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S Levine

Publications and source records attributed to S Levine.

At least 19 recordsLinked to original sources
PubMed2006

Differential disinhibition of the neonatal hypothalamic- pituitary-adrenal axis in brain-specific CRH receptor 1-knockout mice.

In the adult, corticotropin-releasing hormone (CRH) is the key mediator for the behavioural and neuroendocrine response to stress. It has also been hypothesized that, during postnatal development of the stress system, CRH controls the activity of the HPA axis and mediates the effects of early disturbances, e.g. 24 h of maternal deprivation. In the current study we investigated the function of specific brain corticotropin-releasing hormone receptor type 1 (CRHR1) subpopulations in the control of the HPA axis during postnatal development under basal conditions as well as after 24 h of maternal deprivation. We used two conditional CRHR1-deficient mouse lines which lack this receptor, either specifically in forebrain and limbic structures (Cam-CRHR1) or in all neurons (Nes-CRHR1). Basal circulating corticosterone was increased in Nes-CRHR1 mice compared to controls. Corticosterone response to maternal deprivation was significantly increased in both CRHR1-deficient lines. In the paraventricular nucleus, Cam-CRHR1 animals displayed enhanced CRH and decreased vasopressin expression levels. In contrast, gene expression in Nes-CRHR1 pups was strikingly similar to that in maternally deprived control pups. Furthermore, maternal deprivation resulted in an enhanced response of Cam-CRHR1 pups in the brain, while expression levels in Nes-CRHR1 mouse pups were mostly unchanged. Our results demonstrate that brainstem and/or hypothalamic CRHR1 contribute to the suppression of basal corticosterone secretion in the neonate, while limbic and/or forebrain CRHR1 dampen the activation of the neonatal HPA axis induced by maternal deprivation.

Animals↗
PubMed2006

Metabolic signals modulate hypothalamic-pituitary-adrenal axis activation during maternal separation of the neonatal mouse.

The postnatal development of the mouse is characterised by a period of hypo-responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to moderate stressors. Maternal separation disinhibits this blockade of the HPA axis, but the mechanism responsible is not clear. The present study examined the influence of metabolic signals on the central and peripheral components of the HPA axis in neonatal mice aged 8 days in absence or presence of the mother. Reductions in plasma glucose and leptin as well as rapid increases in plasma ghrelin were apparent in the neonate 4 h following maternal deprivation and maximal at 8 h. In addition, maternal separation induced an increase of neuropeptide Y (NPY) mRNA expression in the arcuate nucleus, a decrease of corticotrophin-releasing hormone (CRH) mRNA expression in the paraventricular nucleus and a rise in serum corticosterone. Pharmacological manipulation of the metabolic signals attenuated the HPA response to maternal separation. Thus, the rise in plasma corticosterone induced by maternal separation was ameliorated by prevention of reduction in blood glucose or blockade of the ghrelin signalling pathway, as were the hypothalamic changes in NPY and CRH mRNAs. By contrast, leptin treatment did not affect the HPA axis response to maternal separation. Together these results suggest that metabolic signals play an important role in triggering the HPA response of the neonate to maternal separation.

Analysis of Variance↗
PubMed2005

Stress and salivary cortisol during pregnancy.

The purpose of this study was to determine whether exposure to stressful life events was associated with changes in levels of circulating cortisol during pregnancy in a population of 603 pregnant women. The participating pregnant women filled out a questionnaire and collected a morning and evening sample of saliva in early pregnancy (median 14th gestational week) and in late pregnancy (median and 30th gestational week). They were asked to report the number of life events experienced during first and second trimester, respectively, and were asked to rate the intensity of the experienced events. Complications related to the pregnancy such as vaginal bleeding and suspected growth retardation were registered and the women were asked about concerns about their pregnancy. The salivary samples were analyzed for cortisol and the levels were higher in late than in early pregnancy. In late pregnancy women exposed to more than one life event or were concerned about pregnancy complications during second trimester had a higher evening cortisol level, whereas morning values were unaffected. After adjustment for smoking women who experienced more than one very stressful life event had 27% higher evening cortisol concentrations (95% confidence intervals: 1-59%). Women with worries about pregnancy complications had 27% (95% confidence intervals: 2-57%) higher levels. In early pregnancy women reporting stressful life events did not have higher evening cortisol levels, but tended to have a blunted morning HPA response. In conclusion, we found differences in the associations between chronic stress in early and late pregnancy and cortisol levels indicating that the response to chronic stress is dependent on the stage of the pregnancy.

