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Hershel Raff

Publications and source records attributed to Hershel Raff.

At least 19 recordsLinked to original sources
PubMed2007

Microarray and real-time PCR analysis of adrenal gland gene expression in the 7-day-old rat: effects of hypoxia from birth.

We hypothesize that changes in adrenal gene expression mediate the increased plasma corticosterone and steroidogenesis in rat pups exposed to hypoxia from birth. In the current study, rat pups (with their dams) were exposed to hypoxia from birth and compared with pups from normoxic dams fed ad libitum or pair fed to match the decreased maternal food intake that occurs during hypoxia. Microarray analysis was performed, followed by verification with real-time PCR. Furthermore, the expression of selected genes involved in adrenal function was analyzed by real-time PCR, regardless of microarray results. Hypoxia increased plasma ACTH and corticosterone, while food restriction had no effect. Microarray revealed that many of the genes affected by hypoxia encode proteins that require molecular oxygen (monooxygenases, oxidoreductases, and electron transport), whereas only a few genes known to be involved in adrenal steroidogenesis were affected. Interestingly, the expression of genes involved in mitochondrial function and intermediary metabolism was increased by hypoxia. Real-time PCR detected a small but significant increase in the expression of Cyp21a1 mRNA in the hypoxic adrenal. When decreased maternal food intake was controlled for, the effects of hypoxia were more pronounced, in that real-time PCR detected significant increases in the expression of Star (244%), Cyp21a1 (208%), and Ldlr (233%). The present study revealed that increased plasma corticosterone in rat pups was due to hypoxia per se, and not as a result of decreased food intake by the hypoxic dam. Furthermore, hypoxia induced changes in gene expression that account for more productive and efficient steroidogenesis.

Adrenal Glands↗
PubMed2006

Association of adrenal steroids with hypertension and the metabolic syndrome in blacks.

Blacks have a high prevalence of hypertension and adrenal cortical adenomas/hyperplasia. We evaluated the hypothesis that adrenal steroids are associated with hypertension and the metabolic syndrome in blacks. Ambulatory blood pressures, anthropometric measurements, and measurements of plasma renin activity (PRA), aldosterone, fasting lipids, glucose, and insulin were obtained in 397 subjects (46% hypertensive and 50% female) after discontinuing antihypertensive and lipid-lowering medications. Hypertension was defined as average ambulatory blood pressure >130/85 mm Hg. Late-night and early morning salivary cortisol, 24-hour urine-free cortisol, and cortisone excretion were measured in a consecutive subsample of 97 subjects (40% hypertensive and 52% female). Compared with normotensive subjects, hypertensive subjects had greater waist circumference and unfavorable lipid profiles, were more insulin resistant, and had lower PRA and higher plasma aldosterone and both late-night and early morning salivary cortisol concentrations. Twenty-four-hour urine-free cortisol and cortisone did not differ. Overall, ambulatory blood pressure was positively correlated with plasma aldosterone (r=0.22; P<0.0001) and late-night salivary cortisol (r=0.23; P=0.03) and inversely correlated with PRA (r=-0.21; P<0.001). Plasma aldosterone correlated significantly with waist circumference, total cholesterol, triglycerides, insulin, and the insulin-resistance index. Based on Adult Treatment Panel III criteria, 17% of all of the subjects were classified as having the metabolic syndrome. Plasma aldosterone levels, but not PRA, were elevated in subjects with the metabolic syndrome (P=0.0002). The association of aldosterone with blood pressure, waist circumference, and insulin resistance suggests that aldosterone may contribute to obesity-related hypertension in blacks. In addition, we speculate that relatively high aldosterone and low PRA in these hypertensive individuals may reflect a mild variant of primary aldosteronism.

Adolescent↗
PubMed2006

Position statement: Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement.

