in one of these cases. In total our results indicate both differences and similarities between the molecular genetic alterations in tumors with oligodendroglial and astrocytic differentiation. The loss of genetic information from 19q and 1p as well as the rarity of TP53 mutations in oligodendroglial tumors suggests that the early events in their oncogenesis are distinct from those associated with astrocytic tumors. However, similarities are indicated by the allelic losses on 9p and 10 in the anaplastic tumors, suggesting the utilization of common pathways of progression.
TL;DR: In this article, the authors examined the empirical validity of a model of human motivation as it applies to school success and failure in 3 independent samples of 10- to 16-year-old African-American youth.
Abstract: This study examined the empirical validity of a model of human motivation as it applies to school success and failure in 3 independent samples of 10- to 16-year-old African-American youth. Specifically, we assessed how indicators of context, self, and action relate to measures of risk and resilient outcomes in school in 3 different samples, using 3 different measurement strategies. Correlational and path analyses on the 3 data sets supported the empirical validity of the model. African-American youth's experience of their parents' school involvement predicted a composite of self-system processes, which in turn predicted the subjects' reports of their engagement in school. Engagement then predicted school performance and adjustment. The data supported a reciprocal path from action to context, suggesting that youth who show more disaffected patterns of behavior and emotion in school experience less support from their families than those reporting more engaged patterns of action. Implications for program and policy decisions are discussed.
Journal Article•
TL;DR: The growth literature from developing countries is reviewed to assess the extent to which stunting can be reversed in later childhood and adolescence and one study cautions that in older adopted subjects, accelerated growth may accelerate maturation, shorten the growth period and lead to short adult stature.
Abstract: The growth literature from developing countries is reviewed to assess the extent to which stunting, a phenomenon of early childhood, can be reversed in later childhood and adolescence. The potential for catch-up growth increases as maturation is delayed and the growth period is prolonged. However, maturational delays in developing countries are usually less than two years, only enough to compensate for a small fraction of the growth retardation of early childhood. Follow-up studies find that subjects who remain in the setting in which they became stunted experience little or no catch-up in growth later in life. Improvements in living conditions, as through food supplementation or through adoption, trigger catch-up growth but do so more effectively in the very young. One study cautions that in older adopted subjects, accelerated growth may accelerate maturation, shorten the growth period and lead to short adult stature.
TL;DR: Almost 75% of the racial difference in survival was explained by the prognostic factors studied, and Sociodemographic variables appeared to act largely through racial differences in stage at diagnosis, which may be amenable to change through improved access to and use of screening for black women.
Abstract: Objective. —To examine the ability of recognized prognostic factors for breast cancer to account for the observed poorer survival in blacks compared with their white counterparts. Design and Participants. —Subjects included 1130 women (612 blacks and 518 whites) aged 20 to 79 years residing in metropolitan Atlanta, Ga, New Orleans, La, or San Francisco/Oakland, Calif, who were diagnosed with primary invasive breast cancer. Information on stage, tumor characteristics, treatment, comorbid conditions, and sociodemographic factors was obtained from personal interview, physician and hospital records, and a pathology review of biopsy and surgical specimens. Main Outcome Measure. —Multivariable survival models were used to estimate the hazard ratio (relative risk of mortality) for blacks compared with whites, adjusting for various combinations of potential explanatory factors. Results. —After controlling for geographic site and age, the risk of dying was 2.2 times (95% confidence interval [CI], 1.8 to 2.8) greater for blacks than whites. Adjustment for stage reduced the risk from 2.2 to 1.7; further adjustment for sociodemographic variables had no effect. Treatment was not a contributing factor once stage and tumor pathology were in the model. After adjusting for stage, treatment, comorbid illness, and pathologic and sociodemographic variables, blacks continued to demonstrate a slightly increased, but not statistically significant, risk of death (hazard ratio=1.3; 95% CI, 1.0 to 1.8). Results were similar for all-cause mortality and breast cancer—specific mortality. Conclusions. —Approximately 75% of the racial difference in survival was explained by the prognostic factors studied. Sociodemographic variables appeared to act largely through racial differences in stage at diagnosis, which may be amenable to change through improved access to and use of screening for black women. ( JAMA . 1994;272:947-954)
TL;DR: A low CSF 5-HIAA concentration was primarily associated with impulsivity and high CSF testosterone concentration, with aggressiveness or interpersonal violence in alcoholic, impulsive and nonimpulsive offenders.
