bluuebunny/crossref_metadata_2025 huggingface dataset:
Adrenomedullin Administration Immediately After Myocardial Infarction Ameliorates Progression of Heart Failure in Rats
Authors: Nakamura Ryosai , Kato Johji , Kitamura Kazuo , Onitsuka Hisamitsu , Imamura Takuroh , Cao Yuanning , Marutsuka Kousuke , Asada Yujiro , Kangawa Kenji , Eto Tanenao
Published: July 2004

Background—

Adrenomedullin (AM) is expressed in cardiac tissue, and plasma AM levels increase in patients with acute myocardial infarction (MI). This study was performed to determine whether AM administration immediately after acute MI inhibits progression of heart failure in rats.

Methods and Results—

Rats were infused with 1.0 μg/h IP AM or saline over 7 days immediately after MI inducted by left coronary ligation and were examined 9 weeks after MI. Compared with the saline infusion, AM infusion significantly improved survival (59% versus 81%;
P
<0.05) and body weight gain (32%;
P
<0.01) and reduced heart weight (−28%;
P
<0.01), lung weight (−26%;
P
<0.01), left ventricular (LV) end-diastolic pressure (11.4±2.0 versus 4.0±0.6 mm Hg, mean± SEM;
P
<0.01), collagen volume fraction of noninfarcted LV (−39%;
P
<0.05), and plasma levels of endogenous rat AM (−38%;
P
<0.05) without affecting infarct size. To investigate the mechanism of AM actions, another series of MI rats infused with AM were killed on day 7. AM infusion had no effect on organ weights and hemodynamic parameters on day 7 of MI but significantly reduced urinary excretion of isoprostane (−61%;
P
<0.01) and noninfarcted LV mRNA levels of ACE (−31%;
P
<0.05) and p22-phox (−30%;
P
<0.05).

Conclusions—

AM administration during the early period of MI improved the survival and ameliorated progression of LV remodeling and heart failure. This beneficial effect was accompanied by reductions in oxidative stress and ACE mRNA expression in noninfarcted LV in the AM infusion period.
Relationship Between Arterial Stiffness and Subclinical Aortic Atherosclerosis
Authors: Herrington David M. , Brown W. Virgil , Mosca Lori , Davis Warren , Eggleston Barry , Hundley W. Gregory , Raines Jeffrey
Published: July 2004

Background—

Noninvasive measures of arterial compliance may be useful for the detection of subclinical atherosclerosis.

Methods and Results—

Measures of calf and thigh arterial compliance (MaxV50) were recorded in 267 subjects who also underwent MRI of the distal aorta to quantify distal aorta atherosclerosis. The average of calf and thigh MaxV50 was strongly predictive of extent of aortic atherosclerosis and risk of being in the top quartile of aortic atherosclerosis after adjustment for the Framingham Coronary Risk Score (FCRS) or the combination of the FCRS and C-reactive protein (
P
<0.0001). The areas under the receiver operating curves predicting the top quartile of gender-specific aortic atherosclerosis were 0.57, 0.60, and 0.75 for models containing the FCRS, the FCRS and C-reactive protein, and the FCRS, C-reactive protein, and the average of calf and thigh MaxV50.

Conclusions—

Lower-extremity arterial compliance may identify subjects with extensive subclinical atherosclerosis. Further studies examining the potential value of arterial stiffness as a screening tool to guide initiation of more aggressive preventive interventions are warranted.
Effect of Atorvastatin on Risk of Recurrent Cardiovascular Events After an Acute Coronary Syndrome Associated With High Soluble CD40 Ligand in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study
Authors: Kinlay Scott , Schwartz Gregory G. , Olsson Anders G. , Rifai Nader , Sasiela William J. , Szarek Michael , Ganz Peter , Libby Peter
Published: July 2004

Background—

Patients with acute coronary syndromes have elevated plasma levels of the proinflammatory, prothrombotic cytokine CD40 ligand (sCD40L). Statins inhibit CD40L signaling in vitro, but there are no prospective studies of statins and sCD40L in acute coronary syndromes.

Methods and Results—

We measured sCD40L in subjects with an acute coronary syndrome enrolled in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study. Subjects were randomized in this double-blind trial to atorvastatin 80 mg/d or placebo for 16 weeks. Plasma CD40L was measured from 2908 (94%) of 3086 subjects at baseline and 2352 (76%) at 16 weeks. Odds ratios (ORs) and 95% CIs from logistic regression models assessed the risk of recurrent cardiovascular events over 16 weeks (death, nonfatal myocardial infarction, cardiac arrest, and worsening angina requiring rehospitalization) in the placebo group from baseline sCD40L and the effect of atorvastatin on the risk associated with CD40L in all subjects. The effects of atorvastatin on plasma concentrations of CD40L were assessed by Wilcoxon tests. There was a threshold effect, with only high sCD40L (>90th centile) being a risk factor for a recurrent cardiovascular event (OR 1.86, 95% CI 1.25 to 2.77). This risk was abolished by atorvastatin (OR 1.09, 95% CI 0.69 to 1.76), which reduced the risk by 48%. Atorvastatin had only a modest effect on sCD40L (
P
=0.08).

