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Biomedical subjects

S Levine

Publications and source records attributed to S Levine.

At least 109 records · Page 6Linked to original sources
PubMed1997

Developmental expression of the NGF receptor p140trk in the septohippocampal system of the rat: a quantitative analysis.

An RNAse protection assay was used to identify p140trk mRNA in the developing rat septohippocampal system. In both the septum and hippocampus, levels of p140trk mRNA were low at birth and increased thereafter. Levels of transcripts were found to be much higher in the septum than in the hippocampus, whereas another brain region, the hypothalamus, showed levels of expression intermediate between these two structures. Only one isoform of the p140trk receptor was found to be expressed in the rat central nervous system (CNS) during development. This isoform corresponds to the one preferentially expressed in neural tissues in the adult animal. These data show that expression of the high affinity nerve growth factor (NGF) receptor is developmentally regulated during postnatal brain development and suggest that it might mediate NGF effects on developing central cholinergic systems.

Animals↗
PubMed1997

Critical features of an auditable management system for an ISO 9000-compatible occupational health and safety standard.

An International Organization for Standardization (ISO) 9001: 1994-harmonized occupational health and safety (OHS) management system has been written at the University of Michigan, and reviewed, revised, and accepted under the direction of the American Industrial Hygiene Association (AIHA) Occupational Health and Safety Management Systems (OHSMS) Task Force and the Board of Directors. This system is easily adaptable to the ISO 14001 format and to both OHS and environmental management system applications. As was the case with ISO 9001: 1994, this system is expected to be compatible with current production quality and OHS quality systems and standards, have forward compatibility for new applications, and forward flexibility, with new features added as needed. Since ISO 9001: 1987 and 9001: 1994 have been applied worldwide, the incorporation of harmonized OHS and environmental management system components should be acceptable to business units already performing first-party (self-) auditing, and second-party (contract qualification) auditing. This article explains the basis of this OHS management system, its relationship to ISO 9001 and 14001 standards, the philosophy and methodology of an ISO-harmonized system audit, the relationship of these systems to traditional OHS audit systems, and the authors' vision of the future for application of such systems.

Environmental Health↗
PubMed1997

Maternal deprivation and stress induce immediate early genes in the infant rat brain.

The hypothalamic-pituitary-adrenal (HPA) axis is normally quiescent during the stress-hyporesponsive period (SHRP) from day 4-14 in infant rats. However, maternal deprivation (DEP) can disinhibit the HPA axis, thus enabling neonatal rats to respond to mild stressors. In an effort to understand how DEP may alter HPA axis sensitivity, we used in situ hybridization to measure changes in the expression of stress-responsive genes in the brains of neonatal rats. Despite the minimal HPA axis response in nondeprived rats during the SHRP (postnatal day 12), the mild stress of a saline injection significantly increased messenger RNA levels of two immediate-early genes (IEGs), c-fos and NGFI-B, in the hypothalamic paraventricular nucleus (PVN) and in the cerebral cortex. Following 24 h of DEP, the induction of IEGs in response to stress was greatly potentiated in the PVN of P12 neonates. In contrast, DEP attenuated the effects of stress on IEG induction in rats that had matured beyond the SHRP (P20). Surprisingly, DEP decreased basal levels of CRH messenger RNA in the PVN at P12 and P20. Thus the SHRP most accurately refers to HPA axis insensitivity to stress because the brain itself readily responds to stress as evidenced by the induction of IEGs.

Adrenocorticotropic Hormone↗
PubMed1997

Effect of Interleukin-1beta on Pituitary-Adrenal Responses and Body Weight in Neonatal Rats: Interaction with Maternal Deprivation.

