bluuebunny/crossref_metadata_2025 huggingface dataset:
Emotional Stress‐Induced Tako‐tsubo Cardiomyopathy: Animal Model and Molecular Mechanism
Authors: UEYAMA TAKASHI
Published: July 2004

Abstract: Emotional or physical stress triggers Tako‐tsubo cardiomyopathy in postmenopausal females, which is characterized by an elevation of the ST segment in the electrocardiogram (ECG) and left ventricular apical ballooning in the left ventriculogram (LVG). Immobilization stress (IMO) of rats can reproduce these ECG and LVG changes, both of which are normalized by combined blockade of α‐ and β‐adrenoceptors. An increase of serum estrogen partially attenuated these cardiac changes. IMO induced a rapid activation of p44/p42 mitogen‐activated protein kinase, followed by a transient upregulation of immediate early genes (IEG) in the coronary artery and myocardium. Blocking of both α‐ and β‐adrenoceptors eliminated the upregulation of IEG induced by stress, while α‐ or β‐agonists upregulated IEG in the perfused heart. Heat shock protein 70 was induced in the aorta, coronary artery, and the myocardium. Natriuretic peptide genes (ANP and BNP) were also upregulated in the myocardium. Sequential gene expression can be considered as an adaptive response to stress. Activation of α‐ or β‐adrenoceptors is the primary trigger of emotional stress‐induced cardiac changes.
Catecholamine Synthesizing Enzymes and Their Modulation by Immobilization Stress in Knockout Mice
Authors: KUBOVCAKOVA L , TYBITANCLOVA K , SABBAN E L , MAJZOUB J , ZORAD S , VIETOR I , WAGNER E F , KRIZANOVA O , KVETNANSKY R
Published: July 2004

Abstract:The c‐fos knockout mice (c‐fos KO) and corticotropin‐releasing hormone knockout mice (CRH KO) can serve as interesting models for studying mechanisms involved in response of the organism to stress, focused mainly on the hypothalamic‐pituitary‐adrenal (HPA) axis and sympathoadrenal system (SAS). The present study focused on the investigation of changes in gene expression of catecholamine biosynthesizing enzymes tyrosine hydroxylase (TH), dopamine‐β‐hydroxylase (DBH), and phenylethanolamine N‐methyltransferase (PNMT) in adrenal medulla of c‐fos KO and CRH KO mice stressed by immobilization. Levels of TH, DBH, and PNMT mRNA were determined by reverse transcription‐polymerase chain reaction (RT‐PCR). Single immobilization for 2 h significantly increased adrenomedullary TH, DBH, and PNMT mRNA levels in both c‐fos KO and wild‐type (WT) mice compared to unstressed controls. In CRH KO mice, PNMT gene expression was not increased to the same extent after single, but especially after repeated immobilization as in WT mice, in contrast to TH and DBH mRNA levels. Thus, our data indicate that CRH deficiency can influence the PNMT mRNA level in adrenal medulla during stress, confirming the idea that the HPA axis plays the crucial role in PNMT gene regulation in mice. On the other hand, c‐Fos protein probably does not play a crucial role in TH, DBH, and PNMT gene expression in adrenal medulla under stress conditions.
Angiotensin II AT1 Receptor Antagonism Downregulates Stress‐Related Gene Expression in Brain Microvessels from Spontaneously Hypertensive and Normotensive Rats
Authors: ZHOU J , JEZOVA M , ELKAHLOUN A G , SAAVEDRA J M
Published: July 2004

Abstract: We studied the effect of treatment with the Angiotensin II AT1 receptor antagonist candesartan (0.3 mg/kg/day via osmotic minipumps for 4 weeks compared with administration of vehicle) in brain microvessels in adult spontaneously hypertensive rats (SHR) that were vulnerable to stroke and normotensive control rats (WKY). At the dose administered, candesartan normalized blood pressure in SHR without significantly affecting blood pressure in WKY rats. We performed the gene expression analysis in rat brain microvessels using the Affymetrix Gene Chip Expression Analysis Technique. From a total of 8,799 probe array sets analyzed, we found abundant abnormalities in gene expression in SHR. Because stress has been suggested as a precipitant factor in brain ischemia and treatment with AT1 receptor antagonist candesartan prevents the hormonal and sympathoadrenal reaction to isolation stress and protects from stress‐induced gastric ulcers, we focused on the expression of stress‐related genes. We found a higher number of probe array sets modified by candesartan treatment in normotensive WKY rats than in hypertensive SHR. AT1 receptor blockade decreased the transcription levels of the stress‐related tyrosine kinase receptor, stathmin, and fibroblast growth receptor genes in WKY and SHR rats. Our results indicate that Angiotensin II and its AT1 receptors can influence gene expression independently of the effects on blood pressure. In addition, AT1 receptor regulation of stress‐related genes in brain microvessels may explain the proposed association between stress and ischemic disorders of the brain.
New Tools to Monitor Stress Using Non‐Invasive PET Imaging
Authors: ECKELMAN WILLIAM C. , RICE KENNER C. , CONTOREGGI CARLO
Published: July 2004

Abstract: Noninvasive imaging using positron emission tomography (PET) is playing an increasing role in monitoring biochemical changes in vivo in various diseases. For example, many of the neurochemical systems activated by stress can be monitored using this technique. Examples of neurotransmitter interactions with CRH, serotonin, dopamine, and muscarinic cholinergic receptors demonstrate this approach.
Anatomical and Functional Imaging of Metastatic Pheochromocytoma
Authors: ILIAS IOANNIS , PACAK KAREL
Published: July 2004