Conclusions—

In patients with acute coronary syndromes, atorvastatin abrogated the risk of recurrent cardiovascular events associated with high sCD40L. Early statin therapy after acute coronary syndromes counters the risk associated with elevated sCD40L.
Urinary 20-Hydroxyeicosatetraenoic Acid Is Associated With Endothelial Dysfunction in Humans
Authors: Ward Natalie C. , Rivera Jennifer , Hodgson Jonathan , Puddey Ian B. , Beilin Lawrie J. , Falck John R. , Croft Kevin D.
Published: July 2004

Background—

20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P450 (ω-hydroxylase) metabolite of arachidonic acid with vasoconstrictor activity that may be involved in the pathogenesis of hypertension. In humans, there are few data relating 20-HETE to vascular pathophysiology. This study aimed to determine whether urinary 20-HETE excretion is related to blood pressure or vascular endothelial function in humans.

Methods and Results—

Sixty-six subjects (37 males, 29 females), including 29 with untreated hypertension, had urinary 20-HETE excretion measured by gas chromatography/mass spectrometry. There was no significant difference for 20-HETE excretion between hypertensive and normotensive subjects. 20-HETE excretion was positively related to body mass index and sodium excretion. There was a significant inverse association between urinary 20-HETE and endothelium-dependent vasodilation measured by flow-mediated dilation of the brachial artery (
P
=0.006). There was no association with vasodilator responses to nitroglycerin. In multiple regression analysis, 20-HETE remained an independent predictor of endothelium-dependent vasodilation after adjustment for age, body mass index, and blood pressure. When gender was included in the model, the relationship between 20-HETE and flow-mediated dilation was attenuated. Separate analysis by gender revealed that in women, hypertensive subjects had significantly higher 20-HETE excretion than normotensive subjects, but this was not seen in men. In women, 20-HETE was positively related to diastolic and systolic blood pressure. In men, 20-HETE was positively related to body mass index.

Conclusions—

This is the first demonstration of an association between 20-HETE excretion and in vivo vascular function in humans. Given the negative modulatory role of nitric oxide on ω-hydroxylase, the present results suggest a potentially important role for 20-HETE in human vascular physiology.
Sirolimus in De Novo Heart Transplant Recipients Reduces Acute Rejection and Prevents Coronary Artery Disease at 2 Years
Authors: Keogh Anne , Richardson Meroula , Ruygrok Peter , Spratt Phillip , Galbraith Andrew , O’Driscoll Gerry , Macdonald Peter , Esmore Don , Muller David , Faddy Steve
Published: July 2004

Background—

Sirolimus reduces acute rejection in renal transplant recipients and prevents vasculopathy in nonhuman primates and in-stent restenosis in humans. Its effects on rejection and transplant vasculopathy in human heart transplant recipients are unknown.

Methods and Results—

In a randomized, open-label study, sirolimus was compared with azathioprine in combination with cyclosporine and steroids administered from the time of cardiac transplantation. We report 6-month rejection rates (primary end point), 12-month safety and efficacy data, and 6- and 24-month graft vasculopathy data in 136 cardiac allograft recipients randomly assigned (2:1) to sirolimus (n=92) or azathioprine (n=44). At 6 months, the proportion of patients with grade 3a or greater acute rejection was 32.4% for sirolimus 3 mg/d (
P
=0.027), 32.8% for sirolimus 5 mg/d (
P
=0.013), and 56.8% for azathioprine. Patient survival at 12 months was comparable among groups. Intracoronary ultrasound at 6 weeks, 6 months, and 2 years demonstrated highly significant progression of transplant vasculopathy in azathioprine-treated patients. At 6 months, a highly significant absence of progression in intimal plus medial proliferation and significant protection against luminal encroachment was evident in sirolimus-treated patients, and these effects were sustained at 2 years.

Conclusions—

Sirolimus use from the time of transplantation approximately halved the number of patients experiencing acute rejection. The measurable development of transplant vasculopathy at 6 months and 2 years in patients receiving azathioprine was not observed in patients receiving sirolimus.
Prognostic Value of Health Status in Patients With Heart Failure After Acute Myocardial Infarction
Authors: Soto Gabriel E. , Jones Philip , Weintraub William S. , Krumholz Harlan M. , Spertus John A.
Published: July 2004

Background—

Disease-specific health status instruments such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) can quantify symptoms, functional limitations, and quality of life in patients with heart failure. Understanding the relationship between KCCQ scores and prognosis may assist clinicians in both interpreting KCCQ scores and stratifying risk in patients.

Methods and Results—

We examined the prognostic value of the KCCQ in a prospective, international cohort of 1516 patients with heart failure after a recent acute myocardial infarction. We focused on the relationship between the KCCQ overall score (KCCQ-os), measured at the first outpatient visit (4 weeks after enrollment), and subsequent 1-year cardiovascular mortality or hospitalization (n=258, 20.3%). KCCQ-os was strongly associated with subsequent cardiovascular events in that those with a score ≥75 had an 84% 1-year event-free survival compared with 59% for those with a score <25 (
P
<0.001). After demographic and other clinical characteristics were controlled for in multivariable models, KCCQ-os remained strongly associated with outcome (hazard ratio, 2.02; 95% CI, 1.24 to 3.27 for KCCQ-os <25;
P
<0.001).

Conclusions—

In outpatients with heart failure complicating an acute myocardial infarction, KCCQ-os is strongly associated with subsequent 1-year cardiovascular mortality and hospitalization. Use of the KCCQ in outpatient clinical practice can both quantify patients’ health status and provide insight into their prognosis. (Circulation. 2004;110:546-551.)
Temporal Trends in Coronary Heart Disease Mortality and Sudden Cardiac Death From 1950 to 1999
Authors: Fox Caroline S. , Evans Jane C. , Larson Martin G. , Kannel William B. , Levy Daniel
Published: July 2004

Background—

Throughout the past 50 years, heart disease has been the leading cause of death in the United States. Although declines in coronary heart disease (CHD) mortality have been noted, there is still uncertainty about the magnitude of the decline and whether the trend is similar for sudden cardiac death (SCD).

