bluuebunny/crossref_metadata_2025 huggingface dataset:
High Prevalence of Cardiac Parvovirus B19 Infection in Patients With Isolated Left Ventricular Diastolic Dysfunction
Authors: Tschöpe C. , Bock C.-T. , Kasner M. , Noutsias M. , Westermann D. , Schwimmbeck P.-L. , Pauschinger M. , Poller W.-C. , Kühl U. , Kandolf R. , Schultheiss H.-P.
Published: February 2005

Background—

The etiology of left ventricular (LV) isolated diastolic dysfunction often remains unclear. In the present study, we report a strong association between parvovirus B19 (PVB19) genomes and isolated LV diastolic dysfunction.

Methods and Results—

In 70 patients (mean±SD age, 43±11 years) admitted with exertional dyspnea and/or reduced exercise tolerance despite preserved LV systolic contractility (ejection fraction=68%), isolated diastolic dysfunction was clinically suspected. Patients with classic risk factors for diastolic dysfunction such as hypertension, coronary heart disease, diabetes mellitus, or pulmonary disease had been excluded. Diastolic function was assessed by echocardiography and LV and RV catheterization. Endomyocardial biopsies (EMBs) were analyzed for the presence of storage or infiltrative diseases or myocarditis, including molecular screening for cardiotropic virus genomes. In a substudy of 24 patients who reported atypical angina, coronary endothelial function was additionally investigated with a coronary Doppler flow-wire technique. In 37 of 70 patients (53%), isolated diastolic dysfunction was confirmed as the cause of their clinical symptoms. No evidence for cardiac storage or infiltrative diseases was found in these cases, but in 35 of 37 of these patients (95%), cardiotropic virus genomes were detected in EMBs (
P
<0.001). PVB19 was the most frequent pathogen in 31 of 37 patients (84%). In a subgroup of 10 patients with diastolic dysfunction and coexisting endothelial dysfunction, all 10 (100%) were PVB19 positive.

Conclusions—

PVB19 genomes were predominant in patients with unexplained, isolated diastolic dysfunction. A strong association with the incidence of endothelial dysfunction was obvious, consistent with the hypothesis that PVB19-induced endothelial dysfunction may be a possible pathomechanism underlying diastolic dysfunction.
QTc Prolongation by Grapefruit Juice and Its Potential Pharmacological Basis
Authors: Zitron Edgar , Scholz Eberhard , Owen Robert W. , Lück Sonja , Kiesecker Claudia , Thomas Dierk , Kathöfer Sven , Niroomand Feraydoon , Kiehn Johann , Kreye Volker A.W. , Katus Hugo A. , Schoels Wolfgang , Karle Christoph A.
Published: February 2005

Background—

A high intake of dietary flavonoids, which are abundant in fruits, vegetables, tea, and wine, is known to reduce cardiovascular mortality. The effects of flavonoids on cardiac electrophysiology, which theoretically may have both antiarrhythmic and proarrhythmic consequences, have not been studied systematically to date.

Methods and Results—

We screened a broad spectrum of flavonoids for their inhibitory activity on HERG channels by using heterologous expression in
Xenopus
oocytes. At a concentration of 1 mmol/L, 10 compounds caused a significant inhibition of HERG currents, whereas 11 other flavonoids had no effect. The IC
50
value for HERG block by naringenin, the most potent inhibitor, was 102.3 μmol/L in
Xenopus
oocytes and 36.5 μmol/L in HEK cells. To demonstrate the physiological relevance of these findings, we studied the effects of pink grapefruit juice, which contains large amounts of naringenin glycosides (>1000 μmol/L), in human volunteers. In 10 persons, we observed a peak QTc prolongation of 12.5±4.2 ms 5 hours after oral ingestion of 1 L of grapefruit juice. This effect was significant (
P
=0.02).

Conclusions—

We found a significant QTc prolongation by grapefruit juice in healthy volunteers, probably caused by block of HERG channels by flavonoids. These findings reveal new perspectives on the potential for dietary modification of cardiac electrophysiology.
Resistin Is an Inflammatory Marker of Atherosclerosis in Humans
Authors: Reilly Muredach P. , Lehrke Michael , Wolfe Megan L. , Rohatgi Anand , Lazar Mitchell A. , Rader Daniel J.
Published: February 2005

Background—

Resistin, a plasma protein, induces insulin resistance in rodents. Recent reports suggest that circulating levels of resistin are elevated in obese and insulin-resistant rodents and humans. Whereas rodent resistin is made in adipocytes, macrophages are a major source of human resistin. Given the convergence of adipocyte and macrophage function, resistin may provide unique insight into links between obesity, inflammation, and atherosclerosis in humans.

