bluuebunny/crossref_metadata_2025 huggingface dataset:
Baroreflex Sensitivity and Oxidative Stress in Adriamycin-Induced Heart Failure
Authors: Rabelo Eneida , De Angelis Kátia , Bock Patrícia , Gatelli Fernandes Tânia , Cervo Fábio , Belló Klein Adriane , Clausell Nadine , Cláudia Irigoyen Maria
Published: September 2007

Abstract
—

— Adriamycin cardiotoxicity is associated with oxidative stress in the presence of globally depressed cardiac function. It is unknown if there is a similar profile with early diastolic changes and how it relates to baroreflex control of circulation. In this study, we evaluated baroreflex control of circulation in adriamycin-treated Wistar rats compared with controls, using invasive blood pressure recording processed by a data acquisition system (CODAS, 1 KHz). Baroreflex sensitivity was evaluated by modulating blood pressure with phenylephrine and sodium nitroprusside. Oxidative stress was quantified by chemiluminescence and by glutathione peroxidase enzyme activity. Diastolic dysfunction was characterized by increased left ventricle end-diastolic pressure in adriamycin-treated rats compared with controls with preserved ascending aortic flow. Baroreflex sensitivity in response to blood pressure elevation and reduction were similar in adriamycin (−2±0.27 and −3.19±0.56 bpm/mm Hg) and control rats (−1.35±0.15 and −2.52±0.39 bpm/mm Hg). Chemiluminescence was higher (20450±1286 versus 16517±1020 counts per second/mg protein) and glutathione peroxidase activity was lower (45.6±4.3 versus 76.4±6.9 μmol · min
−1
· mg
−1
protein) in adriamycin rats compared with controls. Inverse correlations were observed between glutathione peroxidase activity and left ventricle end-diastolic pressure (
r
=−0.72,
P
=0.02), between baroreflex sensitivity to phenylephrine and left ventricle end-diastolic pressure (
r
=−0.77,
P
=0.004), and between chemiluminescence and baroreflex sensitivity to sodium nitroprusside (
r
=−0.75,
P
=0.02), whereas a positive correlation was observed between baroreflex sensitivity to sodium nitroprusside and glutathione peroxidase activity (
r
=0.7,
P
=0.04). Thus, adriamycin led to increased left ventricle end-diastolic pressure without changes in baroreflex sensitivity, and associated increased oxidative stress appeared to be related to reduction of reflex control of circulation.
Attenuation of Cardiac Failure, Dilatation, Damage, and Detrimental Interstitial Remodeling Without Regression of Hypertrophy in Hypertensive Rats
Authors: Tsotetsi Oupa J. , Woodiwiss Angela J. , Netjhardt Martin , Qubu Daniel , Brooksbank Richard , Norton Gavin R.
Published: September 2007

Whether left ventricular (LV) hypertrophy is important in the development of LV failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling in hypertension has not been established. We examined the effect of an antihypertensive agent without the ability to regress LV hypertrophy on the development of LV changes in spontaneously hypertensive rats (SHR). Hydralazine given to SHR from 5.2 to 26 months of age returned systolic blood pressure to Wistar Kyoto (WKY) control values but failed to prevent the increase in LV mass noted in SHR (at 26 months of age: WKY, 0.99±0.02 g; untreated SHR, 1.40±0.02 g; treated SHR, 1.36±0.02 g;
P
<0.001 in SHR versus WKY). In comparison to both 16-month-old SHR and age-matched WKY, 26-month-old untreated SHR developed signs consistent with heart failure, LV dilatation (an increased LV internal radius), an eccentric LV geometry, advanced myocyte necrosis, an increase in myocardial collagen solubility (an index of decreases in myocardial collagen cross-linking), and marked increases in myocardial total, type III, and non-cross-linked myocardial collagen concentrations. Despite the inability of hydralazine to regress LV hypertrophy, treated SHR did not develop signs of heart failure, myocyte necrosis, decreases in myocardial collagen cross-linking, or increases in myocardial total, type III, and non-cross-linked collagen at 26 months of age. Moreover, treatment attenuated the development of LV dilatation and an eccentric LV geometry. In conclusion, antihypertensive therapy that does not attenuate LV hypertrophy but achieves normal blood pressure in SHR, is able to hinder the development of heart failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling.
Aminoguanidine and Aortic Wall Mechanics, Structure, and Composition in Aged Rats
Authors: Cantini Caroline , Kieffer Pascal , Corman Bruno , Limiñana Patrick , Atkinson Jeffrey , Lartaud-Idjouadiene Isabelle
Published: September 2007