Methods and Results—

We examined temporal trends in SCD and nonsudden CHD death in the Framingham Heart Study original and offspring cohorts from 1950 to 1999. SCD was defined as a death attributed to CHD with preceding symptoms that lasted less than 1 hour; all deaths were adjudicated by a physician panel. Log-linear Poisson regression was used to estimate CHD mortality and SCD risk ratios (RRs); RRs were adjusted for age and gender. There were 811 CHD deaths: 453 nonsudden and 358 SCDs. Ninety-one (20%) of nonsudden CHD deaths and 173 (48%) of SCDs were in subjects free of antecedent CHD. From 1950–1969 to 1990–1999, overall CHD death rates decreased by 59% (95% CI 47% to 68%,
P
trend
<0.001). Nonsudden CHD death decreased by 64% (95% CI 50% to 74%,
P
trend
<0.001), and SCD rates decreased by 49% (95% CI 28% to 64%,
P
trend
<0.001). These trends were seen in men and women, in subjects with and without a prior history of CHD, and in smokers and nonsmokers.

Conclusions—

The risks of SCD and nonsudden CHD mortality have decreased by 49% to 64% over the past 50 years. These trends were evident in subjects with and without heart disease, which suggests important contributions of primary and secondary prevention to the decreasing risk of CHD death and SCD.
Mitochondrial Uncoupling Protein 1 Expressed in the Heart of Transgenic Mice Protects Against Ischemic-Reperfusion Damage
Authors: Hoerter Jacqueline , Gonzalez-Barroso Maria-del-Mar , Couplan Elodie , Mateo Philippe , Gelly Chantal , Cassard-Doulcier Anne-Marie , Diolez Philippe , Bouillaud Frederic
Published: July 2004

Background—

Mitochondrial respiration is the main source of energy in aerobic animal cells and is adapted to the energy demand by respiratory coupling. Uncoupling proteins (UCPs) perturb respiratory coupling by inducing a proton leak through the mitochondrial inner membrane. Although this could lead to deleterious energy waste, it may prevent the production of oxygen radicals when the rate of phosphorylation of ADP into ATP is low, whereas oxygen and substrate availability to mitochondria is high. The latter conditions are encountered during cardiac reperfusion after ischemia and are highly relevant to heart infarction.

Methods and Results—

Heart function of 6 transgenic mice expressing high amounts of UCP1 and of 6 littermate controls was compared in isolated perfused hearts in normoxia, after 40-minute global ischemia, and on reperfusion. In normoxia, oxygen consumption, contractility (quantified as the rate-pressure product), and their relationship (energetic yield) were similar in controls and transgenic mice. Although UCP1 expression did not alter the sensitivity to ischemia, it significantly improved functional recovery on reperfusion. After 60 minutes of reperfusion, contractility was 2-fold higher in transgenic mice than in controls. Oxygen consumption remained significantly depressed in controls (53±27% of control), whereas it recovered strikingly to preischemic values in transgenic mice, showing uncoupling of respiration by UCP1 activity. Glutathione and aconitase, markers of oxidative damage, indicated lower oxidative stress in transgenic mice.

Conclusions—

UCP1 activity is low under normoxia but is induced during ischemia-reperfusion. The presence of UCP1 mitigates reperfusion-induced damage, probably because it lowers mitochondrial hyperpolarization at reperfusion.
Thrombolysis Compared With Heparin for the Initial Treatment of Pulmonary Embolism
Authors: Wan Susan , Quinlan Daniel J. , Agnelli Giancarlo , Eikelboom John W.
Published: July 2004

Background—

Randomized trials and meta-analyses have reached conflicting conclusions about the role of thrombolytic therapy for the treatment of acute pulmonary embolism.

Methods and Results—

We performed a meta-analysis of all randomized trials comparing thrombolytic therapy with heparin in patients with acute pulmonary embolism. Eleven trials, involving 748 patients, were included. Compared with heparin, thrombolytic therapy was associated with a nonsignificant reduction in recurrent pulmonary embolism or death (6.7% versus 9.6%; OR 0.67, 95% CI 0.40 to 1.12,
P
for heterogeneity=0.48), a nonsignificant increase in major bleeding (9.1% versus 6.1%; OR 1.42, 95% CI 0.81 to 2.46), and a significant increase in nonmajor bleeding (22.7% versus 10.0%; OR 2.63, 95% CI 1.53 to 4.54; number needed to harm=8). Thrombolytic therapy compared with heparin was associated with a significant reduction in recurrent pulmonary embolism or death in trials that also enrolled patients with major (hemodynamically unstable) pulmonary embolism (9.4% versus 19.0%; OR 0.45, 95% CI 0.22 to 0.92; number needed to treat=10) but not in trials that excluded these patients (5.3% versus 4.8%; OR 1.07, 95% CI 0.50 to 2.30), with significant heterogeneity between these 2 groups of trials (
P
=0.10).

Conclusions—

Currently available data provide no evidence for a benefit of thrombolytic therapy compared with heparin for the initial treatment of unselected patients with acute pulmonary embolism. A benefit is suggested in those at highest risk of recurrence or death. The number of patients enrolled in randomized trials to date is modest, and further evaluation of the efficacy and safety of thrombolytic therapy for the treatment of high-risk patients with acute pulmonary embolism appears warranted.
Clinical Inhibition of the Seven-Transmembrane Thrombin Receptor (PAR1) by Intravenous Aprotinin During Cardiothoracic Surgery
Authors: Day J.R.S. , Punjabi P.P. , Randi A.M. , Haskard D.O. , Landis R.C. , Taylor K.M.
Published: July 2004

Background—

Protease-activated receptor-1 (PAR1) is the principal thrombin receptor in the vasculature, and antagonists against this receptor are in preclinical trials. Aprotinin, already approved for clinical use to reduce transfusion requirements in cardiopulmonary bypass (CPB) surgery, has been shown to inhibit PAR1 activation in vitro. Here, we exploit CPB as a model for thrombin generation in humans to examine whether aprotinin can inhibit platelet PAR1 activation clinically.