OBJECTIVE: The objective of the study was to evaluate the current state of clinical assays for total and free testosterone. PARTICIPANTS: The five participants were appointed by the Council of The Endocrine Society and charged with attaining the objective using published data and expert opinion. EVIDENCE: Data were gleaned from published sources via online databases (principally PubMed, Ovid MEDLINE, Google Scholar), the College of American Pathologists, and the clinical and laboratory experiences of the participants. CONSENSUS PROCESS: The statement was an effort of the committee and was reviewed in detail by each member. The Council of The Endocrine Society reviewed a late draft and made specific recommendations. CONCLUSIONS: Laboratory proficiency testing should be based on the ability to measure accurately and precisely samples containing known concentrations of testosterone, not only on agreement with others using the same method. When such standardization is in place, normative values for total and free testosterone should be established for both genders and children, taking into account the many variables that influence serum testosterone concentration.

Chemistry, Clinical↗
PubMed2006

Cushing's Syndrome: important issues in diagnosis and management.

CONTEXT: The diagnosis, differential diagnosis, and treatment of Cushing's syndrome are challenging problems in clinical endocrinology. We focus on critical questions addressing screening for Cushing's syndrome, differentiation of Cushing's subtypes, and treatment options. EVIDENCE ACQUISITION: Ovid's MEDLINE (1996 through April 2006) was used to search the general literature. We also relied on previously published reviews and a recent monograph and cite a mix of primary articles and recent reviews. EVIDENCE SYNTHESIS: Although this article represents our opinion, it draws heavily on a recent consensus statement from experts in the field and a recent monograph on Cushing's syndrome. CONCLUSIONS: We concluded that: 1) measurement of late-night or bedtime salivary cortisol is a useful approach to screen for Cushing's syndrome; 2) measurement of suppressed plasma ACTH by immunometric assay is useful to differentiate ACTH-dependent and -independent Cushing's syndrome; 3) inferior petrosal sinus sampling for ACTH should be performed in patients with ACTH-dependent hypercortisolism in whom a pituitary magnetic resonance imaging is normal or equivocal (in the absence of a pituitary ACTH gradient, prolactin levels should be measured to confirm the integrity of venous sampling); 4) computed tomography of the chest and abdomen and somatostatin receptor scintigraphy should be performed in patients with the occult ectopic ACTH syndrome; and 5) patients with Cushing's disease should be referred to a neurosurgeon with extensive experience operating on corticotroph microadenomas. Bilateral laparoscopic adrenalectomy should be considered in patients with Cushing's disease who fail therapies directed at the pituitary.

Adrenocorticotropic Hormone↗
PubMed2006

Characterization of pituitary-adrenocortical activity in the Malayan flying fox (Pteropus vampyrus).

Pituitary-adrenocortical and gonadal endocrine activity was investigated in a captive colony of Pteropus vampyrus, a highly social Old World fruit bat. Both cortisol and corticosterone were present in plasma, at a ratio of approximately 5:1, respectively. Glucocorticoid but not testosterone levels significantly increased prior to and concomitant with the evening active period. Restraint stress for 15-60 min resulted in a significant and rapid increase in plasma levels of adrenocorticotropic hormone (ACTH) and glucocorticoids. ACTH levels quickly returned to baseline following restraint whereas glucocorticoid levels remained elevated for at least 30 min after restraint ended. Plasma ACTH levels after stress were similar to levels reported after stress in other mammals. Stress-induced glucocorticoid levels were several-fold greater than those reported for most mammals. Restraint for 15 min significantly inhibited testosterone levels. Restraint stress did not affect hormone levels on the morning following restraint. Brief capture, handling, and release of the animals did not elicit increases in these hormones. The physiological responsiveness of the pituitary and adrenal glands, along with P. vampyrus's documented seasonality and range of social behaviors, makes these bats an excellent model for exploring the general physiology of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, as well as social influences on these axes.

Adrenocorticotropic Hormone↗
PubMed2006

Adiponectin and resistin in the neonatal rat: effects of dexamethasone and hypoxia.