Adult↗
PubMed2005

Histopathological features of chronic granulomatous disease (CGD) in childhood.

AIMS: To describe the spectrum of histopathological features encountered in children with chronic granulomatous disease (CGD) at a specialist centre. METHODS AND RESULTS: The histopathological findings of 88 surgical pathology requests from a range of organ systems including upper and lower gastrointestinal tract biopsy series, liver, bladder, bone, lung, skin, soft tissue, bone marrow and lymph node biopsy specimens, in 32 patients aged 4 months to 18 years (median 7 years) with CGD were reviewed. In most tissues the features were those of active chronic inflammation, with or without abscess or granuloma formation, often associated with fungal infection. In some tissues, more characteristic findings were identified, including the presence of pigmented macrophages, especially in hepatic sinusoids and colonic mucosa, where active chronic eosinophil predominant colitis was also observed. CONCLUSIONS: Chronic granulomatous disease may present to histopathologists in a wide range of tissue specimens most often demonstrating features of active chronic inflammation with or without granuloma formation. The presence of numerous pigmented macrophages in association with such inflammation should raise suspicion of the diagnosis. In addition, diffuse granulomatous inflammation of the lung and hepatic abscess formation should be regarded as suggestive of the diagnosis.

Adolescent↗
PubMed2004

Glucocorticoid receptor blockade disinhibits pituitary-adrenal activity during the stress hyporesponsive period of the mouse.

During postnatal development, mice undergo a period of reduced responsiveness of the pituitary-adrenal axis, the stress hyporesponsive period (SHRP), which is largely under control of maternal signals. The present study was designed to test the hypothesis that this quiescence in hypothalamic-pituitary-adrenal (HPA) activity is mediated by glucocorticoid feedback. For this purpose, the role of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in control of HPA activity was examined during the SHRP and in response to 24 h of maternal deprivation. Nondeprived or deprived (24 h) CD1 mice on postnatal d 8 were injected sc at 16 and 8 h before testing with the MR antagonist RU28318 or the GR antagonist RU38486. The results showed that, in nondeprived mice, blockade of GR rather than MR triggered a profound increase in anterior pituitary proopiomelanocortin mRNA, circulating ACTH, and corticosterone concentrations. In contrast, CRH mRNA in hypothalamus and GR mRNA in hippocampus and hypothalamus were decreased. Blockade of the GR during the deprivation period amplified the rise in corticosterone induced by maternal deprivation, whereas it reversed the deprivation effect on the other HPA markers, leading to profound increases in plasma ACTH, proopiomelanocortin mRNA expression in the anterior pituitary, CRH mRNA expression in the paraventricular nucleus, and MR mRNA expression in the hippocampus, but not in GR mRNA expression in the hippocampus and paraventricular nucleus. In conclusion, the data suggest that control of postnatal pituitary-adrenal activity during the SHRP involves GR-mediated feedback in the anterior pituitary, which is further potentiated in the absence of the mother.

Adrenal Glands↗
PubMed2004

The dynamics of the hypothalamic-pituitary-adrenal axis during maternal deprivation.

A close contact between the dam and the litter is essential for the normal development of the hypothalamic-pituitary-adrenal (HPA) axis in rats and mice. Maternal signals, as licking and feeding, have been shown to sustain the HPA axis of the pups in a hypo-responsive state. Disruption of this mother-pup interaction by 24 h of maternal deprivation activates the otherwise quiescent stress system of the neonates, resulting in an enhanced adrenal sensitivity to adrenocorticotropic hormone (ACTH) and a decreased expression of central HPA markers, such as corticotropin-releasing hormone (CRH). However, the dynamics of these central and peripheral changes over the 24h period are largely unknown. In this study, we examined the time course of some of the central and peripheral indices of HPA activity during 24 h of maternal deprivation. We measured corticosterone and ACTH in the blood as well as CRH, mineralocorticoid and glucocorticoid receptor expression in the brain. Our results demonstrate that each of the components of the HPA axis responds to maternal deprivation at different time points following removal of the mother and with a very specific time course. The main activation of the HPA axis occurred between 4 h and 8 h of maternal absence. By contrast, during the second half of the deprivation period, negativefeedback mechanisms restrained the further increase in ACTH and corticosterone release. We conclude that maternal deprivation triggers a cascade of sequential changes at the various levels of the stress system, and that measuring only one aspect of the system at one time point does not accurately reflect the dynamic alterations of the HPA axis.