Methods and Results—

PAR1 expression and function on platelets was examined in coronary artery bypass grafting (CABG) patients randomized into 2 groups: (1) those receiving saline infusion during CPB (n=17) and (2) those receiving aprotinin (2×10
6
kallikrein inhibitor units [KIU] in pump prime, 2×10
6
KIU loading dose, followed by 0.5×10
6
KIU/h [n=13]). Platelets in the saline group showed loss of PAR1-specific function at 2 hours after CPB, but this was preserved in the aprotinin group (
P
<0.001). These effects were most likely targeted at PAR1 receptor cleavage, because (1) the level of thrombin generated during CPB did not vary significantly between groups, (2) expression of SPAN12, which detects only uncleaved PAR1 receptors, was preserved in the aprotinin but not the placebo group (
P
<0.05), and (3) supporting evidence in vitro showed reduced thrombin-induced PAR1 cleavage (
P
<0.001) and platelet aggregation (
P
<0.001) in the presence of aprotinin.

Conclusions—

This study demonstrates that platelet PAR1 activation by thrombin can be inhibited by aprotinin. Our results extend the clinical mechanism of action of aprotinin and provide the first proof of principle that PAR1 can be inhibited clinically. This has implications beyond cardiac surgery for the development of therapeutic PAR1 blockade.
Membrane Trafficking of Angiotensin Receptor Type-1 and Mechanochemical Signal Transduction in Proximal Tubule Cells
Authors: Kolb Robert J. , Woost Philip G. , Hopfer Ulrich
Published: July 2004

Cellular localization and trafficking of the major angiotensin receptor, AT
1
, was studied in mouse proximal tubule cell lines because angiotensin II concentrations in the luminal fluid of proximal tubules are greater than the K
d
of the receptor and would predict high turnover rates of the receptor. Mouse proximal tubule cells can exist in 2 polarized, differentiated states after confluence: a protoepithelium and a highly differentiated epithelium. The latter is distinguished by greater polarization of the microtubule cytoskeleton and collection of apical microtubule-dependent membrane proteins in condensed apical recycling endosomes (CARE) in proximity to the primary cilium. AT
1
, AT
2
, and the sodium hydrogen exchanger NHE3 are localized to CARE. With fluid movement, AT
1
receptors externalize from CARE to the apical plasma membrane and allow luminal angiotensin II to initiate cell signaling. These data suggest that fluid movement controls receptor externalization and, hence, a model in which ciliary deflection results in transduction of a mechanical stimulus into the chemical signaling of the AT
1
receptor.
Transcriptional Regulation of Type B Human Natriuretic Peptide Receptor Gene Promoter
Authors: Rahmutula Dolkun , Cui Junfeng , Chen Songcang , Gardner David G.
Published: July 2004

The type B natriuretic peptide receptor (NPR-B) is the cognate receptor for the C-type natriuretic peptide and, as such, is responsible for signaling growth-suppressant activity in vascular smooth muscle cells. Here we report the isolation and characterization of the human (h) NPR-B gene promoter. Using 5′ rapid amplification of cDNA ends analysis, we have identified the 5′ terminus of the hNPR-B gene transcript ≈732 base pairs upstream from the presumed translation start site of the protein. We generated a series of 5′ deletion mutants linked to a luciferase reporter and introduced these constructs into rat aortic smooth muscle cells or neonatal rat cardiac fibroblasts. Maximal expression was seen with a construct harboring 441 base pairs of 5′ flanking sequence. Site-directed mutagenesis of the proximal promoter revealed a series of GC-rich sequences, 5 of which contributed modestly (≈25%) to basal hNPR-B promoter activity. Mutation of a sixth GC-rich sequence led to a >90% reduction in promoter activity. This sequence was shown to associate with Sp1 and Sp3 in vitro. The same mutation that resulted in loss of functional activity also resulted in loss of binding activity in vitro. Overexpression of Sp1 or Sp3 in
Drosophila
Schneider cells resulted in an increase in hNPR-B promoter activity that was completely nullified with the Sp1 binding site mutation described above. These studies provide the first description and characterization of the NPR-B gene promoter and suggest that this promoter’s activity is dominated by a single cluster of Sp1-binding elements in the proximal 5′ flanking sequence of the gene.
Nebivolol Increases Arterial Distensibility In Vivo
Authors: McEniery Carmel M. , Schmitt Matthias , Qasem Ahmad , Webb David J. , Avolio Alberto P. , Wilkinson Ian B. , Cockcroft John R.
Published: July 2004