Hypoxia is a common neonatal stress that induces insulin resistance and a decrease in body weight gain. Dexamethasone is often used to treat neonatal cardiopulmonary disease, and also leads to insulin resistance and a decrease in body weight gain. The current study addressed the hypothesis that serum concentrations of the adipokines adiponectin and/or resistin are altered during hypoxia and/or dexamethasone therapy in neonatal rats. Rat pups with their lactating dams were exposed to hypoxia (11% O2) from birth and treated with a tapering regimen of dexamethasone from postnatal day (PD) 3-6. Serum adiponectin and resistin were measured on PD7. Hypoxia and dexamethasone independently decreased body weight gain and increased adiponectin levels. The combination of hypoxia and dexamethasone did not further increase adiponectin. Dexamethasone caused a small increase in resistin in normoxic pups, which may facilitate the hyperinsulemic- normoglycemic state we previously described. We also conclude that adiponectin is increased during hypoxia in response to a decrease in the sensitivity to insulin.

Adiponectin↗
PubMed2006

Comparative evaluation of a new immunoradiometric assay for corticotropin.

We have characterized the performance of a commercial two-site immunoradiometric assay for manual in vitro diagnostic measurement of plasma corticotropin from Scantibodies Laboratory. We compared the results with those of a similar commonly used assay from Nichols Institute Diagnostics that has recently been withdrawn from production. The lower detection limit, range of the standard curve, cross-reactivity, and intra-assay and inter-assay imprecision of the two assays are very similar. Measurement of clinical samples and a series of samples from an experimental subject demonstrate high correlations between the two assays. These factors, together with recent clearance by the United States Food and Drug Administration for manual in vitro diagnostic measurement, make the Scantibodies corticotropin immunoradiometric assay an appropriate replacement for the Nichols assay.

Adrenocorticotropic Hormone↗
PubMed2005

Steroidogenesis in human aldosterone-secreting adenomas and adrenal hyperplasias: effects of hypoxia in vitro.

The synthesis of adrenal steroids requires molecular oxygen. Because arterial hypoxemia is a common clinical condition, the purpose of the present study was to examine steroidogenesis in vitro under physiological changes in O(2) tension (Po(2)) in cells from human adrenal glands with aldosterone-secreting adenomas (ASA; n=3) or with bilateral adrenal hyperplasia causing Cushing's syndrome (n=4). A decrease in Po(2) from 150 mmHg (mild hyperoxia) to 80 mmHg had minimal effect on steroid production. A reduction to 40 mmHg (still well within the physiological range) significantly inhibited cAMP- and ACTH-stimulated aldosterone, cortisol, and dehydroepiandrosterone (DHEA) production from ASA. Furthermore, cortisol and DHEA production in cells from histologically normal tissue, adjacent to ASA and from bilateral adrenal hyperplasias, was also inhibited under a Po(2) of 40 mmHg. We conclude that physiological decreases in Po(2) to levels typical for adrenal venous Po(2) under mild hypoxia inhibit steroidogenesis. These studies may have implications for oxygen therapy in critically ill patients with functional adrenal insufficiency, as well as for therapeutic options in patients with adrenal neoplasms.

Adrenal Glands↗
PubMed2005

Screening and diagnosis of Cushing's syndrome.

Screening studies in high-risk populations have suggested that Cushing's syndrome is more common than previously appreciated. Patients who have specific signs and symptoms or clinical diagnoses known to be associated with hypercortisolism should be considered for screening. The measurement of late-night salivary cortisol provides the most sensitive method for screening, and urine-free cortisol and low-dose dexamethasone suppression testing may be used for confirmation of the diagnosis of endogenous hypercortisolism

Cushing Syndrome↗
PubMed2005

Elevated late-night salivary cortisol levels in elderly male type 2 diabetic veterans.