With aging, the aortic wall becomes stiffer. This could be because of changes in wall stress or composition. We investigated whether a specific change in wall composition, ie, accumulation of advanced glycation end products (AGEs) on the extracellular matrix, is a major factor. We measured aortic mechanics, geometry, and composition in 3-, 10-, 15-, 20-, and 30-month-old inbred normotensive Wistar-Glaxo/Rijswick rats and in a group of 30-month-old rats treated from 20 months onward with aminoguanidine (AG, 42 mg/kg per day), an inhibitor of AGE formation. Thoracoabdominal aortic (pressure) pulse-wave velocity (PWV) increased progressively with age (44% from 3 to 30 months). This age-related increase in aortic PWV was not related to changes in wall stress. For all ages, central (and peripheral) aortic mean blood pressures were not statistically different. Dilatation occurred (18% increase in internal diameter from 3 to 30 months), but this was accompanied by outward hypertrophic remodeling, with an increase in the medial cross-sectional area of 95% and in the ratio of medial thickness to internal diameter of 29%. Wall stress decreased with age (−34%). There was an increase in the ratio of elastic modulus (calculated from the Moens-Korteweg equation) to wall stress (calculated from the Lamé equation, 117% from 3 to 30 months), suggesting that a change in the composition of the wall is responsible for the age-linked increase in wall stiffness. Dry weight decreased slightly but significantly (−14%) with age. Total protein, elastin, collagen, and nonscleroprotein protein [total−(elastin+collagen)] contents did not change with age, but calculated densities of all 4 were halved (as the medial cross-sectional area doubled). The elastin/collagen ratio was statistically similar at all ages. The only significant effect of AG treatment was a fall in PWV (−20%), leading to a fall in the elastic modulus/wall stress ratio (−27% at 10 months of AG treatment versus 30 months of no treatment). In conclusion, the age-related increase in aortic wall stiffness is prevented by 10 months of treatment with AG, which has no effect on wall stress or composition, suggesting that AG may improve aortic wall stiffness by lowering the degree of AGE-induced cross-linking of the extracellular matrix scleroproteins, such as collagen.
Genetic and Environmental Determinants of Plasma Nitrogen Oxides and Risk of Ischemic Heart Disease
Authors: Jeerooburkhan Noor , Jones Lisa C. , Bujac Sarah , Cooper Jacqueleine A. , Miller George J. , Vallance Patrick , Humphries Steve E. , Hingorani Aroon D.
Published: September 2007

Endothelial dysfunction, caused in part by reduced NO bioavailability, is a feature of hypercholesterolemia, hypertension, smoking, and atherosclerosis. We examined whether cholesterol, blood pressure, smoking status, and polymorphisms in the endothelial NO synthase gene (
NOS 3
) influence NO production (as assessed by the plasma levels of nitrogen oxides, NO
x
) in middle-aged men. We also determined whether plasma NO
x
or
NOS 3
genotype predicted the risk of is chemic heart disease (IHD). We studied 3052 men who were initially free of IHD and recruited from 9 UK primary care practices. Blood pressure, age, body mass index, serum cholesterol, and smoking status were assessed at baseline and annually over 8.1 years of follow-up, and all IHD events were recorded. DNA samples were screened for 4
NOS 3
gene polymorphisms: −786 T/C, −922 A/G, 894 G/T (which predicts a Glu
298
→Asp amino acid substitution in the mature protein), and a 27-bp tandem repeat in intron 4 (eNOS4a/4b). NO
x
was measured in plasma samples obtained on entry in 1121 participants from North Mymms and Chesterfield general practices, together with an additional 571 recruits selected at random. Genotype frequencies were in Hardy-Weinberg equilibrium, and linkage disequilibrium was detected between all the
NOS 3
polymorphismsstudied, with the strongest allelic association being detected between −922 A/G and −786 T/C polymorphisms in the gene promoter (Δ=0.90,
P
<0.001). Plasma NO
x
was lower in smokers than in nonsmokers in the North Mymms (10.8±4.5 versus 11.8±4.6 μmol/L,
P
=0.13), Chesterfield (8.4±3.6 versus 9.9±4.0 μmol/L,
P
=0.01), and random samples (10.7±5.1 versus 11.7±4.7 μmol/L,
P
=0.03). A weak but significant inverse relationship was detected between plasma NO
x
and serum cholesterol only in the North Mymms data set (
r
=−0.14,
P
=0.02). No relationship was detected between plasma NO
x
and any of the
NOS 3
polymorphisms, nor was there any association between any
NOS 3
polymorphism and risk of an IHD event in either smokers or nonsmokers. These data support the hypothesis that the endothelial dysfunction observed in the blood vessels of smokers is related to reduced NO bioactivity but indicate that
NOS 3
genotype does not influence significantly the level of plasma NO
x
or the risk of IHD in this population sample of middle-aged British men.
NADH/NADPH Oxidase and Enhanced Superoxide Production in the Mineralocorticoid Hypertensive Rat
Authors: Beswick Richard A. , Dorrance Anne M. , Leite Romulo , Webb R. Clinton
Published: September 2007

We previously reported increased aortic reactive oxygen species (ROS) production in mineralocorticoid (deoxycorticosterone acetate [DOCA]-salt) hypertensive rats. In the present study, we tested the hypothesis that NADH/NADPH oxidase is responsible for increased ROS production, namely superoxide (O
2
−
), in aorta from the DOCA-salt rat. Treatment of aortic rings from DOCA-salt rats with the NO synthase inhibitor
N
-nitro-
l
-arginine and the xanthine oxidase inhibitor allopurinol did not significantly change O
2
−
production. Furthermore, de-endothelialization of aorta from DOCA-salt rats did not affect O
2
−
production compared with that of sham-operated rats. Thus, xanthine oxidase and uncoupled endothelial NO synthase were not responsible for increased O
2
−
production in the DOCA-salt rats. In contrast, treatment with the NADPH oxidase inhibitor apocynin significantly decreased O
2
−
production in aortic rings from DOCA-salt rats compared with sham-operated rats. Moreover, long-term administration of apocynin (in drinking water, 1.5 mmol/L, 28 days) to DOCA-salt rats significantly decreased systolic blood pressure compared with that of rats treated with DOCA-salt alone. Furthermore, O
2
−
production in aortic rings from DOCA-salt rats treated with apocynin for 28 days was reduced compared with that of untreated DOCA-salt rats. Reverse transcriptase–polymerase chain reaction (RT-PCR) analysis demonstrated that DOCA-salt rats have significantly greater mRNA levels of the NADPH oxidase subunit p22phox than do sham-operated rats. These findings suggest that NADPH oxidase is increased and is responsible for increased O
2
−
production and possibly contributes to increased blood pressure in the DOCA-salt hypertensive rat.
One-Year Study of Felodipine or Placebo for Stage 1 Isolated Systolic Hypertension
Authors: Black Henry R. , Elliott William J. , Weber Michael A. , Frishman William H. , Strom Joel A. , Liebson Philip R. , Hwang Clara T. , Ruff Dennis A. , Montoro Rafael , DeQuattro Vincent , Zhang Danyi , Schleman Margo M. , Klibaner Michael I.
Published: September 2007