The hypothalamic-pituitary-adrenal (HPA) axis of the infant rat is normally hyporesponsive during postnatal days (pnd) four to fourteen. This interval is termed the stress hyporesponsive period (SHRP). The HPA axis, however, does respond to selective stimuli, such as interleukin-1beta (IL-1beta) during this period. Furthermore, maternal deprivation has been shown to alter the system so that it is responsive to mild stimuli. The present studies examined the interaction between 24 h of maternal deprivation and intraperitoneal administration of recombinant human (rh) IL-1beta (4 µg/kg) at 3 ages (i.e., pnd 6, 12, 18) during or after the SHRP. The results demonstrate that maternal deprivation modifies the response of the HPA axis induced by IL-1beta in an age-dependent fashion: 1) a greater response at pnd 6; 2) a quicker response at pnd 12; and 3) a suppressed response pattern at pnd 18. Moreover, these responses across ages differ as a function of maternal contact postinjection: 1) deprivation augments the ACTH and CORT response and maternal contact postinjection further augments this response at pnd 6; 2) deprivation increases the ACTH and CORT response to vehicle and the CORT response to IL-1beta in 12 day-old pups and the mother has a modest inhibitory effect; and 3) at pnd 18 deprivation leads to lower ACTH concentrations, but higher overall CORT levels and maternal contact postinjection effectively suppresses both the ACTH and CORT response to IL-1. These differences in the HPA response do not appear to be due to differences in the immune response. Plasma concentrations of endogenous rat IL-1beta determined 1 and 2 h after injection of rhIL-1beta were not modified by deprivation and were reduced at pnd 18 compared to pnd 6 and 12 in NDEP pups. Finally, IL-1beta reduced food intake, as reflected by a decrease in body weight, in deprived pups at all 3 ages. The findings in the present experiments suggest that there are additional pathways through which IL-1beta can act on the CNS to activate the HPA axis besides direct action at the hypothalamus.

Journal Article↗
PubMed1997

Persistent, but Paradoxical, Effects on HPA Regulation of Infants Maternally Deprived at Different Ages.

Twenty-four hours of maternal deprivation have been shown to have immediate and long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis. In the first experiment the influence of such a maternal deprivation period (pnd 11-12) on basal and stress-induced ACTH and CORT levels 4 and 8 days following reunion was investigated. The results revealed a suppression of the ACTH response in the previously deprived animals which was not reflected in the CORT response. In the second experiment these persistent effects were studied in animals deprived during different stages of development. Deprivation early in development (pnd 3-4) produced an animal with a hyperreactive ACTH response whereas deprivation later (pnd 7-8, pnd 11-12) resulted in a hyporeactive ACTH response to stress at pnd 20. To study further the possible mechanisms leading to these different ACTH responses, we used in situ hybridization to investigate hippocampal mineralocorticoid (MR) and glucocorticoid receptor (GR) gene expression and corticotropin-releasing hormone (CRH) and GR mRNA levels in the paraventricular nucleus of the hypothalamus (PVN) of these 20-day old animals. Permanent changes in hippocampal GR mRNA were seen only in the later deprived pups, whereas GR mRNA was reduced in the PVN in all deprived pups. In conclusion, maternal deprivation during the neonatal period produces alterations in the ACTH response to a mild stress and sustained changes in GR transcript levels. The direction and magnitude of these effects are dependent upon the age at which maternal deprivation is experienced.

Journal Article↗
PubMed1996

Regulation of glucocorticoid and mineralocorticoid receptor mRNAs in the hippocampus of the maternally deprived infant rat.

The hypothalamic-pituitary-adrenal (HPA) axis in the developing rat has a limited response to acute challenges between days 3 and 14 of life. Several hypotheses have been proposed to explain this quiescent state. Immaturity of brain, pituitary and adrenal elements or excessive feedback inhibition are common explanations. Recently, a series of studies by Levine and co-workers has shown that prolonged maternal deprivation (24 h) results in increased basal and stress induced corticosterone (CS) levels. An increased adrenal response to ACTH along with an enhanced and sustained ACTH response have been implicated in this phenomenon. A brain structure that appears to be important for normal HPA function is the hippocampus, a structure rich in corticosteroid receptors, which has been hypothesized to play a role in the basal tone of the HPA and in the magnitude and duration of stress responses. Thus, to study further the possible mechanisms leading to an enhanced and sustained ACTH response that is seen in maternally deprived pups, we used in situ hybridization to investigate hippocampal mineralocorticoid (MR) and glucocorticoid receptor (GR) gene expression in 12 groups of animals: six groups involved 24 h maternally deprived (DEP) and non-deprived (NDEP) rat pups at three ages (6-, 9-, and 12-days-old); the other six groups included pups similarly treated, but challenged with an exposure to a mild stressor (saline injection) and sacrificed 1 h thereafter. We found: (1) an age effect for almost every hippocampal subfield for both MR and GR mRNAs: MR increases with age, while GR decreases: (2) down-regulation of MR mRNA in CA1 region in the DEP animals; and (3) down-regulation of GR mRNA, also in CA1, in the saline-injected DEP and NDEP animals. Our results indicate that corticoid receptors in the developing CA1 hippocampal region appear to be sensitive to circulating CS. They also suggest that the relative ratio of GR and MR in the CA1 region may contribute to the enhanced and sustained CS response seen after a mild stressor in deprived animals.