Abstract: Although in the majority of patients with pheochromocytoma the tumor is localized in the adrenal, up to 26% of patients have malignant/metastatic disease. Metastatic disease should be ruled out before initial surgery is attempted. Anatomical imaging modalities (computed tomography or magnetic resonance imaging) should be done first over the adrenals, and if negative over the abdomen and if no tumor is found, then the chest and neck should be covered. Regardless of the anatomical imaging results functional imaging with [123‐I]‐ or [131‐I]‐metaiodobenzylguanidine (MIBG) scintigraphy should be done to corroborate the diagnosis. Negative MIBG scans should be followed by positron emission tomography (PET) studies with specific ligands like [18‐F]‐dopamine. Persistently negative evaluations should be followed by PET studies with non‐specific ligands such as [18‐F]‐deoxyglucose or somatostatin receptor scintigraphy.
Cardiac Sympathetic Nerve Biology and Brain Monoamine Turnover in Panic Disorder
Authors: ESLER MURRAY , ALVARENGA MARLIES , LAMBERT GAVIN , KAYE DAVID , HASTINGS JACQUI , JENNINGS GARRY , MORRIS MARGARET , SCHWARZ ROSEMARY , RICHARDS JEFF
Published: July 2004

Abstract: Panic disorder serves as a clinical model for testing whether mental stress can cause heart disease. Our own cardiologic management of panic disorder provides case material of recurrent emergency room attendances with angina and electrocardiogram ischemia, triggered arrhythmias (atrial fibrillation, ventricular fibrillation), and documented coronary artery spasm, in some cases with coronary spasm being complicated by coronary thrombosis. Application of radiotracer catecholamine kinetics and clinical microneurography methodology suggests there is a genetic predisposition to panic disorder that involves faulty neuronal norepinephrine uptake, possibly sensitizing the heart to symptom generation. During panic attacks there are large sympathetic bursts, recorded by clinical microneurography in the muscle sympathetic nerve neurogram, and large increases in cardiac norepinephrine spillover, accompanied by surges of adrenal medullary epinephrine secretion. In other conditions such as heart failure and presumably here also, a high level of sympathetic nervous activation can mediate increased cardiac risk. The sympathetic nerve cotransmitter, neuropeptide Y (NPY), is released from the cardiac sympathetics during panic attacks, an intriguing finding given that NPY can cause coronary artery spasm. There is ongoing, continuous release of epinephrine from the heart in panic sufferers, perhaps attributable to epinephrine loading of cardiac sympathetic nerves by uptake from plasma during panic attacks, or possibly to in situ synthesis of epinephrine through the action of intracardiac phenylethanolamine‐N‐methytransferase (PNMT) activated by repeated cortisol responses. We have used internal jugular venous sampling and measurement of overflowing lipophilic brain monoamine metabolites to quantify brain norepinephrine and serotonin turnover in untreated patients with panic disorder. We find normal norepinephrine turnover but a marked increase in brain serotonin turnover in patients with panic disorder, in the absence of a panic attack, which presumably represents an underlying neurotransmitter substrate for the condition.
Behavioral and Neuroendocrine Changes during Mental Stress and Repeated Treatment with Antidepressants in Healthy Men
Authors: DUNCKO R , NOVAKOVA L , NOTOVA P , STEPANKOVA O , JEZOVA D
Published: July 2004

Abstract: Excessive stress loadings in daily life are believed to play a role in the development of affective disorders. Our recent finding of enhanced neuroendocrine activation during stress of hypoglycemia after repeated antidepressant treatment in healthy men supports the hypothesis that the clinical effects of antidepressant treatment may be partly due to the adjustment of the stress response, which was reported to be blunted in depressive patients. The present double‐blind placebo‐controlled study investigated the effects of 6 days of treatment with the antidepressants citalopram or tianeptine on neuroendocrine activation during mental stress. Blood pressure, heart rate, and salivary cortisol values were measured. The stress procedure, lasting 17 min, consisted of a short intelligence test followed by the Stroop word‐color interference test. Citalopram treatment was associated with a significant enhancement of stress‐related increase in systolic and diastolic blood pressure. No differences were observed in the heart rates and salivary cortisol. Comparisons based on cluster analysis revealed that subjects with poor performance in the Stroop test displayed a significantly lower rise of systolic and diastolic blood pressure values after the stress procedure and lower prestress cortisol levels in saliva when compared to the good performing subjects. Our findings show that antidepressant treatment can enhance the neuroendocrine response also during mental stress, and suggest that mental performance during stress is related to the pattern of cardiovascular and adrenocortical activation.
Changes of Noradrenergic Activity and Lipolysis in the Subcutaneous Abdominal Adipose Tissue of Hypo‐ and Hyperthyroid Patients: An In Vivo Microdialysis Study
Authors: NEDVIDKOVA JARA , HALUZIK MARTIN , BARTAK VLADIMIR , DOSTALOVA IVANA , VLCEK PETR , RACEK PAVEL , TAUS MICHAL , BEHANOVA MAGDALENA , SVACINA STEPAN , ALESCI SALVATORE , PACAK KAREL
Published: July 2004