A substantial number of older hypertensive patients have stage 1 isolated systolic hypertension (systolic blood pressure between 140 and 159 mm Hg and diastolic blood pressure <90 mm Hg), but there are currently no data showing that drug treatment is effective, safe, and/or beneficial. To compare the effects of active treatment compared with placebo on blood pressure, left ventricular hypertrophy, and quality of life among older stage 1 isolated systolic hypertensive patients, a randomized, double-blind, parallel-group, multicenter clinical trial comparing felodipine (2.5, 5, or 10 mg once daily) and matching placebo was performed in 171 patients (49% male, average age 66±7 years, with 49% white and 30% Hispanic) with a baseline blood pressure of 149±7/83±6 mm Hg. During 52 weeks of treatment, patients randomized to active treatment achieved significantly lower blood pressures (137.0±11.7/80.2±7.6 mm Hg for extended-release felodipine versus 147.5±16.0/83.5±9.7 mm Hg for placebo,
P
<0.01 for each), a reduced incidence of left ventricular hypertrophy (7% for extended release felodipine versus 24% for placebo,
P
<0.04), and improved quality of life (change in Psychological General Well-Being index, 3.0±6.8 for extended-release felodipine versus −0.8±10.3 for placebo,
P
<0.01) versus baseline. There were no clinically significant differences between treatments in tolerability or adverse effects. Stage 1 isolated systolic hypertension can be effectively and safely treated pharmacologically. Treatment reduced progression to the higher stages of hypertension, reduced the incidence of left ventricular hypertrophy, and improved an overall measure of the quality of life. Larger and longer studies will be needed to document any long-term reduction in cardiovascular event rates associated with treating stage 1 systolic hypertension.
Endothelium-Derived Nitric Oxide Regulates Arterial Elasticity in Human Arteries In Vivo
Authors: Kinlay Scott , Creager Mark A. , Fukumoto Mariko , Hikita Hiroyuki , Fang James C. , Selwyn Andrew P. , Ganz Peter
Published: September 2007

Arterial elasticity is determined by structural characteristics of the artery wall and by vascular smooth muscle tone. The identity of endogenous vasoactive substances that regulate elasticity has not been defined in humans. We hypothesized that NO, a vasodilator released constitutively by the endothelium, augments arterial elasticity. Seven healthy young men were studied. A 20-MHz intravascular ultrasound catheter was introduced through an arterial sheath to measure brachial artery cross-sectional area, wall thickness, and intra-arterial pressure. After control was established, indices of elasticity (pressure-area relationship, instantaneous compliance, and stress-strain, pressure–incremental elastic modulus (E
inc
), and pressure–pulse wave velocity relationships) were examined over 0 to 100 mm Hg transmural pressure obtained by inflation of an external cuff. Thereafter, the basal production of endothelium-derived NO was inhibited by
N
G
-monomethyl-
l
-arginine (L-NMMA) (4 and 8 mg/min). Finally, nitroglycerin (2.5 and 12.5 μg/min), an exogenous donor of NO, was given to relax the vascular smooth muscle. Elasticity was measured under all of these conditions. L-NMMA (8 mg/min) decreased brachial artery area (
P
=0.016) and compliance (
P
<0.0001) and increased E
inc
(
P
<0.01) and pulse wave velocity (
P
<0.0001). Nitroglycerin (12.5 μg/min) increased brachial artery area (
P
<0.001) and compliance (
P
<0.001) and decreased pulse wave velocity (
P
=0.02). NO, an endothelium-derived vasodilator, augments arterial elasticity in the human brachial artery. Loss of constitutively released NO associated with cardiovascular risk factors may adversely affect arterial elasticity in humans.
Carotid and Femoral Artery Stiffness in Relation to Three Candidate Genes in a White Population
Authors: Balkestein Elisabeth J. , Staessen Jan A. , Wang Ji-Guang , van der Heijden-Spek Janneke J. , Van Bortel Luc M. , Barlassina Cristina , Bianchi Giuseppe , Brand Eva , Herrmann Stefan-Martin , Struijker-Boudier Harry A.
Published: September 2007

Different genetic polymorphisms influence cardiovascular disease. We recently discovered a relationship between the intima-media thickness of the muscular femoral artery, but not the elastic common carotid artery, and the combined ACE (
ACE, I/D
), α-adducin (
Gly460Trp
),and aldosterone synthase (
AS
,
C−344T
) gene polymorphisms. To investigate the relationship between these polymorphisms and functional properties of the carotid artery and femoral artery, a sample of 756 subjects enrolled in a population study were genotyped for the presence of the
ACE D,
α-adducin
460Trp
, and aldosterone synthase
−344T
alleles. Vessel wall properties were assessed using a vessel wall movement detector system in combination with applanation tonometry. Statistical analysis allowed for confounders and interaction among genes. Cross-sectional compliance of the common carotid artery was negatively associated with the
ACE D
allele.
ACE II
versus
ACE DD
homozygotes differed, expressed as a percentage of the population mean (7.0%; 95% confidence interval [CI], 1.6% to 12.4%;
P
=0.02). In multigene analysis,
ACE DD
subjects also deviated significantly from the population mean for the distensibility coefficient of the common carotid artery when carrying the
AS/T
allele (−5.5%; 95% CI, −9.3% to −1.7%;
P
<0.01), without a change in cross-sectional compliance.
ACE DD
subjects, when homozygote for α-adducin
Gly460
, had a lower femoral cross-sectional compliance (−10.4%; 95% CI, −1.9% to −18.9%;
P
<0.03) and a lower distensibility (−9.7%; 95% CI, −2.1% to −17.3%;
P
<0.02) compared with the population mean. These data show that functional large artery properties are influenced by the
ACE I/D
polymorphism. Cross-sectional compliance and distensibility coefficients are influenced by the
ACE I/D
genotype, but this influence depends on the vascular territory and genetic background.
Decreased Nitric Oxide Availability in Normotensive and Hypertensive Rats With Failing Hearts After Myocardial Infarction
Authors: Wiemer Gabriele , Itter Gabi , Malinski Tadeusz , Linz Wolfgang
Published: September 2007