Methods and Results—

We examined whether plasma resistin levels were associated with metabolic and inflammatory markers, as well as with coronary artery calcification (CAC), a quantitative index of atherosclerosis, in 879 asymptomatic subjects in the Study of Inherited Risk of Coronary Atherosclerosis. Resistin levels were positively associated with levels of inflammatory markers, including soluble tumor necrosis factor-α receptor-2 (
P
<0.001), interleukin-6 (
P
=0.04), and lipoprotein-associated phospholipase A
2
(
P
=0.002), but not measures of insulin resistance in multivariable analysis. Resistin levels also were associated (odds ratio and 95% confidence interval in ordinal regression) with increasing CAC after adjustment for age, sex, and established risk factors (OR, 1.23 [CI, 1.03 to 1.52],
P
=0.03) and further control for metabolic syndrome and plasma C-reactive protein (CRP) levels (OR, 1.25 [CI, 1.04 to 1.50],
P
=0.01). In subjects with metabolic syndrome, resistin levels further predicted CAC, whereas CRP levels did not.

Conclusions—

Plasma resistin levels are correlated with markers of inflammation and are predictive of coronary atherosclerosis in humans, independent of CRP. Resistin may represent a novel link between metabolic signals, inflammation, and atherosclerosis. Further studies are needed to define the relationship of resistin to clinical cardiovascular disease.
Hyperparathyroidism and the Calcium Paradox of Aldosteronism
Authors: Chhokar Vikram S. , Sun Yao , Bhattacharya Syamal K. , Ahokas Robert A. , Myers Linda K. , Xing Zhiqing , Smith Richard A. , Gerling Ivan C. , Weber Karl T.
Published: February 2005

Background—

Aldosteronism may account for oxi/nitrosative stress, a proinflammatory phenotype, and wasting in congestive heart failure. We hypothesized that aldosterone/1% NaCl treatment (ALDOST) in rats enhances Ca
2+
and Mg
2+
excretion and leads to systemic effects, including bone loss.

Methods and Results—

At 1, 2, 4, and 6 weeks of ALDOST, we monitored Ca
2+
and Mg
2+
excretion, ionized [Ca
2+
]
o
and [Mg
2+
]
o
, parathyroid hormone and α
1
-antiproteinase activity in plasma, bone mineral density, bone strength, Ca
2+
and Mg
2+
content in peripheral blood mononuclear cells (PBMCs) and ventricular tissue, and lymphocyte H
2
O
2
production. A separate group received spironolactone (Spiro), an aldosterone receptor antagonist. Age- and gender-matched unoperated and untreated rats served as controls. ALDOST induced a marked (
P
<0.05) and persistent rise in urinary and fecal Ca
2+
and Mg
2+
excretion, a progressive reduction (
P
<0.05) in [Ca
2+
]
o
and [Mg
2+
]
o
, and an elevation in parathyroid hormone (
P
<0.05) with a fall (
P
<0.05) in bone mineral density and strength. An early, sustained increase (
P
<0.05) in PBMC Ca
2+
and Mg
2+
was found, together with an increase (
P
<0.05) in tissue Ca
2+
. Plasma α
1
-antiproteinase activity was reduced (
P
<0.05), whereas lymphocyte H
2
O
2
production was increased (
P
<0.05) at all time points. Spiro cotreatment attenuated (
P
<0.05) urinary and fecal Ca
2+
and Mg
2+
excretion, prevented the fall in [Ca
2+
]
o
and [Mg
2+
]
o
, rescued bone mineral density and strength, and prevented Ca
2+
overloading of PBMCs and cardiomyocytes.