Abstract: Thyroid function plays an important role in the regulation of overall metabolic rate and lipid metabolism. However, it is uncertain whether thyroid hormones directly affect lipolysis in adipose tissue and to what extent those changes contribute to overall metabolic phenotype. Our study was designed, using the microdialysis technique, to determine basal and isoprenaline‐stimulated local lipolysis and to determine local concentrations of lipolysis‐regulating catecholamines in abdominal subcutaneous adipose tissue in 12 patients with hypothyroidism, 6 patients with hyperthyroidism, and 12 healthy control subjects. Plasma norepinephrine (NE) concentrations in hypothyroid subjects were significantly higher than in the control and hyperthyroid groups. In contrast, systemic, adipose NE levels in hypothyroid patients were decreased relative to controls. Hyperthyroidism, on the other hand, resulted in four‐fold higher adipose NE levels. Basal lipolysis measured by glycerol concentrations in adipose tissue was significantly attenuated in hypothyroid patients and markedly increased in hyperthyroid patients in comparison with the control group. In addition to differences in basal lipolysis, hypothyroidism resulted in attenuated, and hyperthyroidism in enhanced, lipolytic response to local stimulation with β1,2‐adrenergic agonist isoprenaline. These results demonstrate that lipolysis in abdominal subcutaneous adipose tissue is strongly modulated by thyroid function. We suggest that thyroid hormones regulate lipolysis primarily by affecting local NE concentration and/or adrenergic postreceptor signaling.
Effects of Real and Simulated Microgravity on Response of Sympathoadrenal System to Various Stress Stimuli
Authors: MACHO LADISLAV , KOŠKA JURAJ , KŠÍNANTOVÁ LUCIA , VIGAŠ MILAN , BLAŽÍČEK PAVEL , NOSKOV VITALIJ B. , GRIGORIEV ANATOLIJ I. , PACÁK KAREL , KVETŇANSKÝ RICHARD
Published: July 2004

Abstract: Changes in plasma levels of epinephrine (EPI) and norepinephrine (NE) were investigated in humans exposed to physical exercise (WL), to psychic stressor (mental arithmetic test, MAT), and to oral glucose administration (oGTT) before and during a stay in microgravity (real space flight, SF) or in simulated microgravity (head‐down bed rest, HDBR). A permanent cannula inserted into the cubital vein and a special appliance, Plasma‐03, were used for blood collection, plasma separation, and freezing of samples during SF. Plasma EPI, NE, dihydroxyphenylglycol (DHPG), and dihydroxyphenylalanine (DOPA) levels were measured by the high‐pressure liquid chromatography (HPLC) method. Basal plasma EPI, NE, DHPG, and DOPA levels were found within the range of control values during SF. Preflight WL produced high increase in plasma NE and moderate elevation of plasma EPI, DHPG, and DOPA levels. Exaggerated exercise induced increases in plasma NE, DHPG, EPI, and DOPA levels were demonstrated in real microgravity. A return to preflight responses of sympathoadrenal system was seen after the landing. Plasma EPI, NE, and DHPG responses to MAT were relatively small, but increased during SF. During the oGTT the plasma EPI levels were slightly reduced in microgravity. Similarly as in SF, WL in HDBR was followed by significantly exaggerated responses of plasma catecholamines. These results show that both somatic and psychological stressors are able to induce an increased activation of sympathoadrenal system during SF or simulated microgravity in HDBR.
Effects of Space Flight and −6° Bed Rest on the Neuroendocrine Response to Metabolic Stress in Physically Fit Subjects
Authors: KŠINANTOVÁ LUCIA , KOŠKA JURAJ , MARTINKOVIČ MIROSLAV , VIGAŠ MILAN , MACHO LADISLAV , KVETŇANSKÝ RICHARD
Published: July 2004

Abstract: The aim of this study was to evaluate the association of plasma epinephrine (EPI) and norepinephrine (NE) responses to insulin‐induced hypoglycemia (ITT) 3 weeks before the space flight (SF), on the fifth day of SF, on days 2 and 16 after landing in the first Slovak astronaut, and before and on the fifth day of prolonged bed rest (BR) in 15 military aircraft pilots, aged 33.5 ± 1.4 years, body mass index (BMI) 26.5 ± 0.7 kg/m2, maximal oxygen uptake (VO2max) 55.2 ± 2.4 mL/kg/min, who volunteered for the study. ITT was induced by i.v. administrations of 0.1 IU/kg body weight insulin (Actrapid HM) in a bolus. Insulin administration led to a comparable hypoglycemia in preflight, actual flight conditions, and before and after bed rest. ITT led to a pronounced increase in EPI levels and moderate increase in NE in preflight studies. However, an evidently reduced plasma elevation of EPI was found after insulin administration during SF and during BR. Thus, during the real microgravity in SF and simulated microgravity in BR, ITT activates the adrenomedullary system to less extent that at conditions of the Earth's gravitation. Post‐flight changes in EPI and NE did not differ from those of preflight values, since SF was relatively short (8 days) and the readaptation to Earth's gravitation was fast. It seems that an increased blood flow in brain might be responsible for the reduced EPI response to insulin. Responses to ITT in physically fit subjects indicate the stimulus specificity of the deconditioning effect of 5 days of bed rest on the stress response.
Does Orthostatic Stress Influence the Neuroendocrine Response to Subsequent Hypoglycemia in Humans?
Authors: RADIKOVA Z , PENESOVA A , KOSKA J , KVETNANSKY R , JEZOVA D , HUCKOVA M , VIGAS M , MACHO L
Published: July 2004

Abstract:Neuroendocrine response to stress stimuli is influenced by previous stimuli of different nature. The aim of the study was to test whether antecedent orthostatic stress may affect the neuroendocrine response to subsequent hypoglycemia. A group of 12 (6 men, 6 women) nonobese, healthy volunteers aged 19 to 27 y (mean 24 ± 0.8) participated in the study in two sessions: controlled insulin‐induced hypoglycemia to 2.7 mmol/L for 15 min either with or without antecedent orthostatic stress (30 min of 60° head‐up tilt before insulin administration). Orthostatic stress caused a significant decrease in plasma volume (−9.6%;P< 0.001) and a significant increase in plasma renin activity, aldosterone, norepinephrine (P< 0.01), and adrenocorticotropic hormone (ACTH) concentrations (P< 0.05) in all subjects. Growth hormone response to hypoglycemia was diminished in women (P< 0.01). The epinephrine response to hypoglycemia was diminished in women in comparison to men (P< 0.001), but was unaffected by antecedent orthostatic stress. Hypoglycemia failed to induce the ACTH release after its elevation during orthostatic stress. ACTH response to moderate hypoglycemia without previous orthostatic stress was evident only in men in comparison to women (P< 0.05). We conclude that the epinephrine, growth hormone, and ACTH responses to hypoglycemia were diminished in women. Except ACTH, the neuroendocrine response to mild hypoglycemia was not affected by previous orthostatic stress in healthy subjects. In the case of ACTH, the first stress stimulus is consequential for the subsequent response of this hormone, probably due to short‐loop negative feedback effects.
Markedly Diminished Lipolysis and Partial Restoration of Glucose Metabolism, without Changes in Fat Distribution after Extended Discontinuation of Protease Inhibitors in Severe Lipodystrophic Human Immunodeficient Virus-1-Infected Patients
Authors: van der Valk Marc , Allick Gideon , Weverling Gerrit Jan , Romijn Johannes A. , Ackermans Mariette T. , Lange Joep M. A. , van Eck-Smit Berthe L. F. , van Kuijk Cornelis , Endert Erik , Sauerwein Hans P. , Reiss Peter
Published: July 2004