Abstract
—6

Endothelial NO synthase, being deficient in arginine and/or tetrahydrobiopterin, produces in addition to NO a significant concentration of superoxide (O
2
−
). We investigated whether such an imbalance between O
2
−
and NO production is present in dysfunctional aortas of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) with failing hearts after myocardial infarction. Heart failure was induced by permanent occlusion of the left coronary artery, resulting in a large infarction of the free left ventricular wall. Eight weeks after myocardial infarction, when WKY and SHR had compensated heart failure and congestive heart failure, respectively, calcium ionophore-induced NO release (assessed by a NO-sensitive microsensor) from aortic endothelial cells was significantly reduced from 478±48 to 216±16 nmol/L and 693±131 to 257±53 nmol/L in WKY and SHR, respectively. Concomitantly, significant increases in calcium ionophore-stimulated O
2
−
production (assessed by an electrochemical sensor) could be observed in aortic endothelial cells from infarcted WKY rats (22±3.2 versus sham, 10.1±1.2 nmol/L) and SHR (102±8 versus sham, 67±5 nmol/L). A dramatic increase in endothelial peroxynitrite concentration (chemiluminescence method) from 35±4 to 90±3 nmol/L for WKY and from 60±5 to 170±10 nmol/L for SHR also was detected. Thus, the markedly decreased NO availability probably caused by impaired endothelial NO synthase activity with enhanced O
2
−
and peroxynitrite production appears to be attributable to endothelial dysfunction in normotensive rats with chronic heart failure and especially in hypertensive rats with severe congestive heart failure.
Sodium Intake, Large Artery Stiffness, and Proteoglycans in the Spontaneously Hypertensive Rat
Authors: Et-taouil Karima , Schiavi Pierre , Lévy Bernard I. , Plante Gérard E.
Published: September 2007

Although the role of sodium in hypertension has been documented extensively, its effect on large arteries has not been well documented. We examined the effect of high-sodium (8%) diet and the diuretic indapamide (IND) on systemic hemodynamics and aortic wall structure and composition in collagen, elastin, and hyaluronan. Four groups of spontaneously hypertensive rats (SHR) were studied after 8 weeks: those on a normal diet (SHR), a high-sodium diet (SHR+NaCl), a normal diet with IND (SHR+IND), and a high-sodium diet with IND (SHR+NaCl+IND). Mean BP, which was not normalized with IND, was comparable for all groups. Systemic arterial compliance averaged 3.8, 2.5, 4.9, and 3.3 mL/mm Hg · 10
−3
, respectively, for the SHR, SHR+NaCl, SHR+IND, and SHR+NaCl+IND groups (
P
<0.003 and <0.05 for NaCl and IND effects). Wall thickness increased only in the SHR+NaCl group (
P
<0.01). Aortic wall COL decreased from 16 116 in the SHR to 12 382 μm
2
/mm in the SHR+NaCl+IND (
P
<0.005) group. IND alone had no effect on elastin, but the elastin/collagen ratio was increased significantly. Aortic hyaluronan averaged 2343, 266, 3243, and 1052 μm
2
/mm, respectively, for the SHR, SHR+NaCl, SHR+IND, and SHR+NaCl+IND groups (
P
<0.0001 for NaCl and IND effects). Changes in systemic arterial compliance were significantly and positively correlated with aortic hyaluronan contents. Thus, high-sodium diet affects the structural and functional characteristics of large arteries independently of BP. A high-sodium diet, in addition to a diuretic regimen with IND, affects simultaneously aortic hyaluronan contents and large artery mechanical properties through pressure-independent mechanisms that remain to be defined.
Limited Effect of Systemic β-Blockade on Sympathetic Outflow
Authors: Tank Jens , Diedrich André , Schroeder Christoph , Stoffels Mandy , Franke Gabi , Sharma Arya M. , Luft Friedrich C. , Jordan Jens
Published: September 2007