Abstract: Background: There is an extensive literature describing a central serotonin deficit in alcoholic, impulsive, violent offenders and fire setters In the present study, we investigated biochemical concomitants of impulsivity and aggressiveness, and the physiological consequences of reduced central serotonin turnover Methods: Forty-three impulsive and 15 nonimpulsive alcoholic offenders and 21 healthy volunteers were studied in the forensic psychiatry ward of a university psychiatric department The subjects underwent lumbar punctures and oral glucose and aspartame challenges, and their diurnal activity rhythm was measured with physical activity monitors Discriminant function analyses were used to investigate psychophysiological and biochemical concomitants of aggressive and impulsive behaviors Results: Alcoholic, impulsive offenders with antisocial personality disorder had low mean cerebrospinal fluid (CSF) 5-hydroxyindoleaceticacid (5-HIAA) and corticotropin levels and high mean CSF testosterone concentrations Compared with healthy volunteers, they showed increased physical activity during the daytime Alcoholic, impulsive offenders with intermittent explosive disorder had a low mean CSF 5-HIAA concentration and blood glucose nadir after an oral glucose challenge, and desychronized diuranalactivityrhythm Healthy volunteers had mean CSF 5-HIAA concentrations that were intermediate between those of alcoholic, impulsive and nonimpulsive offenders Alcoholic, nonimpulsive offenders had a significantly higher mean CSF 5-HIAA concentration than all the other groups, including healthy volunteers In the present sample, a low CSF 5-HIAA concentration was primarily associated with impulsivity and high CSF testosterone concentration, with aggressiveness or interpersonal violence Conclusions: In the present sample, a low CSF 5-HIAA concentration was primarily associated with impulsivity and high CSF testosterone concentration, with aggressiveness or interpersonal violence
TL;DR: All extant mutations of this class are recent and associated with more devastating diseases of young adults and children and provide a molecular clock that measures the authors' age and may cause a progressive decline in tissue energy output that could precipitate the onset of degenerative diseases in individuals harboring inherited deleterious mutations.
Abstract: Germ-line and somatic mtDNA mutations are hypothesized to act together to shape our history and our health. Germ-line mtDNA mutations, both ancient and recent, have been associated with a variety of degenerative diseases. Mildly to moderately deleterious germ-line mutations, like neutral polymorphisms, have become established in the distant past through genetic drift but now may predispose certain individuals to late-onset degenerative diseases. As an example, a homoplasmic, Caucasian, tRNA(Gln) mutation at nucleotide pair (np) 4336 has been observed in 5% of Alzheimer disease and Parkinson disease patients and may contribute to the multifactorial etiology of these diseases. Moderately to severely deleterious germ-line mutations, on the other hand, appear repeatedly but are eliminated by selection. Hence, all extant mutations of this class are recent and associated with more devastating diseases of young adults and children. Representative of these mutations is a heteroplasmic mutation in MTND6 at np 14459 whose clinical presentations range from adult-onset blindness to pediatric dystonia and basal ganglial degeneration. To the inherited mutations are added somatic mtDNA mutations which accumulate in random arrays within stable tissues. These mutations provide a molecular clock that measures our age and may cause a progressive decline in tissue energy output that could precipitate the onset of degenerative diseases in individuals harboring inherited deleterious mutations.
TL;DR: A set of six lexical principles for making object label learning a manageable task are presented and critically evaluated, with the effect of reducing the amount of information that language-learning children must consider for what a new word might mean.
Abstract: Universally, object names make up the largest proportion of any word type found in children's early lexicons. Here we present and critically evaluate a set of six lexical principles (some previously proposed and some new) for making object label learning a manageable task. Overall, the principles have the effect of reducing the amount of information that language-learning children must consider for what a new word might mean. These principles are constructed by children in a two-tiered developmental sequence, as a function of their sensitivity to linguistic input, contextual information, and social-interactional cues. Thus, the process of lexical acquisition changes as a result of the particular principles a given child has at his or her disposal. For children who have only the principles of the first tier (reference, extendibility, and object scope), word learning has a deliberate and laborious look. The principles of the second tier (categorical scope, novel name-nameless category' or N3C, and conventionality) enable the child to acquire many new labels rapidly. The present unified account is argued to have a number of advantages over treating such principles separately and non-developmentally. Further, the explicit recognition that the acquisition and operation of these principles is influenced by the child's interpretation of both linguistic and non-linguistic input is seen as an advance.
TL;DR: The results suggest that TuJ1 immunoreactivity distinguishes two neuronal populations: those that remain for an indefinite period of time in the proliferative zones, and those that leave the proliferation zones soon after being generated.