Treatment for HIV-1 infection is often complicated by a lipodystrophy syndrome associated with insulin resistance and an elevated rate of lipolysis. In eight HIV-1 infected men with lipodystrophy syndrome, we studied the effects of replacement of protease inhibitor (PI) by abacavir on insulin sensitivity and lipolysis by hyperinsulinemic euglycemic clamp and on fat distribution assessed by dual-energy x-ray absorptiometry and computed tomography scan.

Glucose metabolism and lipolysis were assessed by tracer dilution employing [6,6-2H2]glucose and [2H5]glycerol, respectively. Data are expressed as mean ± sd or 95% confidence interval (CI), as appropriate.

There were no significant changes in fat distribution assessed by dual-energy x-ray absorptiometry and computed tomography scan at wk 36 and wk 96. The fasting total glucose production decreased from 16.1 ± 2.5 at study entry by 1.1 (range, −2.1 to −0.1) to 15.0 ± 1.5 μmol/kg·min after PI withdrawal at wk 36 (n = 8). In an analysis restricted to the patients on treatment at wk 96 (n = 6), the decrease was 0.9 (range, −2.1 to 0.3) μmol/kg·min. During insulin infusion, glucose oxidation (as percent of total glucose disposal) increased from 36.8 ± 12.7% by 11.0% (range, 1.3–20.8) to 47.9 ± 13.9% in the wk 36 analysis. In the analysis restricted to the patients on treatment at wk 96 (n = 6) the increase was 7.7 (−4.0 to 19.4)%. Fasting lipolysis decreased from 2.7 ± 0.6 μmol/kg·min by 0.9 (−1.6 to −0.2) to 1.8 ± 0.3 μmol/kg·min in the wk-96 analysis (n = 6).

The replacement of the studied PIs by abacavir in severe lipodystrophic HIV-1-infected patients results in a marked reduction of lipolysis. In contrast, fasting glucose production and insulin-stimulated glucose oxidation improve moderately, whereas insulin-stimulated glucose disposal and fat distribution do not change.
Relationship between Follicle-Stimulating Hormone Levels at the Beginning of the Human Menstrual Cycle, Length of the Follicular Phase and Excreted Estrogens: The FREEDOM Study
Authors: Miro F. , Parker S. W. , Aspinall L. J. , Coley J. , Perry P. W. , Ellis J. E.
Published: July 2004

Although reproductive aging has been separately related to elevated FSH and shorter follicular phase (FP), the direct association between both parameters has not been investigated. Also, the exact effects of increased FSH on estrogen production are yet to be established.

A large database of daily urinary concentrations of FSH, LH, and estrone 3-glucuronide (E1G) from 37 regularly menstruating women (median 11 cycles per patient) was used. Initial FSH levels (iFSH) were estimated as the mean value of d 1–5. The day of E1G take-off (ETO) was determined by an algorithm, and accordingly, the FP was divided into early (d 1 to ETO) and late (ETO+1 to LH peak). FP maximum and integrated E1G were calculated.

Subjects were distributed according to their mean iFSH into three categories (≤5, >5 to 10, and >10 IU/liter). There was a gradual decrease in FP length with increasing category (15.2 ± 3.8, 14.1 ± 3.6, and 13 ± 2.6 d, respectively; P < 0.0001). A similar effect occurred in early FP (7.5 ± 4, 6.4 ± 3.7, and 5.4 ± 2.7; P < 0.0001); in contrast, late FP was unaffected (7.7 ± 2.1, 7.7 ± 2.1, and 7.6 ± 2.4; P = 0.86). No consistent increase in E1G was found with advancing iFSH category; however, women with mean initial LH higher than 6 IU/liter had significantly elevated maximum (P < 0.0001) and integrated (P = 0.002) E1G.

FP length decreases in parallel with increasing iFSH, with a selective effect on the early FP. Increased FSH does not affect E1G; however, elevated initial LH level was related to higher E1G.
Ginsenoside-Rb1 from Panax ginseng C.A. Meyer Activates Estrogen Receptor-α and -β, Independent of Ligand Binding
Authors: Cho JungYoon , Park Wankyu , Lee SeungKi , Ahn Woongshick , Lee YoungJoo
Published: July 2004