Central β-adrenoreceptors may augment sympathetic outflow. We tested the hypothesis that β-blockade attenuates central sympathetic outflow by inhibiting central adrenoreceptors. We studied 18 healthy controls (4 female, 14 male; age, 26±6 years, body mass index, 23±3 kg/m
2
). ECG, brachial, and finger arterial blood pressure, muscle sympathetic nerve activity, and respiration were measured continuously before and during complete β-blockade. Subjects received a total intravenous dose of 0.21 mg/kg of propranolol in 15 minutes. Spontaneous baroreflex slopes were calculated using the sequence technique (BRSup, BRSdown). The sympathetic baroreflex slope was determined at baseline using phenylephrine and sodium nitroprusside infusions. The subjects underwent cold pressor testing before and during β-blockade. The R-R interval increased from 861±119 ms at baseline to 952±141 ms during β-blockade (
P
<0.01). Blood pressure was 117±9/65±8 mm Hg at baseline and 117±10/67±8 mm Hg during β-Blockade (
P
=NS). β-Blockade did not affect baroreflex sensitivity (BRSup: 21±10 versus 28±11 ms/mmHg,
P
<0.1; BRSdown: 17±8 versus 20±8 ms/mmHg,
P
=NS). Muscle sympathetic nerve activity increased significantly during β-blockade (number of bursts/100 beats: 32±9 versus 40±14,
P
<0.05), compared with baseline. However, the operating points of the parasympathetic and sympathetic baroreflex during β-blockade were on the baroreflex curves obtained at baseline. β-Blockade blunted the heart rate response to cold pressor testing; blood pressure and muscle sympathetic nerve activity responses were similar. Our study demonstrates that propranolol does not cause an acute decrease in sympathetic activity in normotensive young subjects. This, observation is not consistent with an important tonic stimulatory effect of β-adrenoreceptors in the brain.
Structural Adaptation of Vascular Networks
Authors: Pries Axel R. , Reglin Bettina , Secomb Timothy W.
Published: September 2007

Structural reductions in vessel luminal diameters in response to elevated pressure may play a role in the elevation of peripheral resistance generally observed in hypertension. In the present study, a theoretical model is used to simulate the effect of increased driving pressure on flow resistance in microvascular networks. The angioarchitecture (lengths and diameters of all segments, topology) of microvascular networks (n=6) in the rat mesentery was recorded by intravital microscopy. The model simulation of vascular adaptation in response to local wall shear stress, transmural pressure, and tissue P
o
2
was used to predict changes in network pressure drop and flow resistance for a given change of driving pressure (ΔP). For ΔP increasing from 15% to 190% of the normotensive value, a 3.3-fold increase in flow resistance was observed (structural autoregulation). If vascular reactivity to pressure was suppressed, the resistance increase was abolished. Suppressing pressure sensitivity also led to a rise in mean capillary pressure at normal driving pressure from 23.8±7.3 mm Hg to 34±6.9 mm Hg. These results indicate that low capillary pressure levels as well as structural autoregulation depend on vascular responses to circumferential wall stress (corresponding to pressure). This tendency of peripheral vascular beds to increase flow resistance for a given increase of bulk flow or driving pressure may amplify and stabilize blood pressure elevation in the development of hypertension.
Spontaneously Hypertensive Rats Are Highly Vulnerable to AMPA-Induced Brain Lesions
Authors: Lecrux Clotilde , Nicole Olivier , Chazalviel Laurent , Catone Christelle , Chuquet Julien , MacKenzie Eric T. , Touzani Omar
Published: September 2007

Background and Purpose—

Whereas the effects of chronic arterial hypertension on the cerebral vasculature have been widely studied, its effects on brain tissue have been studied less so. Here we examined if spontaneously hypertensive rats (SHRs) or the normotensive control Wistar Kyoto rats (WKYs) made hypertensive by renal artery stenosis (R-WKYs) are vulnerable to an excitotoxic brain lesion provoked by an overactivation of glutamate receptors.

Methods—

Lesion volumes were quantified by histology in WKYs and SHRs subjected to striatal administration of
N
-methyl-
d
-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). The expression of AMPA receptors subunits and calcium/calmodulin kinase-IIα was analyzed by real-time polymerase chain reaction and Western blot.

Results—

NMDA (50 and 75 nmol) induced similar lesions in both SHRs (10±2 mm
3
and 16±4 mm
3
, respectively) and WKYs (11±2 mm
3
and 19±7 mm
3
, respectively). However, AMPA-induced (2.5 and 5 nmol) lesions were significantly greater in 14-week-old SHRs (14±3 mm
3
and 20±5 mm
3
, respectively) than WKYs (4±2 mm
3
,
P
<0.05 and 7±4 mm
3
,
P
<0.001, respectively). Furthermore, normotensive 7-week-old SHRs also displayed an aggravated AMPA-induced lesion compared with age-matched WKYs (10±3 mm
3
vs 6±3 mm
3
;
P
<0.05). Neither NMDA nor AMPA produced increased lesion volumes in R-WKYs (12±3 mm
3
and 5±4 mm
3
, respectively) compared with WKYs. Striatal levels of AMPA receptors subunits, GluR1 and GluR2, were not different between SHRs and WKYs. However, SHRs displayed an increase in phosphorylated form of GluR1 at Ser-831 (
P
<0.05), as well as in calcium/calmodulin kinase-IIα (
P
<0.002). Selective inhibition of this kinase by KN-93 reduced AMPA-induced damage in SHRs (
P
<0.01 vs vehicle).

Conclusions—

These findings show that an increase in phosphorylated GluR1, which increases AMPA receptor conductance, may be involved in the vulnerability of SHRs to AMPA.
Color Bind: Lessons from the Failed Homeland Security Advisory System
Authors: Shapiro Jacob N. , Cohen Dara Kay
Published: September 2007

An effective terrorism alert system in a federal government has one central task: to motivate actors to take costly protective measures. The United States' color-coded Homeland Security Advisory System (HSAS) failed in this mission. In federal systems, national leaders cannot compel protective actions by setting an alert level; they must convince constituent governments and private parties that the desired actions are worth the costs. Such beliefs can be generated either by sharing the information behind an alert or by developing enough confidence in the alert system that the government's word alone suffices. The HSAS did neither, largely because it was not designed to generate confidence. Rather, the system's creators assumed that the public would trust the national leadership and believe in the utility of the system's information. Over time, as the HSAS became increasingly perceived as politically manipulated, there was no built-in mechanism to recover confidence in the system. An alternative, trust-based terrorist alert system could solve this problem. Building on the notion of “procedural fairness” from the psychological and legal traditions, this system would retain the political advantages of the HSAS, facilitate greater compliance among the requisite actors, and ameliorate many of the strategic problems inherent in terror alert systems.
Muting the Alarm over the Israeli-Palestinian Conflict: The New York Times versus Haaretz, 2000–06
Authors: Slater Jerome
Published: September 2007