OBJECTIVE: Late-night salivary cortisol (LNSC) is reportedly highly accurate for the diagnosis of Cushing's syndrome (CS). However, diagnostic thresholds for abnormal results are based on healthy, young populations and limited data are available on its use in elderly populations with chronic medical conditions. The purpose of this study was to evaluate LNSC levels in elderly male veterans with and without diabetes. DESIGN: Prospective evaluation of LNSC levels in male veterans. PATIENTS: One hundred and fifty-four participants with type 2 diabetes and 52 participants without diabetes. MEASUREMENTS: Participants underwent outpatient LNSC (2300 h) testing. Participants with elevated LNSC (> or = 4.3 nmol/l) underwent secondary testing, including 24-h urine free cortisol (24UFC, > 60 microg/day) and dexamethasone suppression testing (DST, serum cortisol > 50 nmol/l). Participants with positive secondary testing had a morning ACTH level analysed and either pituitary or adrenal imaging performed. RESULTS: One hundred and forty-one diabetics and 46 controls (mean age 61 years) returned samples (91% overall). Average LNSC levels (nmol/l) in diabetics were significantly higher than in nondiabetics [median (interquartile range): 2.6 (1.8-4.1) vs. 1.6 (1.0-2.0)] and in those aged > or = 60 compared to < 60 [2.7 (2.0-4.3) vs. 1.9 (1.4-2.9)] (P < 0.001 for both). Thirty-one participants required secondary testing. Seventy-nine per cent of participants who underwent secondary testing had normal 24UFC and DST. No cases of CS have been diagnosed to date. Increasing age [odds ratio (OR) 2.0 per decade], current diabetes mellitus (OR 4.4), and elevated blood pressure (OR 1.3 per 10 mmHg increase in systolic blood pressure) were associated with abnormal LNSC results (P < 0.05 for each). CONCLUSIONS: LNSC has been shown to be sensitive and specific in diagnosing CS in certain high-risk populations, primarily the young and middle-aged. The development of age- and comorbidity-adjusted thresholds may be warranted for LNSC testing in elderly subjects and in those with significant comorbidity.

Aged↗
PubMed2005

Teaching glucocorticoid negative feedback and adrenocortical regulation using a classic paper by Dr. Dwight Ingle.

The American Physiological Society (APS) Legacy Project and its accompanying Essays on APS Classic Papers have allowed the scientific community on-line access to the entire collection of APS publications since their inception in 1898 (http://www.the-aps.org/publications/legacy/ and http://www.the-aps.org/publications/classics/). The availability of the classic physiological studies provides a unique teaching opportunity. The classic paper of Dr. Dwight Ingle represents just such a study. Dr. Ingle demonstrated that, using only purified extracts of the pituitary (ACTH) and adrenal cortex (corticosterone) and hypophysectomized rats, he could establish several of the basic principles of the control of adrenal function and glucocorticoid negative feedback that are now standard teaching material in endocrinology. An annotated figure from Dr. Ingle's paper is provided, which, when assigned to undergraduate or graduate students, will allow discovery learning. Furthermore, the brilliance and imagination of the physiologists of the last century are highlighted, which allows an appreciation of the seminal work of our predecessors.

Adrenal Cortex↗
PubMed2005

Plasma leptin and ghrelin in the neonatal rat: interaction of dexamethasone and hypoxia.

Ghrelin, leptin, and endogenous glucocorticoids play a role in appetite regulation, energy balance, and growth. The present study assessed the effects of dexamethasone (DEX) on these hormones, and on ACTH and pituitary proopiomelanocortin (POMC) and corticotropin-releasing hormone receptor-1 (CRHR1) mRNA expression, during a common metabolic stress - neonatal hypoxia. Newborn rats were raised in room air (21% O2) or under normobaric hypoxia (12% O2) from birth to postnatal day (PD) 7. DEX was administered on PD3 (0.5 mg/kg), PD4 (0.25 mg/kg), PD5 (0.125 mg/kg), and PD6 (0.05 mg/kg). Pups were studied on PD7 (24 h after the last dose of DEX). DEX significantly increased plasma leptin and ghrelin in normoxic pups, but only increased ghrelin in hypoxic pups. Hypoxia alone resulted in a small increase in plasma leptin. Plasma corticosterone and pituitary POMC mRNA expression were decreased 24 h following the last dose of DEX, whereas plasma ACTH and pituitary CRHR1 mRNA expression had already increased (normoxia and hypoxia). Hypoxia alone increased corticosterone, but had no effect on ACTH or pituitary POMC and CRHR1 mRNA expression. Neonatal DEX treatment, hypoxia, and the combination of both affect hormones involved in energy homeostasis. Pituitary function in the neonate was quickly restored following DEX-induced suppression of the hypothalamic-pituitary-adrenal axis. The changes in ghrelin, leptin, and corticosterone may be beneficial to the hypoxic neonate through the maintenance of appetite and shifts in intermediary metabolism.