Adrenocorticotropic Hormone↗
PubMed2003

Regulation of the developing hypothalamic-pituitary-adrenal axis in corticotropin releasing hormone receptor 1-deficient mice.

During postnatal development, mice undergo a so-called stress hyporesponsive period, which is characterized by low basal corticosterone levels and the inability of mild stressors to induce a corticosterone response. The stress hyporesponsiveness is in part regulated by maternal factors. Twenty-four hours of deprivation results in an activation of basal and stress-induced corticosterone and a down-regulation of corticotropin releasing hormone (CRH), mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) expression in the brain. It has been hypothesized that the CRH receptor 1 (CRHr1) may play an important regulatory role during development by mediating the effects of maternal deprivation. Using CRHr1-deficient mice we examined the role of this receptor on the maternal deprivation effects and in regulating the expression of hypothalamic-pituitary-adrenal axis-related genes. We could demonstrate that the CRHr1 is essential for the activation of the corticosterone response following maternal deprivation, most likely due to the lack of the receptor in the pituitary. Furthermore, we could show that the CRHr1 is regulating the expression of CRH and MRs. In contrast, effects of maternal deprivation during postnatal development on GRs are not mediated by this receptor.

Animals↗
PubMed2003

The postnatal development of the hypothalamic-pituitary-adrenal axis in the mouse.

The main characteristic of the postnatal development of the stress system in the rat is the so-called stress hypo-responsive period (SHRP). Lasting from postnatal day (pnd) 4 to pnd 14, this period is characterized by very low basal corticosterone levels and an inability of mild stressors to induce an enhanced ACTH and corticosterone release. During the last years, the mouse has become a generally used animal in stress research, also due to the wide availability of genetically modified mouse strains. However, very few data are available on the ontogeny of the stress system in the mouse. This study therefore describes the postnatal ontogeny of peripheral and central aspects of the hypothalamic-pituitary-adrenal (HPA) axis in the mouse. We measured ACTH and corticosterone in blood and CRH, urocortin 3 (UCN3), mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) transcripts in the brain at postnatal days 1, 2, 4, 6, 9, 12, 14 and 16. Our results show that we can subdivide the postnatal development of the HPA axis in the mouse in two phases. The first phase corresponds to the SHRP in the rat and lasts from right after birth (pnd 1) until pnd 12. Basal corticosterone levels were low and novelty exposure did not enhance corticosterone or ACTH levels. This period is further characterized by a high expression of CRH in the paraventricular nucleus (PVN) of the hypothalamus. Expression levels of GR in the hippocampus and UCN3 in the perifornical area are low at birth but increase significantly during the SHRP, both reaching the highest expression level at pnd 12. In the second phase, the mice have developed past the SHRP and were now exhibiting enhanced corticosterone basal levels and a response of ACTH and corticosterone to mild novelty stress. CRH expression was decreased significantly, while expression of UCN3 and GR remained high, with a small decrease at pnd 16. The expression of MR in the hippocampus was very dynamic throughout the postnatal development of the HPA axis and changed in a time and subregion specific manner. These results demonstrate for the first time the correlation between the postnatal endocrine development of the mouse and gene expression changes of central regulators of HPA axis function.

Adrenocorticotropic Hormone↗
PubMed2002

Pyridoxine (vitamin B6) toxicity: enhancement by uremia in rats.

Pyridoxine is not completely innocuous. Large doses can cause a peripheral neuropathy despite renal excretion of this water-soluble vitamin. Renal failure patients are treated with pyridoxine to prevent a deficiency. The safety of pyridoxine treatment in the presence of renal dysfunction has not been studied. Our experiments on anephric rats show that the uremic state, in a mere 3 or 4 days, causes a 5- to 10-fold increase in susceptibility to pyridoxine-induced neuronopathy. These results suggest a need for caution in prescribing pyridoxine to uremic patients who will probably take the vitamin daily for many years.

Animals↗
PubMed2002

Proliferation of glial cells induced by lithium in the neural lobe of the rat pituitary is enhanced by dehydration.

Rats dehydrated by 6 days of water deprivation had a low level of mitotic activity in the astrocytes ('pituicytes') of the neural lobe of the pituitary. Mitotic activity in the pituicytes was greatly increased when isotonic lithium was administered in the last 3 days of water deprivation. Rehydration on the last day of the experiment produced a further increase in mitoses. Isotonic solutions of sodium, potassium or rubidium chloride did not increase mitoses. This model of cell proliferation is of interest because the mitotic activity is related to a physiological attempt to maintain homeostasis rather than a response to injury or the development of neoplasia.