Abstract: We have used a monoclonal antibody against the neuron-specific class III beta-tubulin (TuJ1; Lee et al., 1990b) to study the distribution and morphology of immature neurons in the proliferative ventricular and subventricular zones of the developing telencephalon. Mouse brains from embryonic day 12 (E12) to postnatal day 5 (P5) were fixed either with a non-cross-linking agent, HistoChoice, or with 4% paraformaldehyde, and processed for TuJ1 immunohistochemistry. TuJ1 immunoreactivity first appeared in the proliferative zones of the developing cerebral cortex at E13-E14 as the cortical plate was emerging. After E14, tangentially oriented TuJ1-positive cells were abundant at the interface between the ventricular and subventricular zones. This tangential pattern was less conspicuous in the developing striatum. Within the cortical and striatal ventricular zone TuJ1-positive cells were less numerous and displayed a variety of orientations and morphologies. Postnatally, after the period of neurogenesis has ended, TuJ1 immunoreactivity continued to increase in the subventricular zone and remained high until the last developmental stage examined (P5). Anti-MAP2, another neuron-specific marker, never labeled the cells of the ventricular and subventricular zones, pre- or postnatally. To determine the birthdates of TuJ1-positive cells in the cortical-ventricular and subventricular zones, brains were double labeled with TuJ1 and bromodeoxyuridine according to different pulse-chase schedules. TuJ1-positive cells were postmitotic and generated throughout the period of cortical neurogenesis. Collectively, the results suggest that TuJ1 immunoreactivity distinguishes two neuronal populations: those that remain for an indefinite period of time in the proliferative zones, and those that leave the proliferative zones soon after being generated. Although the fate of the TuJ1-positive cells that reside in the proliferative zones remains unclear, their tangentially aligned orientation and their distribution suggest that they migrate independent of radial glial fibers.
TL;DR: Group comparisons revealed a higher rate of neuromotor abnormalities in the preschizophrenia children when compared to their healthy siblings, preaffective disorder subjects, the healthy siblings of patients with affective disorder, and subjects from families with no mental illness.
Abstract: Previous research suggests that in addition to being a characteristic of schizophrenia, neuromotor dysfunction also predates the onset of the syndrome. The research reported here was intended to examine further the neuromotor development of children with preschizophrenia traits. This study is part of a larger "archival-observational" project that uses childhood home movies to explore the developmental precursors of schizophrenia. Group comparisons revealed a higher rate of neuromotor abnormalities in the preschizophrenia children when compared to their healthy siblings, preaffective disorder subjects, the healthy siblings of patients with affective disorder, and subjects from families with no mental illness. The preschizophrenia subjects also showed poorer motor skills when compared to their healthy siblings and preaffective disorder subjects. When diagnostic group comparisons were made within age spans, the group differences were significant only in the first 2 years of life. Post hoc analyses also revealed that the preschizophrenia subjects' neuromotor abnormalities occurred primarily on the left side of the body. The abnormalities included choreoathetoid movements and posturing of the upper limbs, similar to the motor signs described in earlier reports on diagnosed schizophrenia patients. The findings are discussed in light of their implications for the developmental origins of schizophrenia. Limitations of the study, including problems with sample representativeness and the reliance on observational data, are also discussed.
TL;DR: Risk of graft failure varies substantially, even within a high-risk population, and the number of risk factors present should be considered by the patient and surgeon when contemplating transplantation and planning follow-up.
TL;DR: The hypothesis that abnormally increased tonic and phasic activity in STN leads to abnormal GPi activity and is a major factor in the development of parkinsonian motor signs is supported and implies that cells in the basal ganglia have the intrinsic property of discharging in periodic bursts, which is unmasked under parkinsonia conditions.
Abstract: 1. The effects of reversible and irreversible pharmacological manipulations of the neuronal activity in the subthalamic nucleus (STN) on parkinsonian motor signs and neuronal activity in the intern...
TL;DR: Electrophysiological recording of human NETs and SERTs stably expressed in HEK-293 cells reveals that both transporters move charge across the plasma membrane following the addition of substrates; these currents can be blocked by NET-and SERT-selective antagonists as well as by cocaine.