Arterial stiffness is a key determinant of cardiovascular risk in hypertensive patients. β-Blockers appear to be less effective than other drugs in improving outcome in hypertensive patients, and a potential explanation may be that β-blockers are less effective in reducing arterial stiffness. The aim of this study was to assess the direct effect of β-blockade on pulse wave velocity (PWV), a robust measure of arterial distensibility, using a local, ovine, hind-limb model. In addition, we hypothesized that the vasodilating β-blocker nebivolol, but not atenolol, would increase arterial distensibility in vivo. All studies were conducted in anesthetized sheep. PWV was recorded in vivo using a dual pressure-sensing catheter placed in the common iliac artery. Intraarterial infusion of nebivolol reduced PWV by 6±3% at the higher dose (
P
<0.001), but did not alter mean arterial pressure (change of −1±3 mm Hg,
P
=0.1). In contrast, atenolol had no effect on PWV (
P
=0.11) despite a small drop in mean pressure (change of −5±3 mm Hg,
P
<0.01). Infusion of glyceryl trinitrate led to a dose-dependent fall in PWV, and 2 nmol/min produced a similar reduction in PWV to the higher dose of nebivolol (500 nmol/min). The effect of nebivolol on PWV was significantly attenuated during coinfusion of
N
G
-monomethyl-
l
-arginine (
P
=0.003) and also during coinfusion of butoxamine (
P
=0.02). These results demonstrate that nebivolol, but not atenolol, increases arterial distensibility. This effect of nebivolol is mediated through the release of NO via a β
2
adrenoceptor–dependent mechanism. Thus, nebivolol may be of benefit in conditions of increased large artery stiffness, such as isolated systolic hypertension.
Is the Extrapolated Adult Dose of Fosinopril Safe and Effective in Treating Hypertensive Children?
Authors: Li Jennifer S. , Berezny Katherine , Kilaru Rakhi , Hazan Lydie , Portman Ronald , Hogg Ronald , Jenkins Randall D. , Kanani Prapti , Cottrill Carol M. , Mattoo Tej K. , Zharkova Ludmila , Kozlova Ludmila , Weisman Irit , Deitchman David , Califf Robert M.
Published: July 2004

We evaluated the efficacy, safety, and dose–response relationship of fosinopril in children aged 6 to 16 years with hypertension or high-normal blood pressure with an associated medical condition requiring treatment. The study was a prospective, double-blind, placebo-controlled trial conducted in 78 clinical sites in the United States, Russia, and Israel. There were 4 phases: a screening phase of 10 days maximum, a 4-week dose–response phase, a placebo withdrawal phase of 2 weeks maximum, and a 52-week open-label safety phase. The primary objective of the dose–response phase was to determine whether low (0.1 mg/kg), medium (0.3 mg/kg), or high (0.6 mg/kg) doses of fosinopril based on established adult dosing affect trough seated systolic blood pressure. During the dose–response phase, all 3 doses were equally effective in lowering systolic blood pressure. During the placebo withdrawal phase, there was an adjusted mean systolic blood pressure increase of 5.2 mm Hg for the placebo group and 1.5 mm Hg for the fosinopril group, a net withdrawal effect of 3.7 mm Hg (
P
=0.013). Fosinopril was well tolerated; serious adverse events occurred infrequently and were generally not attributed to fosinopril. Because children appear to be more sensitive to lower doses of fosinopril than adults, starting doses for children should be ≤0.1 mg/kg.
Reduction of Vascular Noradrenaline Sensitivity by AT
1
Antagonists Depends on Functional Sympathetic Innervation
Authors: Raasch Walter , Dominiak Peter , Ziegler Andreas , Dendorfer Andreas
Published: July 2004

Blockade of angiotensin II type-1 (AT
1
) receptors has been shown to reduce the magnitude of the blood pressure response to noradrenaline in pithed rats via an unidentified mechanism. Dose-response curves were established for the noradrenaline-induced (10
−12
to 10
−7
mol/kg) increase of diastolic blood pressure in pithed rats treated with tubocurarine, propranolol, and atropine. Candesartan (1 mg/kg) increased the
ED
50
of the noradrenaline response (1.3±0.1 nmol/kg) up to 20-fold. Vasopressor responsiveness to noradrenaline was attenuated specifically, whereas the vasopressin-induced increase in diastolic blood pressure was maintained. Specific involvement of AT
1
receptors was confirmed by equivalent actions of losartan. Blockade of norepinephrine transporter or α
2
-adrenoceptors using desipramine or rauwolscine reduced the losartan-induced shifts in the
ED
50
values of noradrenaline by 63% and 21%, respectively. Combined blockade of norepinephrine transporter and α
2
-adrenoceptors eliminated the influence of losartan on noradrenaline sensitivity (
ED
50
5.5±1.3 versus 5.6±1.2 nmol/kg), a result also observed after sympathetic denervation by reserpine (
ED
50
7.1±0.8 versus 7.8±0.8 nmol/kg). Our experiments show that the reduction of vascular noradrenaline sensitivity by AT
1
blockade is dependent on the intact functioning of both neuronal noradrenaline uptake via norepinephrine transporter and presynaptic α
2
-mediated autoinhibition, exclusively provided by the sympathetic innervation. These newly identified mechanisms may contribute to the antihypertensive and protective actions of AT
1
blockers.
"Indianization" from the Indian Point of View: Trade and Cultural Contacts with Southeast Asia in the Early First Millennium C.E.
Authors: Smith Monica
Published: July 2004

The idea that Indian "influence" was responsible for the socio-political development of early Southeast Asia is now largely discredited, but the question of the actual impact of early trade between India and Southeast Asia remains. Prior to the fourth century C.E., Indian trade activities with Southeast Asia appear to have been relatively infrequent, when assessed through the number of items of Indian origin recovered, and the incentives for such trade from the Indian point of view. After the fourth century, the adoption of subcontinental traditions - religious iconography, Sanskrit terminology, coinage, and terms identifying leaders - is seen throughout the area of Southeast Asia, from Bangladesh to Cambodia, Malaysia and Thailand as well as the larger Indonesian islands. Subcontinental traditions became attractive at this time because of the advent of strong political entities in the Indian subcontinent, notably the Guptas, which produced coherent models of political, social and religious organization. Although such models were also available from neighboring China, apprehension about Chinese expansion led the rulers of emergent chiefdoms in Southeast Asia to prefer the adoption of Indian political and religious iconography.
Sufis and Shamans: Some Remarks on the Islamization of the Mongols in the Ilkhanate
Authors: Amitai-Preiss Reuven
Published: July 2004