Adrenocorticotropic Hormone↗
PubMed2004

Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids.

Dexamethasone is used as treatment for a variety of neonatal syndromes, including respiratory distress. The present study utilized the power of comprehensive lipid profiling to characterize changes in lipid metabolism in the neonatal lung and brain associated with dexamethasone treatment and also determined the interaction of dexamethasone with hypoxia. A 4-day tapering-dose regimen of dexamethasone was administered at 0800 on postnatal days 3 (0.5 mg/kg), 4 (0.25 mg/kg), 5 (0.125 mg/kg), and 6 (0.05 mg/kg). A subgroup of rats was exposed to hypoxia from birth to 7 days of age. Dexamethasone treatment elicited numerous specific changes in the lipid profile of the normoxic lung, such as increased concentrations of saturated fatty acids in the phosphatidylcholine and cholesterol ester classes. These increases were more profound in the lungs of hypoxic pups. Additional increases in cardiolipin concentrations were also measured in lungs of hypoxic pups treated with dexamethasone. We measured widespread increases in serum lipids after dexamethasone treatment, but the effects were not equivalent between normoxic and hypoxic pups. Dexamethasone treatment in hypoxic pups increased 20:4n6 and 22:6n3 concentrations in the free fatty acid class of the brain. Our results suggest that dexamethasone treatment in neonates elicits specific changes in lung lipid metabolism associated with surfactant production, independent of changes in serum lipids. These findings illustrate the benefits of dexamethasone on lung function but also raise the potential for negative effects due to hyperlipidemia and subtle changes in brain lipid metabolism.

Animals↗
PubMed2004

Lipid and fatty acid profiles in the brain, liver, and stomach contents of neonatal rats: effects of hypoxia.

Neonatal hypoxia leads to clinically significant fatty liver, presumably due to disturbances in lipid metabolism. To fully evaluate lipid metabolism, the present study analyzed the complete lipid profile of the brain, liver, and ingested stomach contents of 7-day-old rats exposed to hypoxia from birth. Hypoxia had negligible direct effects on lipid metabolism in the brain. Conversely, hypoxia exhibited direct effects on hepatic lipid metabolism that could not be fully explained by changes in dietary intake. Triacylglyceride concentration was significantly increased in the hypoxic liver but remained unchanged in the brain and stomach contents. Diacylglyceride concentration was increased in both the brain and liver, and this was associated with increased diacylglyceride in the stomach contents. Most n-3 and n-6 fatty acids were increased in the liver, but not in the brain, of hypoxic pups. These changes did not reflect those measured in the stomach contents. Saturated fatty acid concentrations were increased in both the hypoxic brain and liver, and these changes reflected those in the stomach contents. Hypoxia also increased total phospholipid concentration in the brain and stomach contents. We conclude that neonatal hypoxia indirectly affects specific lipid and fatty acid concentrations in the brain and liver through alterations in the absorbed stomach contents. Hypoxia also exhibits some direct affects through modulation of metabolic pathways in situ, mostly in the liver. In this respect, the neonatal brain exhibits tighter control on lipid homeostasis than the liver during neonatal hypoxia.

Animals↗
PubMed2004

Metabolic consequences of hypoxia from birth and dexamethasone treatment in the neonatal rat: comprehensive hepatic lipid and fatty acid profiling.