Abstract: Cocaine- and antidepressant-sensitive norepinephrine and serotonin transporters (NETs and SERTs) are closely related members of the Na+/Cl- transporter gene family, whose other members include transporters for inhibitory amino acid transmitters, neuromodulators, osmolytes and nutrients. Availability of cloned NET and SERT cDNAs has permitted rapid progress in the definition of cellular sites of gene expression, the generation of transporter-specific antibodies suitable for biosynthetic and localization studies, the examination of structure-function relationships in heterologous expression systems and a biophysical analysis of transporter function. In situ hybridization and immunocytochemical studies indicate a primary expression of NET and SERT genes in brain by noradrenergic and serotonergic neurons, respectively. Both NET and SERT are synthesized as glycoproteins, with multiple glycosylation states apparent for SERT proteins in the brain and periphery. N-glycosylation of NET and SERT appears to be essential for transporter assembly and surface expression, but not for antagonist binding affinity. Homology cloning efforts have revealed novel NET and SERT homologs in nonmammalian species that are of potential value in the delineation of the precise sites for substrate and antagonist recognition, including a Drosophila melanogaster SERT with NET-like pharmacology. Electrophysiological recording of human NETs and SERTs stably expressed in HEK-293 cells reveals that both transporters move charge across the plasma membrane following the addition of substrates; these currents can be blocked by NET-and SERT-selective antagonists as well as by cocaine.
TL;DR: Results are consistent with, but do not prove that acidosis stimulates muscle proteolysis by activating the ATP-ubiquitin-proteasome-dependent, proteolytic pathway.
Abstract: Metabolic acidosis often leads to loss of body protein due mainly to accelerated protein breakdown in muscle. To identify which proteolytic pathway is activated, we measured protein degradation in incubated epitrochlearis muscles from acidotic (NH4Cl-treated) and pair-fed rats under conditions that block different proteolytic systems. Inhibiting lysosomal and calcium-activated proteases did not reduce the acidosis-induced increase in muscle proteolysis. However, when ATP production was also blocked, proteolysis fell to the same low level in muscles of acidotic and control rats. Acidosis, therefore, stimulates selectively an ATP-dependent, nonlysosomal, proteolytic process. We also examined whether the activated pathway involves ubiquitin and proteasomes (multicatalytic proteinases). Acidosis was associated with a 2.5- to 4-fold increase in ubiquitin mRNA in muscle. There was no increase in muscle heat shock protein 70 mRNA or in kidney ubiquitin mRNA, suggesting specificity of the response. Ubiquitin mRNA in muscle returned to control levels within 24 h after cessation of acidosis. mRNA for subunits of the proteasome (C2 and C3) in muscle were also increased 4-fold and 2.5-fold, respectively, with acidosis; mRNA for cathepsin B did not change. These results are consistent with, but do not prove that acidosis stimulates muscle proteolysis by activating the ATP-ubiquitin-proteasome-dependent, proteolytic pathway.
TL;DR: The findings indicate that the muscarinic receptor proteins occur in distinct populations of striatal neurons; that the receptor proteins concentrate postsynaptically at synapses, including many considered to be noncholinergic; that m2 is the predominantMuscarinic autoreceptor in the striatum; and that each receptor subtype may be a presynaptic heteroceptor inThe striatum modulating extrinsic striatal afferents.
Abstract: Muscarinic ACh receptors mediate complex and clinically important effects in the striatum. To better understand the roles of the different muscarinic receptor subtypes (m1-m4), we have determined the cellular and subcellular distribution of the m1-m4 receptor proteins in the rat neostriatum using subtype-specific antibodies and avidin-biotin-peroxidase immunocytochemistry for light and electron microscopy. m1 receptor protein is expressed in 78% of neurons and is enriched in spiny dendrites and at postsynaptic densities. A small number of m1-immunoreactive axon terminals were observed, all forming asymmetrical synapses. About 2.5% of striatal neurons express m2 receptor protein with reaction product evident, by light microscopy in scattered large oval neurons with enfolded nuclei and long aspiny dendrites. By electron microscopy, m2 immunocytochemistry labeled somata, aspiny dendrites, and many axon terminals. Most axon terminals containing m2 make symmetrical synapses with somata, and dendritic shafts and spines. In addition, many m2-immunoreactive axon terminals formed asymmetrical synapses with spines or dendrites. m3 receptor protein was not evident in somata by light microscopy but was present in a distinct population of small-caliber spiny dendrites as well as in axon terminals forming asymmetrical synapses with spines. m4 receptor protein was heterogeneously distributed in the neostriatum and localized to 44% of striatal cells. m4-positive neurons had the ultrastructural features of medium spiny neurons with reaction product particularly concentrated in spines, often at postsynaptic densities. Axon terminals containing m4 form asymmetrical synapses, primarily with spines. These findings indicate that the muscarinic receptor proteins occur in distinct populations of striatal neurons; that the receptor proteins concentrate postsynaptically at synapses, including many considered to be noncholinergic; that m2 is the predominant muscarinic autoreceptor in the striatum; and that each receptor subtype may be a presynaptic heteroceptor in the striatum modulating extrinsic striatal afferents.
Journal Article•
TL;DR: The results suggest that optimal stimulation of unprimed T cells to proliferate and release cytokines may require participation of both of these CTLA4 counter receptors, and confirm the importance of GM-CSF for the maturation of DC into potent stimulators of T cell activation.