Some scholars have argued that sufis, Muslim mystics, played a decisive role in converting the Mongols in Iran to Islam in the thirteenth and fourteenth centuries, mainly because of the similarity between the extreme sufis (the dervishes) and the shamans of the traditional Mongol religion. This paper maintains that it was primarily some moderate, "institutional" sufis who were close to Mongol ruling circles and thus played a part in their conversion. This, however, had little to so with any resemblance between shamans and sufis, since it is suggested that Muslim mystics, even of the dervish variety, are basically dissimilar to the Inner Asian shamans. If, indeed, both kinds of sufis were successful in influencing the Mongols, it would appear that this is due to other reasons suggested at the end of the paper.
Early Medieval Bengal and the Trade In Horses: a Note
Authors: Chakravarti Ranabir
Published: July 2004

This essay brings into focus a relatively neglected aspect of economic life in early medieval Bengal. Like many other parts of India, Bengal during ancient and early medieval times did not have any indigenous, good quality war horses. The emergence of Bengal as a regional political entity to reckon with during the early medieval times (c. AD 600 - 1300) must have increased the demand for war horses. The paper analyses the epigraphic accounts of the procurement of these indispensable war animals from northern and northwestern India by the rulers of early medieval Bengal. The Tabaqat-i-Nasiri of the thirteenth century gives an indication of the availablity of northeastern horses - probably Tibetan ones - in Bengal. Chinese accounts of the fifteenth century and some Arabic accounts of the invasions of the Deccan by the Delhi Sultante have been utilised here to suggest that early medieval Bengal not only received regular supplies of imported horses, but also witnessed the transportation of some of these war machines to the Deccan and China.
It's a Dog's Life: Elevating Status from Pet to "Fur Baby" at Yappy Hour
Authors: Greenebaum Jessica
Published: July 2004

Nonhuman animals always have played a significant role in people's lives. Lately, the technological and market economy has anthropomorphized dogs to human-like behavior, particularly to status of family member or child. This qualitative study expands upon the current studies on consumption and animals and society by exploring how human-canine relationships are anthropomorphized at the family excursion to "Yappy Hour" at Fido's Barkery. The type of person who attends Yappy Hour on a weekly basis has a unique and special type of connection with their dog that goes beyond most people's relationships with dogs. Most of the dog lovers interviewed do not perceive their dogs as dogs; they are family members, best friends, and "fur babies." These dog lovers also do not perceive themselves as dog owners; they see themselves as mothers and fathers. The social and market environment of Fido's Barkery not only reinforces their relationship with their dog, it shapes community, friendships, and personal identity.
Modification of the Pet Attitude Scale
Authors: Templer Donald , Arikawa Hiroko , Canfield Merle , Munsell Kathleen , Tangan Kimberly
Published: July 2004

This study recruited 203 college students to help determine clarity and precision in the wording of four items in the Templer, Salter, Baldwin, Dickey, and Veleber (1981) Pet Attitude Scale (PAS). Half the college students received the original format, and half received the modified wording format. The correlation with total score did not differ for three of the pairs of items. For one of the items, the correlation was higher with the original wording. The 18-item Pet Attitude Scale—Modified retains the original wording for that item and uses the modified wording for the other three items.
The effect of seed hardness on husking time in finches
Authors: van der Meij  , Griekspoor  , Bout
Published: July 2004

Small granivorous birds crack and remove the seed coat before they swallow the kernel. It is generally assumed that husking time is related to seed hardness and bite force, although direct experimental evidence is scarce. In this study we decreased experimentally the hardness of a single seed species, so that all the seed characters remained the same with the exception of (average) hardness. We determined the husking time for experimental and control seeds in a number of granivorous passerines. Our data show that husking time is directly related to seed hardness: husking time increases with seed hardness. A video-analysis of the seed-cracking process shows that species also apply different numbers of mandibulations to crack the two seed types. The number of seed positioning movements before cracking slightly increases with the size of the seed relative to body size. The largest contribution to differences in husking time among different sized species or between seeds of the same size but of different hardness, however, comes from the number of cracking attempts. It is hypothesised that seeds are squeezed from between the mandibles more easily when relatively large bite force is applied, leading to an increase in failed cracking attempts.
Amplitude spectra of Corncrake calls: what do they signalise?
Authors: Osiejuk Tomasz , Olech Bogumła
Published: July 2004

—The territorial call of corncrake Crex crex males is a disyllabic, loud, pulse repetition signal repeated in long series at night. It seems to be relatively simple as it lacks the repertoire variation typical of passerines, but still seems to be the equivalent of a territorial and/or advertisement song. In this paper we tested: (1) whether the pattern of energy distribution within the call (i. e. amplitude spectrum) is individually invariant; (2) whether it could be a signal used in an individual recognition system; and (3) whether it is a sexually selected honest trait related to male body size. We found that amplitude spectra varied more between than within males, but it is rather unlikely that energy distribution is a single feature encoding identity of a male. We found some weak correlations between body size parameters and variables describing amplitude spectra, either supporting or contradicting the expected relationship (i. e. larger male — more energy in lower frequencies). We also found that the frequency of maximal amplitude, even within a single call, may rapidly change by a few kHz, which is most probably an effect of head and body movements, not changes in sound production itself. The conclusion is that all features of corncrake calls, including energy distribution, indicate that this signal has evolved under a strong pressure towards precise localisation of a sender, which is understandable as corncrakes inhabit dense vegetation and call almost exclusively at night.
Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis
Authors: Hu Liang , Lee Merlin , Campbell Wendy , Perez-Soler Roman , Karpatkin Simon
Published: July 2004