We studied the estrogenic activity of a component of Panax ginseng, ginsenoside-Rb1. The activity of ginsenoside-Rb1 was characterized in a transient transfection system, using estrogen receptor isoforms and estrogen-responsive luciferase plasmids, in COS monkey kidney cells. Ginsenoside-Rb1 activated both α and β estrogen receptors in a dose-dependent manner with maximal activity observed at 100 μm, the highest concentration examined. Activation was inhibited by the estrogen receptor antagonist ICI 182,780, indicating that the effects were mediated through the estrogen receptor. Treatment with 17β-estradiol or ginsenoside-Rb1 increased expression of the progesterone receptor, pS2, and estrogen receptor in MCF-7 cells and of AP-1-driven luciferase genes in COS cells. Although these data suggest that it is functionally very similar to 17β-estradiol, ginsenoside-Rb1 failed to displace specific binding of [3H]17β-estradiol from estrogen receptors in MCF-7 whole-cell ligand binding assays. Our results indicate that the estrogen-like activity of ginsenoside-Rb1 is independent of direct estrogen receptor association.
Polymorphisms in the Cytotoxic T Lymphocyte Antigen-4 Gene Region Confer Susceptibility to Addison’s Disease
Authors: Blomhoff Anne , Lie Benedicte A. , Myhre Anne G. , Kemp E. Helen , Weetman Anthony P. , Akselsen Hanne E. , Huseby Eystein S. , Undlien Dag E.
Published: July 2004

The cytotoxic T lymphocyte antigen-4 (CTLA4) gene on chromosome 2q33 encodes a key regulator in the adaptive immune system. The CTLA4 surface molecule is expressed on activated T lymphocytes and involved in down-regulation of the immune response. Previous studies on a possible association between autoimmune Addison’s disease and CTLA4 polymorphisms have shown conflicting results. A recent study identified new candidate polymorphisms in the CTLA4 region, influencing gene splicing and thereby the relative abundance of soluble CTLA4. We genotyped 134 patients with Addison’s disease and 413 healthy controls from Norway and United Kingdom for these newly identified polymorphisms. Our data demonstrate that the same polymorphisms that have recently been demonstrated to confer susceptibility to autoimmune thyroid disease and type 1 diabetes also confer susceptibility to Addison’s disease. This finding suggests that polymorphisms in CTLA4 confer general risk to develop autoimmunity and identifies a potential therapeutic target in the prevention of autoimmune endocrine disorders.
Calcium Kinetics Are Altered in Clinically Stable Girls with Cystic Fibrosis
Authors: Schulze Kerry J. , O’Brien Kimberly O. , Germain-Lee Emily L. , Booth Sarah L. , Leonard Amanda , Rosenstein Beryl J.
Published: July 2004

Reduced bone mass in individuals with cystic fibrosis (CF) may result from alterations in calcium metabolism. Bone calcium deposition and resorption rates, calcium balance, and markers of bone turnover were assessed using stable isotopes of calcium in 22 prepubertal and pubertal girls with CF. Bone calcium deposition was associated with the availability of dietary calcium, total serum osteocalcin, and leptin concentrations.

Reduced bone mass in individuals with CF may result from inadequate bone calcium (Ca) deposition, and excessive resorption, although these parameters have not been directly assessed in children with CF.

We used stable Ca isotopes to measure rates of bone Ca deposition (Vo+), resorption, and retention in 22 clinically stable girls with CF (aged 7–18 yr). Rates of bone Ca deposition were determined by mathematically modeling the disappearance of iv Ca stable isotope (42Ca) for 6 d post dosing. Indirect markers of bone turnover and hormones associated with pubertal development were also assessed.

Rates of bone Ca deposition and retention were highest during early puberty (Tanner stages 2 and 3). Calcium deposition rates in prepubertal (Tanner 1) and postmenarchal girls (Tanner stages 4 and 5) did not support substantial bone Ca retention. Net absorption of dietary Ca and serum osteocalcin and leptin concentrations were positively associated with Vo+. Time post menarche and serum leptin concentrations explained 91% of the variability in Vo+ (P = 0.0007). Serum total osteocalcin was low (10.9 ± 5.4 ng/ml), and a substantial percentage of osteocalcin was undercarboxylated (54.3 ± 11.8%).

We concluded that increased calcium absorption and serum leptin concentrations were significantly associated with rates of bone Ca deposition, demonstrating an impact of nutritional status on this process. Rates of bone Ca deposition were lower than typically reported in healthy children, as were indirect markers of bone formation. These alterations in bone turnover contribute to reduced bone mass in girls with CF.
Sources of Dietary Iodine: Bread, Cows’ Milk, and Infant Formula in the Boston Area
Authors: Pearce Elizabeth N. , Pino Sam , He Xuemei , Bazrafshan Hamid R. , Lee Stephanie L. , Braverman Lewis E.
Published: July 2004

Dietary iodine is essential for thyroid hormone production. Although U.S. dietary iodine is generally adequate, some groups, especially women of childbearing age, are at risk for mild iodine deficiency. Children’s average urinary iodine is higher than that of adults. U.S. dietary iodine sources have not been assessed recently. A survey of iodine content in 20 brands of bread, 18 brands of cows’ milk, and eight infant formulae was performed between 2001 and 2002. Three bread varieties contained more than 300 μg iodine per slice. Iodine content in other brands was far lower (mean ± sd, 10.1 ± 13.2 μg iodine/slice). All cows’ milk samples had at least 88 μg iodine/250 ml, ranging from 88–168 μg (116.0 ± 22.1 μg/250 ml). Infant formulae values ranged from 16.2 to 56.8 μg iodine/5 oz (23.5 ± 13.78 μg/5 oz). The public should be aware of the need for adequate dietary iodine intake and should be aware that ingredient lists do not reflect the iodine content of foods.
Estrogen to Antiestrogen with a Single Methylene Group Resulting in an Unusual Steroidal Selective Estrogen Receptor Modulator
Authors: Zhang Jing-xin , Labaree David C. , Mor Gil , Hochberg Richard B.
Published: July 2004