Animals↗
PubMed2002

Maternal regulation of the hypothalamic-pituitary-adrenal axis in the 20-day-old rat: consequences of laboratory weaning.

There is a large body of evidence that the development of the hypothalamic-pituitary-adrenal (HPA) system in the rat is under maternal regulation. One method used to study the influence of the dam-pup interaction in neonates and weanlings is the separation of mother and litter for 24 h. Previous studies showed that, even at the time of weaning, maternal deprivation results in a dysregulation of the HPA axis at multiple levels. However, the maternal deprivation paradigm usually includes deprivation of food and water, and it was not clear to which extent the observed effects are due to either maternal cues or dehydration and fasting. The primary purpose of the present study was to determine the role of fasting and/or maternal separation on the HPA axis at the time of weaning. Pups at 20 days after parturition are capable of self-feeding and no longer require tactile stimulation to induce eliminative functions. The results indicated that 24 h of fasting led to increased basal levels and further increases in stress induced corticosterone secretion. Fasting also appeared to contribute to the down regulation of basal glucocorticoid receptor mRNA in the hippocampus. In contrast, abrupt weaning irrespective of fasting or dehydration resulted in a suppressed adrenocorticotropin hormone response to an injection of isotonic saline. Although there was an effect of maternal separation on corticotropin-releasing factor mRNA in the paraventricular nucleus, this effect was further exacerbated by the absence of food. Finally, all rats that were separated from their dams showed more efficient negative-feedback. Thus, different aspects of the HPA system appear to respond differentially to either the absence of food or the absence of the mother or both.

Adrenocorticotropic Hormone↗
PubMed2002

Efficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerases in vitro.

Entecavir (ETV) is a potent and selective inhibitor of hepatitis B virus (HBV) replication in vitro and in vivo that is currently in clinical trials for the treatment of chronic HBV infections. A major limitation of the current HBV antiviral therapy, lamivudine (3TC), is the emergence of drug-resistant HBV in a majority of treated patients due to specific mutations in the nucleotide binding site of HBV DNA polymerase (HBV Pol). To determine the effects of 3TC resistance mutations on inhibition by ETV triphosphate (ETV-TP), a series of in vitro studies were performed. The inhibition of wild-type and 3TC-resistant HBV Pol by ETV-TP was measured using recombinant HBV nucleocapsids, and compared to that of 3TC-TP. These enzyme inhibition studies demonstrated that ETV-TP is a highly potent inhibitor of wild-type HBV Pol and is 100- to 300-fold more potent than 3TC-TP against 3TC-resistant HBV Pol. Cell culture assays were used to gauge the potential for antiviral cross-resistance of 3TC-resistant mutants to ETV. Results demonstrated that ETV inhibited the replication of 3TC-resistant HBV, but 20- to 30-fold higher concentrations were required. To gain further perspective regarding the potential therapeutic use of ETV, its phosphorylation was examined in hepatoma cells treated with extracellular concentrations representative of drug levels in plasma in ETV-treated patients. At these concentrations, intracellular ETV-TP accumulated to levels expected to inhibit the enzyme activity of both wild-type and 3TC-resistant HBV Pol. These findings are predictive of potent antiviral activity of ETV against both wild-type and 3TC-resistant HBV.

Antiviral Agents↗
PubMed2001

Thrombolysis in patients with transient neurologic deficits.

What is the risk of thrombolysis in patients with acute stroke who might recover without treatment? In the National Institute of Neurological Disorders and Stroke rt-PA for Acute Stroke Trial, 2.6% of patients taking placebo showed spontaneous 24-hour recovery, compared to 11.5% of recombinant tissue-type plasminogen activator (rt-PA)-treated patients (p < 0.001). There were no symptomatic ICH in the patients taking placebo; one hypertensive, rt-PA-treated patient hemorrhaged. Assuming the National Institute of Neurological Disorders and Stroke protocol is followed rigorously, patients with acute stroke rarely recover spontaneously and the thrombolytic risk is low.

Aged↗
PubMed2001

Red crossroads.

Explore the source record for details and available documents.

Administrative Personnel↗
PubMed2001

Stress-induced alterations in locus coeruleus gene expression during ontogeny.