Tumor/host-generated thrombin (endogenous thrombin) was investigated with tumor growth and metastasis experiments in mice by the use of hirudin, a highly potent specific inhibitor of thrombin. Pretreatment with hirudin inhibited tumor implantation in nude or syngeneic mice, following subcutaneous injection of 2 human and 2 murine tumors. Hirudin induced a considerable lag period in the appearance of tumor growth, compared with phosphate-buffered saline (PBS) treatment, but had no effect on established tumor nodule growth in vivo or on tumor growth in vitro. Hirudin treatment induced central necrosis of the tumor nodule compared with no effect with PBS treatment. Greater protection was noted with longer duration of treatment. Tumor seeding into blood was examined with green fluorescent protein (GFP)-labeled tumor cells. Hirudin inhibited seeding into the blood as well as systemic organs which varied from complete protection to 15- to 32-fold in the blood and 17- to 395-fold in the lung. Hirudin inhibited spontaneous metastases from subcutaneously implanted tumor by reducing the number of tumor nodules in the lungs. Mouse survival in animals injected subcutaneously with highly aggressive 4T1 cells revealed 5 of 5 deaths of PBS-treated animals on day 40 compared with no deaths with hirudin treatment, with prolongation of survival with hirudin treatment of 16 days to more than 31 days. Thus, endogenous thrombin contributes to tumor implantation, seeding, and spontaneous metastasis. A potent antithrombin agent should be of clinical benefit to patients with cancer. (Blood. 2004;104:2746-2751)
Subnuclear Trafficking and Gene Targeting by Steroid Receptors
Authors: NAGAICH AKHILESH K. , RAYASAM GEETHA V. , MARTINEZ ELISABETH D. , BECKER MATTHIAS , QIU YI , JOHNSON THOMAS A. , ELBI CEM , FLETCHER TERACE M. , JOHN SAM , HAGER GORDON L.
Published: July 2004

Abstract: Through the use of novel imaging techniques, we have observed direct steroid receptor binding to a tandem array of a hormone‐responsive promoter in living cells. We found that the glucocorticoid receptor (GR) exchanges rapidly with regulatory elements in the continued presence of ligand. We have also reconstituted a GR‐dependent nucleoprotein transition with chromatin assembled on promoter DNA, and we discovered that GR is actively displaced from the chromatin template during the chromatin remodeling process. Using high‐intensity UV laser crosslinking, we have observed highly periodic interactions of GR with promoter chromatin. These periodic binding events are dependent on GR‐directed hSWI/SNF remodeling of the template and require the presence of ATP. Both the in vitro and in vivo results are consistent with a dynamic model (“hit‐and‐run”) in which GR first binds to chromatin after ligand activation, recruits a remodeling activity, and is simultaneously lost from the template. We also find that receptor mobility in the nucleoplasm is strongly enhanced by molecular chaperones. These observations indicate that multiple mechanisms are involved in transient receptor interactions with nucleoplasmic targets.
Novel Repression of the Glucocorticoid Receptor by Anthrax Lethal Toxin
Authors: WEBSTER JEANETTE I. , MOAYERI MAHTAB , STERNBERG ESTHER M.
Published: July 2004

Abstract: Death from anthrax has been reported to occur from systemic shock. The lethal toxin (LeTx) is the major effector of anthrax mortality. Although the mechanism of entry of this toxin into cells is well understood, its actions once inside the cell are not as well understood. LeTx is known to cleave and inactivate MAPKKs. We have recently shown that LeTx represses the glucocorticoid receptor (GR) both in vitro and in vivo. This repression is partial and specific, repressing the glucocorticoid, progesterone, and estrogen receptor α, but not the mineralocorticoid or estrogen receptor β. This toxin does not affect GR ligand or DNA binding, and we have suggested that it may function by removing/inactivating one or more of the many cofactors involved in nuclear hormone receptor signaling. Although the precise involvement of this nuclear hormone receptor repression in LeTx toxicity is unknown, examples of blunted HPA axis and glucocorticoid signaling in numerous autoimmune/inflammatory diseases suggest that such repression of critically important receptors could have deleterious effects on health.
Interaction of the Glucocorticoid Receptor and the Chicken Ovalbumin Upstream Promoter‐Transcription Factor II (COUP‐TFII): Implications for the Actions of Glucocorticoids on Glucose, Lipoprotein, and Xenobiotic Metabolism
Authors: DE MARTINO MASSIMO U. , ALESCI SALVATORE , CHROUSOS GEORGE P. , KINO TOMOSHIGE
Published: July 2004