The prospects for a two-state solution to the Israeli-Palestinian conflict remain poor, largely because of Israeli rigidity as well as Palestinian policies and internal conflicts. The United States has failed to use its considerable influence with Israel to seek the necessary changes in Israeli policies, instead providing the country with almost unconditional support. The consequences have been disastrous for the Palestinians, for Israeli security and society, and for critical U.S. national interests in the Middle East. Amajor explanation for the failure of U.S. policies is the largely uninformed and uncritical mainstream and even elite media coverage of the Israeli-Palestinian conflict in the United States. In contrast, the debate in Israel is more self-critical, vigorous, and far-ranging, creating at least the possibility of change, even as U.S. policy stagnates. Acomparison of the coverage of the Israeli-Palestinian conflict by the two most prestigious daily newspapers in the United States and Israel—in particular, over the breakdown of the peace process in 2000 and the ensuing Palestinian intifada, the nature of the Israeli occupation, the problem of violence and terrorism, and the prospects for peace today—underscores these differences. While the New York Times has muted the alarm over the dangers of the United States' near-unconditional support for Israeli policies toward the Palestinians, Haaretz has sought to sound the alarm.
Changes in TRMM Rainfall due to the Orbit Boost Estimated from Buoy Rain Gauge Data
Authors: DeMoss Jeremy D. , Bowman Kenneth P.
Published: September 2007

During the first three-and-a-half years of the Tropical Rainfall Measuring Mission (TRMM), the TRMM satellite operated at a nominal altitude of 350 km. To reduce drag, save maneuvering fuel, and prolong the mission lifetime, the orbit was boosted to 403 km in August 2001. The change in orbit altitude produced small changes in a wide range of observing parameters, including field-of-view size and viewing angles. Due to natural variability in rainfall and sampling error, it is not possible to evaluate possible changes in rainfall estimates from the satellite data alone. Changes in TRMM Microwave Imager (TMI) and the precipitation radar (PR) precipitation observations due to the orbit boost are estimated by comparing them with surface rain gauges on ocean buoys operated by the NOAA/Pacific Marine Environment Laboratory (PMEL). For each rain gauge, the bias between the satellite and the gauge for pre- and postboost time periods is computed. For the TMI, the satellite is biased ∼12% low relative to the gauges during the preboost period and ∼1% low during the postboost period. The mean change in bias relative to the gauges is approximately 0.4 mm day−1. The change in TMI bias is rain-rate-dependent, with larger changes in areas with higher mean precipitation rates. The PR is biased significantly low relative to the gauges during both boost periods, but the change in bias from the pre- to postboost period is not statistically significant.
Pharmacokinetics and Pharmacodynamics of Drospirenone‐Estradiol Combination Hormone Therapy Product Coadministered With Hydrochlorothiazide in Hypertensive Postmenopausal Women
Authors: Karara Adel H. , Hanes Vladimir , Alonso Alberto , Ni Pingping , Poola Nagaraju , Silang Rose , Blode Hartmut , Preston Richard A.
Published: September 2007

The effects of combination hormone therapy of drospirenone (DRSP), a novel progestin with antialdosterone properties, and 17β‐estradiol (E2) on hydrochlorothiazide (HCTZ) pharmacokinetics/pharmacodynamics versus placebo were investigated in a double‐blind, placebo‐controlled, crossover study. Thirty‐six postmenopausal women with stage 1 hypertension maintained on 25 mg of HCTZ once daily were randomized to receive either 3 mg of DRSP/1 mg of E2 or placebo once daily for 4 weeks. Plasma HCTZ, serum DRSP, E2, potassium, aldosterone, and plasma renin activity were determined at baseline and after 4 weeks. Results showed that the combination of DRSP/E2 plus 25 mg of HCTZ is safe and well tolerated in hypertensive postmenopausal women. The pharmacokinetics of HCTZ were not affected by coadministration of DRSP/E2. The geometric mean ratios and 90% confidence intervals ([HCTZ + DRSP/E2]/[HCTZ + placebo]) for HCTZ (a) area under the serum/plasma concentration‐time curve from 0 to 24 hours and (b) maximum plasma concentration were 101 (90.7, 112) and 103 (92.8, 115), respectively. In the HCTZ + DRSP/E2 group, serum potassium, aldosterone, and plasma renin activity all increased in a manner marginally consistent with a beneficial antialdosterone effect, counteracting the HCTZ‐induced potassium loss and lowering both systolic and diastolic blood pressure. No dose adjustment is required when DRSP/E2 is added to antihypertensive therapy with HCTZ in hypertensive postmenopausal women.
The Transaction Cost Theory of the Nonprofit Firm: Beyond Opportunism
Authors: Valentinov Vladislav
Published: September 2007

Building on the transaction cost theory of the for-profit firm, the article argues that the transaction cost-economizing role of the nonprofit firm has two distinct dimensions. One of them consists of reducing the cost of searching for, processing, and communicating information and the other minimizes opportunistic behavior by means of aligning incentives of concerned stakeholders. So far, the transaction cost theory of the nonprofit firm has been emphasizing the second dimension while largely ignoring the first one. The article fills this gap by demonstrating that nonprofit firms are able to economize on transaction cost not only by minimizing opportunism but also by facilitating cooperation among those stakeholders who derive utility from contributing to the realization of their nonprofit firm's missions and hence would not be interested in opportunistic behavior. The article concludes by emphasizing the complementarity of the two dimensions of the nonprofit firm's transaction cost-economizing role.
Nonprofit Management Alumni Knowledge, Skills, and Career Satisfaction in Relation to Nonprofit Academic Centers Council Curricular Guidelines: The Case of One University's Master's of Public Administration Alumni
Authors: Herman Robert D. , Renz David O.
Published: September 2007