Adrenocorticotropic Hormone↗
PubMed1996

Effects of excitatory amino acids on the hypothalamic-pituitary-adrenal axis of the neonatal rat.

Most stimuli that elicit a response by the hypothalamic-pituitary-adrenal (HPA) axis of adult rats fail to do so in infant rats aged 4-14 postnatal days (pnd). This interval is termed the stress hyporesponsive period (SHRP). The present study examined the development of the HPA response to the excitatory amino acids (EAAs), N-methyl-D-aspartic acid (NMDA) and kainic acid (KA), at 3 ages (i.e., pnd 6, 12, 18) during or immediately after the SHRP. Results indicate that intraperitoneal (i.p.) administration of 2.5 mg/kg KA or 5 mg/kg NMDA is capable of inducing age- and time-dependent elevations of ACTH and CORT, with KA being the more potent of the two EAAs. In contrast to other stimuli which are capable of eliciting an HPA response during the SHRP, NMDA and KA appear to possess more potent effects at earlier ages. Administration of lower doses of these EAAs did not elicit an HPA response. Pretreatment with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 0.69 mg/kg i.p.), a KA receptor-specific antagonist, attenuated the effects of KA. These results suggest that KA exerts its effects via the KA receptor and that this receptor appears to be mature at both pnd 12 and 18. In contrast, pretreatment with D,L-2-amino-5 phosphonovaleric acid (APV; 7.5 mg/kg i.p.), an NMDA receptor-specific antagonist, was only effective at pnd 18 suggesting that the NMDA receptor is not yet mature at pnd 12. Finally, EAAs induce age- and time-dependent behavioral modifications (i.e., hindpaw scratching and hyperlocomotion). These effects, however, appear to only contribute to, but not cause, the endocrine responses.

2-Amino-5-phosphonovalerate↗
PubMed1996

Long-term effects of neonatal maternal deprivation and ACTH on hippocampal mineralocorticoid and glucocorticoid receptors.

In the brain, corticosteroids bind to two types of receptors, the classical glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). The effects of different manipulations taking place during early ontogeny on GR and MR binding properties were examined in the adult hippocampus. Infant rats at postnatal day (pnd) 3 were deprived of maternal contact for 24 h and injected with saline or ACTH1-24 at the end of the deprivation period. They were then returned to their dams and weaned on pnd 21. At pnd 48, they were sacrificed (24 h post adrenalectomy) and the hippocampal MR and GR measured using an in vitro cytosol binding assay. In the male rats, deprivation and deprivation + ACTH resulted in a reduction of GRs. MRs were also significantly down regulated in the deprived males. In the female rats, saline injections in deprived female rats resulted in increased GR capacity and ACTH injections led to a further up-regulation of the GRs. None of the early manipulations influenced the regulation of the MRs in females. The binding affinity for corticosteroid receptors was also altered by some of the early manipulations. These results in adult (7-week-old) rats indicate that the receptor systems for corticosteroids in the brain are sensitive to brief manipulations occurring early in development. These changes in receptor capacity and/or affinity may affect corticosteroid-mediated processes in the adult rat.

Adrenalectomy↗
PubMed1996

The family study of otitis media: design and disease and risk factor profiles.