Neonatal hypoxia is a common condition resulting from pulmonary and/or cardiac dysfunction. Dexamethasone therapy is a common treatment for many causes of neonatal distress, including hypoxia. The present study examined the effects of dexamethasone treatment on both normoxic and hypoxic neonatal rats. We performed comprehensive hepatic fatty acid/lipid profiling and evaluated changes in pertinent plasma hormones and lipids and a functional hepatic correlate, i.e. hepatic lipase activity. Rats were exposed to hypoxia from birth to 7 d of age. A 4-d tapering dose regimen of dexamethasone was administered on: postnatal day (PD)3 (0.5 mg/kg), PD4 (0.25 mg/kg), PD5 (0.125 mg/kg), and PD6 (0.05 mg/kg). The most significant finding was that dexamethasone attenuated nearly all hypoxia-induced changes in hepatic lipid profiles. Hypoxia increased the concentration of hepatic triacylglyceride and free fatty acids and, more specifically, increased a number of fatty acid metabolites within these lipid classes. Administration of dexamethasone blocked these increases. Hypoxia alone increased the plasma concentration of cholesterol and triacylglyceride, had no effect on plasma glucose, and only tended to increase plasma insulin. Dexamethasone administration to hypoxic pups resulted in an additional increase in plasma lipid concentrations, an increase in insulin, and a decrease in plasma glucose. Hypoxia and dexamethasone treatment each decreased total hepatic lipase activity. Normoxic pups treated with dexamethasone displayed increased plasma lipids and insulin. The effects of dexamethasone on hepatic function in the hypoxic neonate are dramatic and have significant implications in the assessment and treatment of metabolic dysfunction in the newborn.

Animals↗
PubMed2004

Metabolomic analysis of adrenal lipids during hypoxia in the neonatal rat: implications in steroidogenesis.

The nursing rat pup exposed to hypoxia from birth exhibits ACTH-independent increases in corticosterone and renin/ANG II-independent increases in aldosterone. These increases are accompanied by significant elevation of plasma lipid concentrations in the hypoxic neonates. The purpose of the present study was to compare changes in the concentrations of specific fatty acid metabolites and lipid classes in serum and adrenal tissue from normoxic and hypoxic rat pups. We hypothesized that lipid alterations resulting from hypoxia may partly explain increases in steroidogenesis. Rats were exposed to normoxia or hypoxia from birth, and pooled serum and adrenal tissue from 7-day-old pups were subjected to metabolomic analyses. Hypoxia resulted in specific and significant changes in a number of fatty acid metabolites in both serum and the adrenal. Hypoxia increased the concentrations of oleic (18:1 n-9), eicosapentaenoic (EPA; 20:5 n-3), and arachidonic (20:4 n-6) acids in the triacylglyceride fraction of serum and decreased oleic and EPA concentrations in the cholesterol ester fraction. In the adrenal, hypoxia caused an increase in several n-6 fatty acids in the triacylglyceride fraction, including linoleic (18:2 n-6) and arachidonic acid. There was also an increase in the concentration of alpha-linolenic acid (18:3 n-3) in the triacylglyceride fraction of the hypoxic adrenal, along with an increase in linoleic acid concentration in the diacylglyceride fraction. We propose that specific changes in lipid metabolism in the adrenal, as a result of hypoxia, may partly explain the increased steroidogenesis previously observed. The mechanism responsible may involve alterations in cellular signaling and/or mitochondrial function. These cellular changes may be a mechanism by which the neonate can increase circulating adrenal steroids necessary for survival, therefore bypassing a relative insensitivity to normal stimuli.

Adrenal Glands↗
PubMed2004

Neonatal dexamethasone therapy: short- and long-term consequences.

The discovery of the adrenal steroid hormones was one of the momentous events of science and medicine in the 20th century, highlighted by the awarding of the Nobel Prize in Physiology or Medicine to Kendall, Reichstein and Hench in 1950. Therapy using endogenous and synthetic corticosteroids was thought to be a miracle cure for several illnesses. We now recognize the many short- and long-term side effects of glucocorticoid therapy in neonates, children and adults, including growth retardation, insulin resistance, metabolic disturbances, cognitive and psychological problems, rapidly-progressing and profound osteoporosis, and iatrogenic Cushing's syndrome. Significant attention is now being paid to the long-term consequences of glucocorticoid therapy in premature and full-term neonates.

Animals↗