Selective estrogen receptor (ER) modulators (SERMs) are important therapeutic agents for breast cancer prevention and treatment. We have synthesized two analogs, E11–2,1 [methyl-(3,17β-dihydroxyestra-1,3,5(10)-triene-11β-yl)acetate] and E11–2,2 [ethyl-(3,17β-dihydroxyestra-1,3,5(10)-triene-11β-yl)acetate], the methyl and ethyl esters of an estradiol analog, substituted in the B ring at C-11β with a carboxymethyl group. The shorter methyl ester, E11–2,1, has high ER affinity and high estrogenic potency in the Ishikawa estrogen cell bioassay, whereas the longer ethyl ester, E11–2,2, has even higher ER affinity, but little or no estrogenic activity. We found that this minor change of one methylene group transforms a potent estrogenic agonist into an antagonist in vitro with either ER α or β. In the rat, E11–2,2 acts as a SERM in the uterus, where it inhibits estradiol-induced proliferation, and as an estrogen agonist in the liver and skeleton, where it decreases plasma cholesterol and increases bone growth. The characteristic feature of antiestrogens, including SERMs, is a long and polar side-chain that prevents agonist-induced conformation of helix 12 of ER. E11–2,2 with its short, nonpolar side-chain, lacks this critical structure, presenting the possibility that it might act through a unique mechanism.
Regulation of the Somatotropic Axis by Intensive Insulin Therapy during Protracted Critical Illness
Authors: Mesotten Dieter , Wouters Pieter J. , Peeters Robin P. , Hardman Kevin V. , Holly Jeff M. , Baxter Robert C. , Van den Berghe Greet
Published: July 2004

The catabolic state of critical illness has been linked to the suppressed somatotropic GH-IGF-binding protein (IGFBP) axis. In critically ill patients it has been demonstrated that, compared with the conventional approach, which only recommended insulin therapy when blood glucose levels exceeded 12 mmol/liter, strict maintenance of blood glucose levels below 6.1 mmol/liter with intensive insulin therapy almost halved intensive care mortality, acute renal failure, critical illness polyneuropathy, and bloodstream infections. Poor blood glucose control in diabetes mellitus has also been associated with low serum IGF-I levels, which can be increased by insulin therapy. We hypothesized that intensive insulin therapy would improve the IGF-I axis, possibly contributing to the clinical correlates of anabolism. Therefore, this study of 363 patients, requiring intensive care for more than 7 d and randomly assigned to either conventional or intensive insulin therapy, examines the effects of intensive insulin therapy on the somatotropic axis. Contrary to expectation, intensive insulin therapy suppressed serum IGF-I, IGFBP-3, and acid-labile subunit concentrations. This effect was independent of survival of the critically ill patient. Concomitantly, serum GH levels were increased by intensive insulin therapy. The suppression of IGF-I in association with the increased GH levels suggests GH resistance induced by intensive insulin therapy, which was reflected by the decreased serum GH-binding protein levels. Intensive insulin therapy did not affect IGFBP-3 proteolysis, which was markedly higher in protracted critically ill patients compared with healthy controls. Also, intensive insulin therapy did not suppress the urea/creatinine ratio, a clinical correlate of catabolism. In conclusion, our data suggest that intensive insulin therapy surprisingly suppressed the somatotropic axis despite its beneficial effects on patient outcome. GH resistance accompanied this suppression of the IGF-I axis. To what extent and through which mechanisms the changes in the GH-IGF-IGFBP axis contributed to the survival benefit under intensive insulin therapy remain elusive.
Body Mass Index Determines Evoked Growth Hormone (GH) Responsiveness in Normal Healthy Male Subjects: Diagnostic Caveat for Adult GH Deficiency
Authors: Bonert Vivien S. , Elashoff Janet D. , Barnett Philip , Melmed Shlomo
Published: July 2004

GH secretion is decreased in obese subjects, whereas age-adjusted IGF-I concentrations are normal. This study was undertaken to rigorously delineate the extent of obesity [elevated body mass index (BMI)] associated with decreased somatotrope secretory function resulting in apparent adult GH deficiency. The peak GH response evoked by combined arginine (0.5 g/kg infused iv over 30 min) and GHRH (1 μg/kg iv bolus) was measured in 59 healthy male subjects with BMIs ranging from normal to obese. BMI correlated with the peak evoked GH response (Pearson r = −0.59; P < 0.01), and the percentage of subjects exhibiting an abnormal evoked GH response, i.e. less than 9 ng/ml, increased from 5% for those with a BMI less than 25 (normal), to 13% for those with a BMI of 25–26.9 (mildly overweight), to 33% for those with a BMI of 27–29.9 (moderately overweight), and to 64% for those with a BMI of 30 or more (obese). BMI is a major determinant of evoked adult GH response to provocative testing. The diagnosis of adult GH deficiency using the evoked GH response in patients with even mild BMI elevation does not accurately distinguish normal from deficient responses and may result in the erroneous classification of obese subjects as GH deficient and thus unnecessarily requiring GH replacement.
Impaired Insulin Secretion in the Turner Metabolic Syndrome
Authors: Bakalov Vladimir K. , Cooley Margaret M. , Quon Michael J. , Luo Mei Lin , Yanovski Jack A. , Nelson Lawrence M. , Sullivan Gail , Bondy Carolyn A.
Published: July 2004

An increased prevalence of impaired glucose homeostasis (IGH) and diabetes mellitus is reported in monosomy X, or Turner syndrome (TS). To determine whether IGH is an intrinsic feature of this syndrome, independent of obesity or hypogonadism, we compared results of a standard oral glucose challenge in age- and body mass index-matched women with TS and with karyotypically normal premature ovarian failure (POF). Fasting glucose levels were normal in both groups, but glucose values after oral glucose challenge were higher in TS [2-h glucose, 135 ± 36 mg/dl (7.5 ± 2.0 mmol/liter) in TS and 97 ± 18 mg/dl (5.4 ± 1.0 mmol/liter) in POF; P < 0.0001]. Glucose-stimulated insulin secretion was lower in TS; e.g. the initial insulin response (ΔI/ΔG30) was decreased by 60% compared with POF (P < 0.0001). We also compared responses to a standard iv glucose tolerance test in women with TS and in age- and body mass index-matched normal women and found that the insulin area under the curve was 50% lower in women with TS (P = 0.003). Insulin sensitivity measured by the quantitative insulin sensitivity check index was higher in women with TS compared with both control groups. Thus, IGH is not secondary to obesity or hypogonadism in TS, but it is a distinct entity characterized by decreased insulin secretion, suggesting that haploinsufficiency for X-chromosome gene(s) impairs β-cell function and predisposes to diabetes mellitus in TS.
Comparing Direct Thrombin Inhibitors Using aPTT, Ecarin Clotting Times, and Thrombin Inhibitor Management Testing
Authors: Gosselin Robert C , King Jeffrey H , Janatpour Kim A , Dager William E , Larkin Edward C , Owings John T
Published: July 2004