Conclusions—

In aldosteronism, Ca
2+
and Mg
2+
losses lead to a fall in [Ca
2+
]
o
and [Mg
2+
]
o
with secondary hyperparathyroidism and bone resorption. Ca
2+
overloading of PBMCs and cardiac tissue leads to oxi/nitrosative stress and a proinflammatory phenotype.
Frequency by Decades of Unicuspid, Bicuspid, and Tricuspid Aortic Valves in Adults Having Isolated Aortic Valve Replacement for Aortic Stenosis, With or Without Associated Aortic Regurgitation
Authors: Roberts William C. , Ko Jong M.
Published: February 2005

Background—

Aortic valve stenosis (with or without aortic regurgitation and without associated mitral stenosis) in adults in the Western world has been considered in recent years to most commonly be the result of degenerative or atherosclerotic disease.

Methods and Results—

We examined operatively excised, stenotic aortic valves from 932 patients aged 26 to 91 years (mean±SD, 70±12), and none had associated mitral valve replacement or evidence of mitral stenosis: A total of 504 (54%) had congenitally malformed valves (unicuspid in 46 [unicommissural in 42; acommissural in 4] and bicuspid in 458); 417 (45%) had tricuspid valves (either absent or minimal commissural fusion); and 11 (1%) had valves of undetermined type. It is likely that the latter 11 valves also had been congenitally malformed. Of the 584 men, 343 (59%) had either a unicuspid or a bicuspid valve; of the 348 women, 161 (46%) had either a unicuspid or a bicuspid aortic valve.

Conclusions—

The data from this large study of adults having isolated aortic valve replacement for aortic stenosis (with or without associated aortic regurgitation) and without associated mitral stenosis or mitral valve replacement strongly suggest that an underlying congenitally malformed valve, at least in men, is more common than a tricuspid aortic valve.
Rad GTPase Attenuates Vascular Lesion Formation by Inhibition of Vascular Smooth Muscle Cell Migration
Authors: Fu Mingui , Zhang Jifeng , Tseng Yu-Hua , Cui Taixing , Zhu Xiaojun , Xiao Yan , Mou Yongshan , De Leon Hector , Chang Mary M.J. , Hamamori Yasuo , Kahn C. Ronald , Chen Yuqing E.
Published: February 2005

Background—

Rad (Ras associated with diabetes) GTPase is a prototypic member of a new subfamily of Ras-related GTPases with unique structural features, although its physiological role remains largely unknown. In the present study, we characterized the Rad function in vascular smooth muscle cells (VSMCs) and the influence of adenovirus-mediated Rad (Ad-Rad) gene delivery on vascular remodeling after experimental angioplasty.

Methods and Results—

We documented for the first time that neointimal formation using balloon-injured rat carotid arteries was associated with a significant increase in Rad expression as determined by immunohistochemistry and quantitative real-time reverse-transcriptase polymerase chain reaction. The levels of Rad expression in VSMCs were highly induced by platelet-derived growth factor and tumor necrosis factor-α. Morphometric analyses 14 days after injury revealed significantly diminished neointimal formation in the Ad-Rad–treated carotid arteries compared with Ad-GFP or PBS controls, whereas the mutated form of Rad GTPase, which can bind GDP but not GTP, increased neointimal formation. Overexpression of Rad significantly inhibited the attachment and migration of VSMCs. In addition, Rad expression dramatically reduced the formation of focal contacts and stress fibers in VSMCs by blocking the Rho/ROK signaling pathway.

Conclusions—

Our data clearly identified Rad GTPase as a novel and critical mediator that inhibits vascular lesion formation. Manipulation of the Rad signaling pathway may provide new therapeutic approaches that will limit vascular pathological remodeling.
Acute Intramural Hematoma of the Aorta
Authors: Evangelista Arturo , Mukherjee Debabrata , Mehta Rajendra H. , O’Gara Patrick T. , Fattori Rossella , Cooper Jeanna V. , Smith Dean E. , Oh Jae K. , Hutchison Stuart , Sechtem Udo , Isselbacher Eric M. , Nienaber Christoph A. , Pape Linda A. , Eagle Kim A.
Published: February 2005

Background—

The definition, prevalence, outcomes, and appropriate treatment strategies for acute intramural hematoma (IMH) continue to be debated.