Recurrent acute otitis media (RAOM) and chronic otitis media with effusion (COME) exhibit familial aggregation, but environmental risk factors (day care attendance, cigarette smoke exposure, and bottle feeding) are also important in their development. The Family Study of OM was designed to ascertain the RAOM/ COME status of families whose children participated in Otitis Media Research Center studies between 1978 and 1984. Probands were treated with tympanostomy tubes, and had their RAOM/COME status ascertained as criteria for entry into these studies. For the Family Study of OM parents were interviewed about their otitis media and risk factor history; mothers were interviewed about their children's history, and pertinent medical records were obtained. Members of 173 families were examined with otomicroscopy and multifrequency tympanometry; 19% of parents and 32% of siblings were classified as affected, which is substantially higher than RAOM/COME rates from previous reports. Risk factor profiles differed significantly (P < .001) between parents and their children. Younger generation (adjusted odds ratio [OR] = 4.18, 95% confidence interval [CI], 2.74, 6.36) day care attendance (OR = 1.96, 95% CI, 1.32, 2.91) and male gender (OR = 1.42, 95% CI, 1.03, 1.97) were significantly related to RAOM/ COME using logistic regression. Analyses confirm 1) higher disease rates in families with an affected member compared to existing studies of the general population, 2) increased risk of RAOM/COME associated with known risk factors, and 3) increased risk for parents irrespective of risk factors. Additional analyses will explore competing models of disease susceptibility using genetic models and known risk factors.

Adult↗
PubMed1996

Changes in myofibrillar protein composition of human diaphragm elicited by congestive heart failure.

We describe the changes in proportions of myofibrillar proteins elicited by chronic congestive heart failure in the costal diaphragm (DIA) of humans using one and two-dimensional electrophoretic techniques. Three myosin heavy chain (MHC) isoforms were found in the DIA from control subjects: slow MHC I (43 +/- S.E. 2%), fast MHC IIa (41 +/- 2%) and fast MHC IIb (17 +/- 1%). In heart failure DIA, the percentage of MHC I was increased to 57 +/- 2%, while that of MHC IIb was decreased to 8 +/- 2 (P < 0.001 for both cases). Similarly, this DIA had higher molar ratios (%) of the slow myosin light chain isoforms (i.e. 1sa, 1sb, and 2s), and lower molar ratios of the fast isoforms (i.e. 1f, 2f, and 3f) than control DIA. Heart failure DIA also contained lower proportions of both alpha-tropomyosin and fast isoforms of troponin-T, I and C than control DIA. These results indicate that heart failure elicits fast-to-slow transformations of both myosin and regulatory proteins of human costal DIA. These changes can be viewed as an increase in slow-twitch characteristics of the DIA and differ from the adaptations elicited by heart failure in limb muscles.

Diaphragm↗
PubMed1996

Metallic tin-induced lymphadenopathy in rat strains and hybrids.

Metallic tin powder, injected into Lewis rats obtained from three different sources, caused enlargement of the regional draining lymph nodes. The histopathology featured epithelioid cell granulomas around phagocytosed particles of tin and an intense hyperplasia of plasma cells. The same material injected into August rats enlarged the lymph nodes but the enlargement was caused by granulomas without a major concomitant plasma cell response. In most other strains, tin produced less lymph node enlargement and the plasma cell response was minimal. However, F1 hybrids of Lewis rats with either the August, Brown-Norway (BN), or Dark Agouti (DA) strains developed plasma cell hyperplasia similar to that seen in the parental Lewis strain. The response to tin was the same whether the tin was injected into the feet or into the peritoneal cavity. Thus, the lymph node response to metallic tin varied from a slight, banal response to insoluble foreign particles, to an exuberant granulomatous hyperplasia, to an intense plasmacellular hyperplasia, depending on the genetic characteristics of the subjects.

Animals↗
PubMed1996

Lithium distribution in experimental inflammation of brain and spinal cord.

1. Autoimmune inflammation of the nervous system caused extensive changes in the distribution of lithium injected into rats. 2. Serum lithium levels were greatly increased because of failure of renal excretion caused by pre-renal azotemia, urinary retention and lack of dietary sodium. Brain, spinal cord, pituitary and adrenal levels of lithium were also elevated, reflecting the high serum levels. 3. However, the location and degree of this elevation corresponded to the predominant location of the inflammation. As a result, lithium levels in spinal cord approached and even exceeded the lithium content of brain.