Abstract: Glucocorticoids exert their extremely diverse effects on numerous biologic activities of humans via only one protein module, the glucocorticoid receptor (GR). The GR binds to the glucocorticoid response elements located in the promoter region of target genes and regulates their transcriptional activity. In addition, GR associates with other transcription factors through direct protein‐protein interactions and mutually represses or stimulates each other's transcriptional activities. The latter activity of GR may be more important than the former one, granted that mice harboring a mutant GR, which is active in terms of protein‐protein interactions but inactive in terms of transactivation via DNA, survive and procreate, in contrast to mice with a deletion of the entire GR gene that die immediately after birth. We recently found that GR physically interacts with the chicken ovalbumin upstream promoter‐transcription factor II (COUP‐TFII), which plays a critical role in the metabolism of glucose, cholesterol, and xenobiotics, as well as in the development of the central nervous system in fetus. GR stimulates COUP‐TFII‐induced transactivation by attracting cofactors via its activation function‐1, while COUP‐TFII represses the GR‐governed transcriptional activity by tethering corepressors, such as the silencing mediator for retinoid and thyroid hormone receptors (SMRT) and the nuclear receptor corepressors (NCoRs) via its C‐terminal domain. Their mutual interaction may play an important role in gluconeogenesis, lipoprotein metabolism, and enzymatic clearance of clinically important compounds and bioactive chemicals, by regulating their rate‐limiting enzymes and molecules, including the phosphoenolpyruvate carboxykinase (PEPCK), the cytochrome P450 CYP3A and CYP7A, and several apolipoproteins. It appears that glucocorticoids exert their intermediary effects partly via physical interaction with COUP‐TFII.
The Origin and Functions of Multiple Human Glucocorticoid Receptor Isoforms
Authors: LU NICK Z. , CIDLOWSKI JOHN A.
Published: July 2004

Abstract: Glucocorticoid hormones are necessary for life and are essential in all aspects of human health and disease. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), which binds glucocorticoid hormones and regulates gene expression, cell signaling, and homeostasis. Decades of research have focused on the mechanisms of action of one isoform of GR, GRa. However, in recent years, increasing numbers of human GR (hGR) isoforms have been reported. Evidence obtained from this and other laboratories indicates that multiple hGR isoforms are generated from one single hGR gene via mutations and/or polymorphisms, transcript alternative splicing, and alternative translation initiation. Each hGR protein, in turn, is subject to a variety of posttranslational modifications, and the nature and degree of posttranslational modification affect receptor function. We summarize here the processes that generate and modify various hGR isoforms with a focus on those that impact the ability of hGR to regulate target genes. We speculate that unique receptor compositions and relative receptor proportions within a cell determine the specific response to glucocorticoids. Unchecked expression of some isoforms, for example hGRβ, has been implicated in various diseases.
Overview of the Actions of Glucocorticoids on the Immune Response: A Good Model to Characterize New Pathways of Immunosuppression for New Treatment Strategies
Authors: FRANCHIMONT D
Published: July 2004

Abstract: Glucocorticoids have been used for over 50 years in the treatment of inflammatory and autoimmune diseases and in preventing graft rejection. Today, knowledge of their molecular, cellular, and pharmacological properties allows a better understanding of glucocorticoid‐mediated immunosuppression. Glucocorticoids exert both negative and positive effects with a dynamic and bi‐directional spectrum of activities on various limbs and components of the immune response. They modulate genes involved in the priming of the innate immune response, while their actions on the adaptive immune response are to suppress cellular (Th1) immunity and promote humoral (Th2) immunity. Interestingly, glucocorticoids can also induce tolerance to specific antigens by influencing dendritic cell maturation and function and promoting the development of regulatory high IL‐10‐producing T cells. The ex vivo therapeutic use of glucocorticoids could therefore represent an adjuvant treatment to cell therapy in autoimmune diseases, avoiding the long‐term deleterious adverse effects of glucocorticoids. Thus, the panoramic view of glucocorticoid actions on the immune system provides an interesting model for characterizing important biological pathways of immunosuppression.
Glucocorticoids and the Th1/Th2 Balance
Authors: ELENKOV ILIA J.
Published: July 2004

Abstract: Evidence accumulated over the last 5‐10 years indicates that glucocorticoids (GCs) inhibit the production of interleukin (IL)‐12, interferon (IFN)‐γ, IFN‐α, and tumor necrosis factor (TNF)‐α by antigen‐presenting cells (APCs) and T helper (Th)1 cells, but upregulate the production of IL‐4, IL‐10, and IL‐13 by Th2 cells. Through this mechanism increased levels of GCs may systemically cause a selective suppression of the Th1‐cellular immunity axis, and a shift toward Th2‐mediated humoral immunity, rather than generalized immunosuppression. During an immune response and inflammation, the activation of the stress system, and thus increased levels of systemic GCs through induction of a Th2 shift, may actually protect the organism from systemic “overshooting” with Th1/pro‐inflammatory cytokines and other products of activated macrophages with tissue‐damaging potential. However, conditions associated with significant changes of GCs levels, such as acute or chronic stress or cessation of chronic stress, severe exercise, and pregnancy and postpartum, through modulation of the Th1/Th2 balance may affect the susceptibility to or the course of infections as well as autoimmune and atopic/allergic diseases.
Early Environmental Regulation of Hippocampal Glucocorticoid Receptor Gene Expression: Characterization of Intracellular Mediators and Potential Genomic Target Sites
Authors: WEAVER IAN C.G. , DIORIO JOSIE , SECKL JONATHAN R. , SZYF MOSHE , MEANEY MICHAEL J.
Published: July 2004

Abstract: Environmental conditions in early life permanently alter the development of glucocorticoid receptor gene expression in the hippocampus and hypothalamic‐pituitary‐adrenal responses to acute or chronic stress. In part, these effects can involve an activation of ascending serotonergic pathways and subsequent changes in the expression of transcription factors that might drive glucocorticoid receptor expression in the hippocampus. This paper summarizes the evidence in favor of these pathways as well as recent studies describing regulatory targets within the chromatin structure of the promoter region of the rat hippocampal glucocorticoid receptor gene.