Methods and Results—

We studied 1010 patients with acute aortic syndromes who were enrolled in the International Registry of Aortic Dissection (IRAD) to delineate the prevalence, presentation, management, and outcomes of acute IMH by comparing these patients with those with classic aortic dissection (AD). Fifty-eight (5.7%) patients had IMH, and this cohort tended to be older (68.7 versus 61.7 years;
P
<0.001) and more likely to have distal aortic involvement (60.3% versus 35.3%;
P
<0.001) compared with 952 patients with AD. Patients with IMH described more severe initial pain than did those with AD but were less likely to have ischemic leg pain, pulse deficits, or aortic valve insufficiency; moreover, they required a longer time to diagnosis and more diagnostic tests. Overall mortality of IMH was similar to that of classic AD (20.7% versus 23.9%;
P
=0.57), as was mortality in patients with IMH of the descending aorta (8.3% versus 13.1%;
P
=0.60) and the ascending aorta (39.1% versus 29.9%;
P
=0.34) compared with AD. IMH limited to the aortic arch was seen in 7 patients, with no deaths, despite medical therapy in only 6 of the 7 individuals. Among the 51 patients whose initial diagnostic study showed IMH only, 8 (16%) progressed to AD on a serial imaging study.

Conclusions—

The IRAD data demonstrate a 5.7% prevalence of IMH in patients with acute aortic syndromes. Like classic AD, IMH is a highly lethal condition when it involves the ascending aorta and surgical therapy should be considered, but this condition is less critical when limited to the arch or descending aorta. Fully 16% of patients have evidence of evolution to dissection on serial imaging.
Tricuspid Valve Tethering Predicts Residual Tricuspid Regurgitation After Tricuspid Annuloplasty
Authors: Fukuda Shota , Song Jong-Min , Gillinov A. Marc , McCarthy Patrick M. , Daimon Masao , Kongsaerepong Vorachai , Thomas James D. , Shiota Takahiro
Published: February 2005

Background—

Tricuspid valve (TV) annuloplasty is recommended for functional tricuspid regurgitation (TR), which is caused by TV annulus dilatation and tethering of the leaflets. However, the impact of TV deformations on the outcome of TV annuloplasty remains unknown. The goal of this study was to investigate the relationship between preoperative TV deformation and residual TR after TV annuloplasty.

Methods and Results—

Two hundred sixteen patients with functional TR had 2D echocardiography before and after TV annuloplasty. Right ventricular fractional area change and left ventricular ejection fraction were determined with the apical views. Minimal TV annulus diameter was determined by frame-by-frame analysis. The distance of TV tethering was measured from the annulus plane to the coaptation point and tethering area by tracing the leaflets from the annulus plane. TR severity was determined by the ratio of the maximal jet area to the corresponding right atrial area. The severity of residual TR was associated with age, right and left ventricular dysfunction, tethering distance and area, and severity of preoperative TR (all
P
<0.05). TV annular dimension was not associated with outcome of TV annuloplasty. Multivariate analysis revealed that age, tethering distance, and severity of preoperative TR (all
P
<0.001) were independent parameters predicting residual TR. The sensitivity and specificity in predicting residual TR after surgery were 86% and 80% for tethering distances >0.76 cm and 82% and 84% for tethering areas >1.63 cm
2
, respectively.

Conclusions—

Severe TV tethering predicted residual TR after TV annuloplasty, whereas preoperative TV annular dimension was not associated with outcome of TV annuloplasty.
Platelet-Activating Factor Acetylhydrolase Activity Indicates Angiographic Coronary Artery Disease Independently of Systemic Inflammation and Other Risk Factors
Authors: Winkler Karl , Winkelmann Bernhard R. , Scharnagl Hubert , Hoffmann Michael M. , Grawitz Andrea Busse , Nauck Markus , Böhm Bernhard O. , März Winfried
Published: February 2005

Background—

Platelet-activating factor acetylhydrolase (PAF-AH), also denoted as lipoprotein-associated phospholipase A2, is a lipoprotein-bound enzyme that is possibly involved in inflammation and atherosclerosis. This study investigates the relationship of PAF-AH activity to angiographic coronary artery disease (CAD), the use of cardiovascular drugs, and other established risk factors.