BACKGROUND:

Patients with heparin-induced thrombocytopenia and thrombosis may be acutely anticoagulated with direct thrombin inhibitors (DTIs). The anticoagulation is typically monitored using the activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT).

OBJECTIVE:

To compare 14 methods for measuring aPTT, as well as ECT and thrombin inhibitor management test (TIM), in samples containing DTIs.

METHODS:

DTIs were added to pooled normal plasma to achieve low (0.1–1.2 μg/mL) and high (1.5–8.0 μg/mL) drug concentrations. Each low-concentration DTI sample was tested using all aPTT reagents, while each low- and high-concentration DTI was tested using the ECT and TIM.

RESULTS:

All aPTT reagents had a significant dose-dependent correlation with drug concentration. Only Actin FSL and APTT-S demonstrated equivalent aPTT ratios obtained from any DTI. The TAS-aPTT was the most sensitive aPTT reagent to argatroban, with the aPTT ranging from 52.7 to 121.2 seconds corresponding to 0.1 to 1.2 μg/mL of drug concentration. The TAS-aPTT and Pathromtin were the most sensitive aPTT reagents to bivalirudin, with aPTTs of 87.4 seconds and 101.5 seconds, respectively, at 1.2 μg/mL of drug. Pathromtin was the most sensitive aPTT reagent to lepirudin, with a maximum aPTT of 108.9 seconds at 1.2 μg/mL of drug. There was no statistically significant difference between the TIM and ECT clotting times for each DTI. Lepirudin and bivalirudin ECT and TIM clotting times were equivalent.

CONCLUSIONS:

There are unique differences between reagent manufacturers in the monitoring of DTIs. Acceptable alternatives to aPTT monitoring of DTI anticoagulation include the ECT and TIM.
Self-Reported Morisky Score for Identifying Nonadherence with Cardiovascular Medications
Authors: Shalansky Stephen J , Levy Adrian R , Ignaszewski Andrew P
Published: July 2004

BACKGROUND:

The Morisky medication adherence scale is a commonly used adherence screening tool. It is composed of 4 yes/no questions about past medication use patterns and is thus quick and simple to use during drug history interviews.

OBJECTIVE:

To evaluate the use of the self-reported Morisky score as a screening tool for identifying patients who have been nonadherent with chronic cardiovascular medications.

METHODS:

Patients who had taken an angiotensin-converting enzyme inhibitor or lipid-lowering agent for at least 3 consecutive months were interviewed using a structured questionnaire including the Morisky scale. Nonadherence was defined as taking <80% of chronic cardiovascular medications based on prescription refill data over the previous 14 months.

RESULTS:

Forty-nine of 377 (13%) patients were categorized as nonadherent; however, only 12 (3%) patients had Morisky scores suggesting a high likelihood of nonadherence (3 or 4). While the Morisky score was a significant independent predictor of nonadherence by multivariate analysis, there was no threshold score or individual question that yielded concurrent high sensitivity and positive predictive values (PPVs) for identifying nonadherent patients. The internal consistency of the questions was low (α 0.32), as were item-to-total score correlations, suggesting that the individual questions were not measuring the same attribute.

CONCLUSIONS:

Using the Morisky scale to identify patients who have been nonadherent with chronic cardiovascular medications may be reasonable in some settings; however, the threshold score would have to be chosen based on a trade-off between sensitivity and PPV. These results were likely influenced by the low rate of nonadherence in this cohort. Rewording the questions, increasing the number of questions, and the use of graded response options may improve consistency.
β-Amyloid-Mediated Inhibition of NMDA Receptor-Dependent Long-Term Potentiation Induction Involves Activation of Microglia and Stimulation of Inducible Nitric Oxide Synthase and Superoxide
Authors: Wang Qinwen , Rowan Michael J. , Anwyl Roger
Published: July 2004

The mechanisms underlying the inhibition of long-term potentiation (LTP) induction by amyloidβ-peptide (Aβ) were investigated in the medial perforant path of the rat and mouse dentate gyrusin vitro. Evidence is presented in this study that the Aβ-mediated inhibition of LTP induction involves activation of microglia and production of reactive oxygen and nitrogen species. In control slices, Aβ strongly inhibited induction of NMDA receptor-dependent (NMDAR-dependent) LTP, although not induction of NMDAR-independent LTP or long-term depression (LTD). The inhibition of NMDAR-dependent LTP was prevented by minocycline, an agent that prevents activation of microglia. The involvement of inducible nitric oxide synthase (iNOS) was shown by the inability of Aβ to inhibit LTP induction in iNOS knock-out mice and also by the ability of two iNOS inhibitors, aminoguanidine and 1400W, to prevent the Aβ-mediated inhibition of LTP induction. The Aβ-mediated inhibition of LTP induction also was prevented by the superoxide scavenger superoxide dismutase applied together with catalase. Evidence for involvement of superoxide in the action of Aβ on LTP induction was shown by the ability of an inhibitor of NADPH oxidase to prevent the Aβ-mediated inhibition of LTP induction. The study thus provides evidence that the Aβ-mediated inhibition of LTP induction involves an inflammatory-type reaction in which activation of microglia results in the production of nitric oxide and superoxide and thence possibly peroxynitrite, a highly reactive oxidant.
Point-Light Biological Motion Perception Activates Human Premotor Cortex
Authors: Saygin Ayse Pinar , Wilson Stephen M. , Hagler Donald J. , Bates Elizabeth , Sereno Martin I.
Published: July 2004