Abstract: Dendritic cells (DC) play a critical role in the initiation of T cell-mediated immune responses, and express costimulatory molecules that are required for optimal activation of unprimed T cells. Studies on the regulation of the costimulatory molecules on DC have produced evidence from several systems that GM-CSF can up-regulate expression of CTLA4 counter receptor (CTLA4-CR) (but not intercellular adhesion molecule 1 (ICAM-1) and heat stable Ag (HsAg)) on DC. This is demonstrated on splenic DC, Langerhans cells, kidney DC in culture, and in a skin-explant culture system, in which the increased expression of CTLA4-CR on Langerhans cells (LC) occurs concomitantly with their migration out of skin. Interestingly, despite the ability of both GM-CSF and IFN-gamma to increase CTLA4-CR and maintain similar levels of ICAM-1, HsAg, and MHC molecule expression, the functional consequences of these cytokines on splenic DC are distinctly different. GM-CSF enhances the ability of DC to stimulate both T cell proliferation and cytokine release, whereas IFN-gamma causes no increase in immunostimulatory function. Further analysis of the CTLA4-CR on these cell populations by using the GL-1 and IG10 mAbs has shown that GM-CSF-cultured DC express high levels of both B7-1 and B7-2, whereas IFN-gamma-cultured DC express increased levels of only B7-2. These results suggest that optimal stimulation of unprimed T cells to proliferate and release cytokines may require participation of both of these CTLA4 counter receptors, and confirm the importance of GM-CSF for the maturation of DC into potent stimulators of T cell activation.
TL;DR: The present study tests the degree to which basal ganglia-thalamocortical circuits are functionally segregated at the level of the subthalamic nucleus (STN), and the polarity and latencies of neuronal responses to passive and active movements of the limbs.
Abstract: 1. The present study tests several key aspects of the current model of the intrinsic circuitry of the basal ganglia, in particular the degree to which basal ganglia-thalamocortical circuits are fun...
TL;DR: It was concluded that youngsters were not imitatively learning their communicatory gestures from conspecifics, but rather that they were individually conventionalizing them with each other.
Abstract: Observations of chimpanzee gestural communication are reported. The observations represent the third longitudinal time point of an ongoing study of the Yerkes Primate Center Field Station chimpanzee group. In contrast to observations at the first two time points, the current observations are of a new generation of infants and juveniles. There were two questions. The first concerned how young chimpanzees used their gestures, with special focus on the flexibility or intentionality displayed. It was found that youngsters quite often used the same gesture in different contexts, and different gestures in the same context. In addition, they sometimes used gestures in combinations in a single social encounter, these combinations did not convey intentions that could not be conveyed by the component gestures, however. It was also found that individuals adjusted their choice of signals depending on the attentional state of the recipient. The second question was how chimpanzees acquired their gestural signals. In general, it was found that there was little consistency in the use of gestures among individuals, especially for non-play gestures, with much individual variability both within and across generations. There were also a number of idiosyncratic gestures used by single individuals at each time point. It was concluded from these results that youngsters were not imitatively learning their communicatory gestures from conspecifics, but rather that they were individually conventionalizing them with each other. Implications of these findings for the understanding of chimpanzee communication and social learning are discussed.
TL;DR: Normal alleles with greater than 24 perfect 3' CGG repeats appear more frequently on haplotypes overrepresented among fragile X chromosomes, suggesting stability differences between the leading and lagging strands of DNA replication.
TL;DR: It is shown that treatment of the C3H/He recipient of a BALB/c vascularized cardiac allograft with a 12-day course of CTLA4-Ig produced indefinite graft survival (> 100 days) in the majority of recipients and demonstrated donor- specific transplantation tolerance when tested with donor-specific and third-party skin grafts.
Abstract: The rejection of the transplanted allograft is dependent on T cell activation, which requires T cell receptor engagement by antigen and costimulatory signals delivered by T cell surface molecules such as CD28. CTLA4-Ig is a fusion protein that has previously been shown to block the CD28-mediated costimulatory signal and inhibit immune responses in vitro and in vivo. In this report we show that treatment of the C3H/He recipient of a BALB/c vascularized cardiac allograft with a 12-day course of CTLA4-Ig produced indefinite graft survival (> 100 days) in the majority of recipients. In addition, these recipients demonstrated donor-specific transplantation tolerance when tested with donor-specific (BALB/c) and third-party (C57BL/10) skin grafts. These results demonstrate that CTLA4-Ig can induce transplantation tolerance in the adult murine cardiac allograft model.