Methods and Results—

PAF-AH activity, lipoproteins, sensitive C-reactive protein (sCRP), fibrinogen, serum amyloid A, and white blood cell count were determined in 2454 subjects with angiographically confirmed CAD and in 694 control subjects. PAF-AH activity was highly correlated with LDL cholesterol (
r
=0.517), apolipoprotein B (
r
=0.644), and non-HDL cholesterol (
r
=0.648) but not with sCRP or fibrinogen. PAF-AH activity was lower in women than in men and was affected by the intake of lipid-lowering drugs (−12%;
P
<0.001), aspirin (−6%;
P
<0.001), β-blockers (−6%;
P
<0.001), and digitalis (+7%;
P
<0.001). Unlike sCRP, fibrinogen, and serum amyloid A, PAF-AH activity was not elevated in unstable angina, non–ST-elevation myocardial infarction, or ST-elevation myocardial infarction. When nonusers of lipid-lowering drugs were examined, PAF-AH activity was associated with the severity of CAD and the number of coronary vessels with significant stenoses. In individuals not taking lipid-lowering drugs and after adjustment for use of aspirin, β-blocker, and digitalis, the odds ratio for CAD associated with increasing PAF-AH activity was 1.39 (95% CI 1.26 to 1.54,
P
<0.001), a finding that was robust against further adjustments.

Conclusions—

PAF-AH activity is not an indicator of the systemic inflammation that accompanies acute coronary syndromes. PAF-AH activity is affected by a number of cardiovascular drugs; however, after such medication use was accounted for, PAF-AH activity was associated with angiographic CAD, complementary to sCRP and independently of established risk factors such as LDL cholesterol.
Increased Nitration of Sarcoplasmic Reticulum Ca
2+
-ATPase in Human Heart Failure
Authors: Lokuta Andrew J. , Maertz Nathan A. , Meethal Sivan Vadakkadath , Potter Katherine T. , Kamp Timothy J. , Valdivia Héctor H. , Haworth Robert A.
Published: February 2005

Background—

Reduced sarcoplasmic reticulum (SR) Ca
2+
-ATPase (SERCA2a isoform) activity is a major determinant of reduced contractility in heart failure. Ca
2+
-ATPase inactivation can occur through SERCA2a nitration. We therefore investigated the role of SERCA2a nitration in heart failure.

Methods and Results—

We measured SERCA2a levels and nitrotyrosine levels in tissue from normal and failing human hearts using Western blots. We found that nitrotyrosine levels in idiopathic dilated cardiomyopathic (DCM) hearts were almost double those of control hearts in age-matched groups. Nitrotyrosine was dominantly present in a single protein with the molecular weight of SERCA2a, and immunoprecipitation confirmed that the protein recognized by the nitrotyrosine antibody was SERCA2a. There was a positive correlation between the time to half relaxation and the nitrotyrosine/SERCA2a content (
P
<0.01) in myocytes isolated from control and DCM hearts. In experiments with isolated SR vesicles from porcine hearts, we also showed that the Ca pump is inactivated by peroxynitrite exposure, and inactivation was prevented by protein kinase A pretreatment.

Conclusions—

We conclude that SERCA2a inactivation by nitration may contribute to Ca pump failure and hence heart failure in DCM.
Interleukin-6 Causes Myocardial Failure and Skeletal Muscle Atrophy in Rats
Authors: Janssen Sofie P.M. , Gayan-Ramirez Ghislaine , Van Den Bergh An , Herijgers Paul , Maes Karen , Verbeken Erik , Decramer Marc
Published: February 2005

Background—

The impact of interleukin (IL)-6 on skeletal muscle function remains the subject of controversy.

Methods and Results—

The effects of 7-day subcutaneous administration of recombinant human IL-6 were examined at 3 doses, 50, 100, or 250 μg · kg
−1
· d
−1
, in rats. Skeletal muscle mass decreased dose-dependently (with increasing dose: in the diaphragm, −10%,
P
=NS; −15%,
P
=0.0561; and −15%
P
<0.05; and in the gastrocnemius, −9%,
P
=NS; −9%,
P
=NS; and −18%,
P
<0.005) because of decreases in cross-sectional area of all fiber types without alterations in diaphragm contractile properties. Cardiovascular variables showed a dose-dependent heart dilatation (for end-diastolic volume: control, 78 μL; moderate dose, 123 μL; and high dose, 137 μL,
P
<0.001), reduced end-systolic pressure (control, 113 mm Hg; moderate dose, 87 mm Hg; and high dose, 90 mm Hg;
P
=0.037), and decreased myocardial contractility (for preload recruitable stroke work: control, 79 mm Hg; moderate dose, 67 mm Hg; and high dose, 48 mm Hg;
P
<0.001). Lung edema was confirmed by an increased wet-to-dry ratio (control, 4.2; moderate dose, 4.6; and high dose, 4.5;
P
<0.001) and microscopy findings. These cardiovascular alterations led to decreases in organ blood flow, particularly in the diaphragm (control, 0.56 mL · min
−1
· g
−1
; moderate dose, 0.21 mL · min
−1
· g
−1
; and high dose, 0.23 mL · min
−1
· g
−1
;
P
=0.037). In vitro recombinant human IL-6 administration did not cause any alterations in diaphragm force or endurance capacity.