Motion cues can be surprisingly powerful in defining objects and events. Specifically, a handful of point-lights attached to the joints of a human actor will evoke a vivid percept of action when the body is in motion. The perception of point-light biological motion activates posterior cortical areas of the brain. On the other hand, observation of others' actions is known to also evoke activity in motor and premotor areas in frontal cortex. In the present study, we investigated whether point-light biological motion animations would lead to activity in frontal cortex as well. We performed a human functional magnetic resonance imaging study on a high-field-strength magnet and used a number of methods to increase signal, as well as cortical surface-based analysis methods. Areas that responded selectively to point-light biological motion were found in lateral and inferior temporal cortex and in inferior frontal cortex. The robust responses we observed in frontal areas indicate that these stimuli can also recruit action observation networks, although they are very simplified and characterize actions by motion cues alone. The finding that even point-light animations evoke activity in frontal regions suggests that the motor system of the observer may be recruited to “fill in” these simplified displays.
Tyrosine Phosphorylation and Regulation of the AMPA Receptor by Src Family Tyrosine Kinases
Authors: Hayashi Takashi , Huganir Richard L.
Published: July 2004

Phosphorylation of AMPA receptors is a major mechanism for the regulation of receptor function and underlies several forms of synaptic plasticity in the CNS. Although serine and threonine phosphorylation of AMPA receptors has been well studied, the potential role of tyrosine phosphorylation of AMPA receptors has not been investigated. Here, we show that the GluR2 subunit of AMPA receptors is tyrosine phosphorylatedin vitroandin vivoby Src family tyrosine kinases on tyrosine 876 near its C terminus. In addition, GluR agonist treatment of cultured cortical neurons increased phosphorylation of tyrosine 876. The association with GluR2-interacting molecules GRIP1/2 was decreased by tyrosine phosphorylation of GluR2, whereas PICK1 interaction was not influenced. Moreover, mutation of tyrosine 876 eliminated AMPA- and NMDA-induced internalization of the GluR2 subunit. These data indicate that tyrosine phosphorylation of tyrosine 876 on the GluR2 C terminus by Src family tyrosine kinases is important for the regulation of AMPA receptor function and may be important for synaptic plasticity.
Dual-Gene, Dual-Cell Type Therapy against an Excitotoxic Insult by Bolstering Neuroenergetics
Authors: Bliss Tonya M. , Ip Miranda , Cheng Elise , Minami Masabumi , Pellerin Luc , Magistretti Pierre , Sapolsky Robert M.
Published: July 2004

Increasing evidence suggests that glutamate activates the generation of lactate from glucose in astrocytes; this lactate is shuttled to neurons that use it as a preferential energy source. We explore this multicellular “lactate shuttle” with a novel dual-cell, dual-gene therapy approach and determine the neuroprotective potential of enhancing this shuttle. Viral vector-driven overexpression of a glucose transporter in glia enhanced glucose uptake, lactate efflux, and the glial capacity to protect neurons from excitotoxicity. In parallel, overexpression of a lactate transporter in neurons enhanced lactate uptake and neuronal resistance to excitotoxicity. Finally, overexpression of both transgenes in the respective cell types provided more protection than either therapy alone, demonstrating that a dual-cell, dual-gene therapy approach gives greater neuroprotection than the conventional single-cell, single-gene strategy.
cAMP Response Element-Binding Protein, Activating Transcription Factor-4, and Upstream Stimulatory Factor Differentially Control Hippocampal GABABR1a and GABABR1b Subunit Gene Expression through Alternative Promoters
Authors: Steiger Janine L. , Bandyopadhyay Sabita , Farb David H. , Russek Shelley J.
Published: July 2004

Expression of metabotropic GABABreceptors is essential for slow inhibitory synaptic transmission in the CNS, and disruption of GABABreceptor-mediated responses has been associated with several disorders, including neuropathic pain and epilepsy. The location of GABABreceptors in neurons determines their specific role in synaptic transmission, and it is believed that sorting of subunit isoforms, GABABR1a and GABABR1b, to presynaptic or postsynaptic membranes helps to determine this role. GABABR1a and GABABR1b are thought to arise by alternative splicing of heteronuclear RNA. We now demonstrate that alternative promoters, rather than alternative splicing, produce GABABR1a and GABABR1b isoforms. Our data further show that subunit gene expression in hippocampal neurons is mediated by the cAMP response element-binding protein (CREB) by binding to unique cAMP response elements in the alternative promoter regions. Double-stranded oligonucleotide decoys selectively alter levels of endogenous GABABR1a and GABABR1b in primary hippocampal neurons, and CREB knock-out mice show changes in levels of GABABR1a and GABABR1b transcripts, consistent with decoy competition experiments. These results demonstrate a critical role of CREB in transcriptional mechanisms that control GABABR1 subunit levelsin vivo. In addition, the CREB-related factor activating transcription factor-4 (ATF4) has been shown to interact directly with GABABR1 in neurons, and we show that ATF4 differentially regulates GABABR1a and GABABR1b promoter activity. These results, together with our finding that the depolarization-sensitive upstream stimulatory factor (USF) binds to a composite CREB/ATF4/USF regulatory element only in the absence of CREB binding, indicate that selective control of alternative GABABR1 promoters by CREB, ATF4, and USF may dynamically regulate expression of their gene products in the nervous system.