Drawing on a survey of 88 alumni of a master of public administration program with a long-standing emphasis in nonprofit management, this article addresses three questions: (a) Are alumni who are more satisfied with their careers more satisfied with course work? (yes, substantially); (b) is reported learning in nonprofit management course work related to satisfaction with career and with graduate program? (yes, to some degree); and (c) is alumni satisfaction with careers and graduate program more strongly related to extent of learning in some areas rather than others? (yes). Implications for curricular content of nonprofit management programs are considered, particularly the sort of enterprise nonprofit management education is (and the sort it should be). We conclude by suggesting that nonprofit management education distinctiveness is based on its moral imperative and urge some consideration of such in curricular design.
Ovine Enzootic Abortion (OEA): a comparison of antibody responses in vaccinated and naturally-infected swiss sheep over a two year period
Authors: Gerber Andrea , Thoma Ruedi , Vretou Evangelia , Psarrou Evgenia , Kaiser Carmen , Doherr Marcus G , Zimmermann Dieter R , Polkinghorne Adam , Pospischil Andreas , Borel Nicole
Published: September 2007

Background

Prevention and control of ovine enzootic abortion (OEA) can be achieved by application of a live vaccine. In this study, five sheep flocks with different vaccination and infection status were serologically tested using a competitive enzyme-linked immunosorbent assay (cELISA) specific forChlamydophila (Cp.) abortusover a two-year time period.

Results

Sheep in Flock A with recent OEA history had high antibody values after vaccination similar to Flock C with naturalCp. abortusinfections. In contrast, OEA serology negative sheep (Flock E) showed individual animal-specific immunoreactions after vaccination. Antibody levels of vaccinated ewes in Flock B ranged from negative to positive two and three years after vaccination, respectively. Positive antibody values in the negative control Flock D (without OEA or vaccination) are probably due to asymptomatic intestinal infections withCp. abortus. Excretion of the attenuated strain ofCp. abortusused in the live vaccine through the eye was not observed in vaccinated animals of Flock E.

Conclusion

The findings of our study indicate that, using serology, no distinction can be made between vaccinated and naturally infected sheep. As a result, confirmation of a negative OEA status in vaccinated animals by serology cannot be determined.
Immunohistological assessment of the synovial tissue in small joints in rheumatoid arthritis: validation of a minimally invasive ultrasound-guided synovial biopsy procedure
Authors: Scirè Carlo Alberto , Epis Oscar , Codullo Veronica , Humby Frances , Morbini Patrizia , Manzo Antonio , Caporali Roberto , Pitzalis Costantino , Montecucco Carlomaurizio
Published: September 2007

The aim of the present study was to perform an immunohistological assessment of the synovial tissue from involved small joints in rheumatoid arthritis (RA) and to explore the reliability of a mini-invasive ultrasound (US)-guided technique of small joint synovial biopsy for the histopathological assessment. Synovial tissue collected during arthrotomic surgery of small joints in nine patients served as the gold standard for the validation of the histological assessment. Small hand-joint synovial biopsies from an additional nine patients with erosive RA were obtained by a mini-invasive US-guided procedure, performed percutaneously by the portal and rigid forceps technique. Using digital image analysis, the area fractions of synovial macrophages (CD68 cells), T cells (CD3 cells) and B cells (CD20 cells) were measured in all high-power fields of every sample at different cutting levels. The representative sample was defined as the minimal number of high-power fields whose mean area fraction would reflect the overall mean area fraction within a percentage mean difference of 10%. For each patient, a range of three to five large samples for surgical biopsies and a range of 8–12 samples for US-guided biopsies were collected and analysed. In arthrotomic samples, the analysis of a randomly selected tissue area of 2.5 mm2 was representative of the overall value for CD68, CD3 and CD20 cells. US-guided samples allowed histological evaluation in 100% of cases, with a mean valid area of 18.56 mm2 (range 7.29–38.28 mm2). The analysis of a cumulative area of 2.5 mm2 from eight randomly selected sections (from different samples or from different cutting levels) allowed to reduce the percentage mean difference to less than 10% for CD68, CD3 and CD20 cells. In conclusion, US-guided synovial biopsy represents a reliable tool for the assessment of the histopathological features of RA patients with a mini-invasive approach.
A case study of the reproducibility of transcriptional reporter cell-based RNAi screens in Drosophila
Authors: DasGupta Ramanuj , Nybakken Kent , Booker Matthew , Mathey-Prevot Bernard , Gonsalves Foster , Changkakoty Binita , Perrimon Norbert
Published: September 2007

Off-target effects have been demonstrated to be a major source of false-positives in RNA interference (RNAi) high-throughput screens. In this study, we re-assess the previously published transcriptional reporter-based whole-genome RNAi screens for the Wingless and Hedgehog signaling pathways using second generation double-stranded RNA libraries. Furthermore, we investigate other factors that may influence the outcome of such screens, including cell-type specificity, robustness of reporters, and assay normalization, which determine the efficacy of RNAi-knockdown of target genes.
Clozapine: national review of postcode prescribing
Authors: Downs Johnny , Zinkler Martin
Published: September 2007

Aims and Method

We review the prescribing rates for clozapine among all mental health trusts in England and explore whether it has changed with the introduction of NICE guidelines, generic clozapine and the Healthcare Commission ratings. Data were collected from mental health trusts in 2005–2006 and compared with a previous study from 2000. Mental health star ratings of 2004–2005 were taken from the Healthcare Commission.