Brainstem noradrenergic neurons, particularly the locus-coeruleus (LC), play a pivotal role in modulating the central stress response and have been implicated in regulating the hypothalamic-pituitary-adrenal (HPA) axis. In adult rats, acute stress causes an increase in LC firing and tyrosine hydroxylase (TH) gene expression. While the role of the LC-norepinephrine (LC-NE) system in the adult stress response has been well characterized, there is limited evidence for its participation during development. Previous studies described the neonatal HPA axis as hyporeactive because of stimulus-selective pituitary activation. However, maternal deprivation does reinstate stress-induced endocrine activity and can amplify the neural stress response. Considering that LC neurons can modulate neuroendocrine activity, we hypothesized that the LC-NE system would be stress-responsive during development. Because maternal deprivation (DEP) can alter the central stress response, we examined the LC-NE stress response in both DEP and non-deprived (NDEP) pups. Following an isotonic saline injection (stressor) the time course of TH, c-fos and glucocorticoid receptor (GR) mRNA was examined. Stress-induced TH mRNA was increased in DEP pups at postnatal day (pnd) 12 and in both NDEP and DEP pups at pnd 18. At 15, 30 and 240 min c-fos mRNA was markedly increased in all groups examined. GR mRNA was not altered at pnd 12; however, at pnd 18 NDEP pups showed reduced GR mRNA expression. These data indicate that during ontogeny the LC-NE system is stress-responsive to an acute mild challenge. Activation of LC-NE neurons suggests that this system may participate in modulating the neuroendocrine stress response during development.

Animals↗
PubMed2001

A spike in parathyroid hormone during neck exploration may cause a false-negative intraoperative assay result.

HYPOTHESIS: We hypothesize that false-negative results using the rapid intraoperative parathyroid hormone (IOPTH) assay can be caused by spikes in the level of parathyroid hormone that occur during mobilization of the adenoma. DESIGN: Retrospective analysis of a case series. SETTING: University tertiary care center. PATIENTS: Ten consecutive patients with primary hyperparathyroidism. INTERVENTIONS: All patients underwent neck exploration with IOPTH monitoring. Using a sampling protocol described in the literature, IOPTH values were checked at the time of incision, during mobilization of the adenoma, and 10 minutes after resection of the adenoma. MAIN OUTCOME MEASURES: Patients were evaluated for adequate parathyroid tissue excision as determined by IOPTH levels and examination of ipsilateral glands. All patients had normal serum calcium values documented postoperatively. Parathyroid hormone half-life was calculated assuming first-order kinetic decay. RESULTS: Nine patients had an appropriate decline in IOPTH with a mean +/- SD parathyroid hormone half-life of 3.9 +/- 1.08 minutes. Mobilization of the adenoma resulted in a spike in the IOPTH value, with 1 patient's value increasing from a baseline of 95.5 pg/mL (10.1 pmol/L) to 751 pg/mL (79.1 pmol/L). Another patient who was confirmed to have a solitary adenoma had a false-negative postexcision value. A spike in IOPTH that occurred during neck dissection was not detected by the sampling protocol and explains the false-negative value. A literature review revealed that most protocols check baseline values early in the operation and are at risk for false-negative results due to a spike from mobilization of the adenoma. CONCLUSIONS: These data demonstrate that false-negative IOPTH assay findings can result from a spike in parathyroid hormone level during exploration, which may go unrecognized if baseline values are measured during the early stages of mobilization of the adenoma. We have altered our assay protocol and have begun measuring IOPTH at the time of neck incision, at the time the adenoma is completely removed (time zero [t(0)]), and 10 minutes after excision.

Adenoma↗
PubMed2001

Prevention of chronic peritonitis caused by osmotic dysequilibrium in rats.

OBJECTIVE AND DESIGN: This study was done to determine whether peritonitis caused by osmotic dysequilibrium could be prevented by pretreatment. SUBJECTS: Young adult rats were used after induction of peritonitis by intraperitoneal injections of large volumes of pure water to create severe osmotic dysequilibrium. TREATMENT: During the 1 or 2 weeks before induction of peritonitis, the rats were pretreated by intraperitoneal injections of small volumes of pure water or large volumes of moderately hypotonic electrolytes to produce a slight degree of osmotic dysequilibrium. METHODS: Peritonitis was evaluated by macroscopic and microscopic study of peritoneal tissues. RESULTS: The severity of peritonitis was greatly reduced by the pretreatments. CONCLUSIONS: This study adds the peritoneum to the list of tissues in which adaptation to an injury can be accomplished by pretreatment with the same injurious agent, albeit in a less noxious form.

Animals↗