Animals↗
PubMed1996

The sensation of dyspnea during exercise is not determined by the work of breathing in patients with heart failure.

OBJECTIVES: The present study sought to investigate whether the work of breathing was reduced after heart transplantation. Accordingly, the tension time index of the diaphragm was measured in patients with heart failure and in transplant recipients. BACKGROUND: Patients with heart failure are frequently limited by exertional dyspnea that may be due to the increased work of breathing. After heart transplantation, exertional dyspnea is markedly diminished. Whether work of breathing is reduced in posttransplant recipients is unknown. METHODS: Nine patients with heart failure, six normal subjects and six heart transplant recipients were studied. Transdiaphragmatic pressure was measured throughout exercise. Accessory respiratory muscle oxygenation was assessed using near-infrared spectroscopy. Peak oxygen consumption, time in inspiration, time per breath and maximal inspiratory and expiratory pressures were measured in all subjects. RESULTS: The tension time index remained markedly abnormal after heart transplantation both at rest ([mean +/- SD] normal group 0.01 +/- 0.006, heart failure group 0.026 +/- 0.018, transplant group 0.058 +/- 0.015, p < 0.004) and at peak exercise (normal group 0.03 +/- 0.02, heart failure group 0.10 +/- 0.03, transplant group 0.10 +/- 0.04, p < 0.0001). Accessory respiratory muscle deoxygenation was present only in patients with heart failure (near-infrared absorbency changes [arbitrary units]: normal group -3 +/- 6, heart failure group 28 +/- 5, transplant group -3.5 +/- 4.4, p < 0.0001). CONCLUSIONS: Although heart transplantation alleviates dyspnea in patients with heart failure, the work of breathing as assessed by the tension time index of the diaphragm is not decreased. Amelioration of exertional dyspnea is achieved by other mechanisms, such as improved respiratory muscle perfusion.

Case-Control Studies↗
PubMed1996

Neonatal maternally deprived rats have as adults elevated basal pituitary-adrenal activity and enhanced susceptibility to apomorphine.

Maternal deprivation of neonatal rats for 24 h enhances the adrenocortical response to stress and/or adrenocorticotropin hormone (ACTH) stimulation during the stress hyporesponsive period (SHRP). The present study tests the hypothesis that such maternally deprived neonatal male rats show altered hypothalamic-pituitary-adrenal (HPA) regulation not only immediately after deprivation but also in later life. In addition, we found previously that neonatal changes in HPA activity preceded modulation of nigrostriatal dopamine function. Therefore, we also measured dopamine responsiveness in adult rats which were deprived of their mother during infancy. Neonatal male rats were maternally deprived for 24 h at the age of 3 days, whereas rats of the control group were left undisturbed. At 60 days of age deprived and non-deprived rats were decapitated and brain, adrenal glands and thymus were removed. Trunk blood was collected for determination of plasma ACTH, corticosterone and prolactin concentrations using radioimmunoassay procedures. mRNA levels of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs), corticotropin-releasing hormone (CRH) mRNA and tyrosine hydroxylase (TH) mRNA were measured in brain sections with in situ hybridization. In a second group of male deprived and non-deprived rats apomorphine-induced stereotypic gnawing behaviour was examined at 60 days of age as a measure for functional activity of the dopamine system. Deprived neonatal rats showed the following characteristics as compared with non-deprived rats: (i) lower basal CRH mRNA concentration in parvocellular neurons of the paraventricular nucleus of the hypothalamus (PVN), while basal plasma ACTH and corticosterone concentrations were significantly elevated. Basal prolactin levels were not different. (ii) Similar hippocampal MR and GR mRNA levels. (iii) Significantly reduced GR mRNA levels in PVN and anterior pituitary. (iv) Significantly enhanced apomorphine-induced stereotypic gnawing behaviour and (v) higher TH mRNA levels in substantia nigra, while no changes were found in the ventral tegmental area (VTA). It is concluded that maternally deprived neonatal male rats display as young adults elevated basal pituitary-adrenal activity and enhanced apomorphine susceptibility.

Animals↗