Results

We found a reduced inter-trust variability from 34-fold variation in 2000 to 5-fold variation in 2005–2006. There was a significant inverse relationship between star rating and clozapine prescribing.

Clinical Implications

NICE guidelines and generic clozapine seem to have improved access to gold standard therapy for treatment-resistant schizophrenia. Star ratings have little bearing on the implementation of NICE guidelines.
Long-Term Health Status Among Survivors of Childhood Cancer: Does Sex Matter?
Authors: Armstrong Gregory T. , Sklar Charles A. , Hudson Melissa M. , Robison Leslie L.
Published: September 2007

Increasing numbers of children diagnosed with cancer will survive their primary malignancy. Within this growing population of long-term survivors, considerable effort has been put forth to identify treatment-related risks for adverse health-related outcomes, such as exposure to alkylating agents, anthracyclines, radiotherapy, and surgery. Patient sex has been identified as a risk factor for numerous long-term adverse outcomes, with female sex more commonly associated with higher risks. In this article, we review the literature, which generally supports associations between female sex and cognitive dysfunction after cranial irradiation, cardiovascular outcomes, obesity, radiation-associated differences in pubertal timing, development of primary hypothyroidism, breast cancer as a second malignant neoplasm and suggests an increased prevalence for the development of osteonecrosis among females. Results of this review support future investigations to further define sex as a risk factor for other common treatment-specific exposures and outcomes. Additionally, research should focus on understanding the underlying biologic and physiological basis of these sex-specific risks. Historically, evidence from both basic science and clinical research has been used to develop risk-stratified therapy, allowing reduction of toxic therapies to low-risk patients without compromising overall survival. With greater knowledge of sex-specific risks, the potential application of sex-specific therapy designed to avoid poor long-term adverse outcomes may become a viable strategy.
Chronic Estradiol Treatment Improves Brain Homeostasis during Aging in Female Rats
Authors: Alonso Ana , Moreno María , Ordóñez Patricia , Fernández Rebeca , Pérez Cristina , Díaz Fernando , Navarro Ana , Tolivia Jorge , González Celestino
Published: September 2007

Aging is associated with a reduction in metabolic function, insulin resistance, increased incidence of neurodegenerative diseases, and memory or cognitive dysfunction. In aging females, loss of gonadal function determines the beginning of the period of reduced metabolic function. Estrogens have neuroprotective effects, but the mechanisms by which they exert these effects remain unclear. The effects of estradiol treatment on the activation of the insulin receptor substrate (IRS)-1 signaling pathway, the interactions between estrogen receptor (ER)-α and IRS-1 and the p85α subunit of phosphatidylinositol-3 kinase, together with the possible effects of estradiol treatment on glucose transporter-3 and -4 levels, were investigated in female rats. The level of expression of each glucose transporter was greater in control and estradiol-treated groups than in the ovariectomized group. Interactions of ERα46-IRS-1, ERα46-p85α, and p85α-IRS-1, as well as IRS-1 phosphorylation, appeared to increase with estradiol treatment. The results indicate that estradiol treatment improves some aspects of neuronal homeostasis that are affected by aging; this may indicate that estradiol has neuroprotective effects in female rats. Additional animal studies are required to clarify the neuroprotective role of estradiol in relation to other important molecules involved in the IRS-1-phosphatidylinositol-3 kinase signaling pathway.
Gonadotropin-Inhibitory Hormone Neurons Interact Directly with Gonadotropin-Releasing Hormone-I and -II Neurons in European Starling Brain
Authors: Ubuka Takayoshi , Kim Stephanie , Huang Yu-chi , Reid Jessica , Jiang Jennifer , Osugi Tomohiro , Chowdhury Vishwajit S. , Tsutsui Kazuyoshi , Bentley George E.
Published: September 2007

Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic dodecapeptide (SIKPSAYLPLRF-NH2) that directly inhibits gonadotropin synthesis and release from quail pituitary. The action of GnIH is mediated by a novel G-protein coupled receptor. This gonadotropin-inhibitory system may be widespread in vertebrates, at least birds and mammals. In these higher vertebrates, histological evidence suggests contact of GnIH immunoreactive axon terminals with GnRH neurons, thus indicating direct regulation of GnRH neuronal activity by GnIH. In this study we investigated the interaction of GnIH and GnRH-I and -II neurons in European starling (Sturnus vulgaris) brain. Cloned starling GnIH precursor cDNA encoded three peptides that possess characteristic LPXRF-amide (X = L or Q) motifs at the C termini. Starling GnIH was further identified as SIKPFANLPLRF-NH2 by mass spectrometry combined with immunoaffinity purification. GnIH neurons, identified by in situ hybridization and immunocytochemistry (ICC), were clustered in the hypothalamic paraventricular nucleus. GnIH immunoreactive fiber terminals were present in the external layer of the median eminence in addition to the preoptic area and midbrain, where GnRH-I and GnRH-II neuronal cell bodies exist, respectively. GnIH axon terminals on GnRH-I and -II neurons were shown by GnIH and GnRH double-label ICC. Furthermore, the expression of starling GnIH receptor mRNA was identified in both GnRH-I and GnRH-II neurons by in situ hybridization combined with GnRH ICC. The cellular localization of GnIH receptor has not previously been identified in any vertebrate brain. Thus, GnIH may regulate reproduction of vertebrates by directly modulating GnRH-I and GnRH-II neuronal activity, in addition to influencing the pituitary gland.