Conclusions—

IL-6 clearly caused ventilatory and peripheral skeletal muscle atrophy, even after short-term administration. Blood flow redistribution, resulting from the myocardial failure induced by IL-6, was likely responsible for this muscle atrophy, because IL-6 did not exert any direct effect on the diaphragm.
Angiotensin II Type 2 Receptor–Mediated Gene Expression Profiling in Human Coronary Artery Endothelial Cells
Authors: Falcón Beverly L. , Veerasingham Shereeni J. , Sumners Colin , Raizada Mohan K.
Published: February 2005

Despite intensive investigation, the molecular mechanism by which the angiotensin II type 2 (AT
2
) receptor exerts its cellular and physiological actions remains elusive. In the present study, we have used microarray expression analysis to identify genes whose expression was regulated by this receptor and to determine its cellular consequences. Lentiviral vector was used to express the AT
2
receptor in human coronary artery endothelial cells (HCAECs), followed by analysis of expression profiles. We observed ≈5224 genes regulated in an AT
2
receptor ligand-independent manner in HCAECs expressing the AT
2
receptor. In addition, 1235 genes were differentially expressed in response to the AT
2
receptor-specific ligand, CGP42112A. Validity of the expression profiles was demonstrated by real-time reverse-transcriptase polymerase chain reaction quantitation of 5 genes. Because some of these genes could be linked to the regulation of extracellular matrix association, we studied the effect of the AT
2
receptor on cell migration. Expression of the AT
2
receptor resulted in a 2-fold inhibition of HCAEC migration. Taken together, these observations demonstrate that the AT
2
receptor regulates expression of genes relevant to cell migration, protein processing, intracellular signaling, and DNA repair in both ligand-dependent and ligand-independent manners.
Combined Genealogical, Mapping, and Expression Approaches to Identify Spontaneously Hypertensive Rat Hypertension Candidate Genes
Authors: Hinojos Cruz A. , Boerwinkle Eric , Fornage Myriam , Doris Peter A.
Published: February 2005

Allelic expression in genes has become recognized as a heritable trait by which phenotypes are generated. We have examined gene expression in the rat kidney using genome-wide microarray technology (Affymetrix). Gene expression was determined across 4 rat strains, 3 hypertensive spontaneously hypertensive rat (SHR) substrains (SHR-A3, SHR-B2, and SHR-C), and a normotensive strain (Wistar-Kyoto [WKY]). Expression measurements were made in multiple animals from all strains at 4 time points (4 weeks, 8 weeks, 12 weeks, and 18 weeks of age), covering the prehypertensive period in SHR (4 weeks), and the period of rapidly rising blood pressure (8 and 12 weeks) and of sustained hypertension (18 weeks). Regression analysis revealed a close relationship across all strains during the first 3 time points, after which SHR-A3 became a substantial outlier. SHR-B2 and SHR-C demonstrated a very close relationship in gene expression at all times but also showed increased differences compared with the other strains at 18 weeks of age. We identified genes that were consistently different in expression, comparing all SHR substrains at each time point with WKY. The resulting list of genes was compared with blood pressure quantitative trait loci reported for SHR to refine a number of genes consistently differentially expressed between SHR substrains and WKY, persistently differentially expressed across multiple time points, and located in SHR blood pressure–determinative regions of the genome. Genealogical relationships and SHR substrain intercrosses suggest that genes responsible for heritable hypertension in SHR are shared across SHR substrains. The present approach identifies a number of genes that may influence blood pressure in SHR by virtue of allelic effects on gene expression.
Putting the Brakes on Cardiac Hypertrophy
Authors: Booz George W.
Published: February 2005

We know a great deal about the receptors and signaling pathways in cardiomyocytes that contribute to hypertrophic growth. Although drugs that target them have proven effective in substantially reducing left ventricular hypertrophy and associated mortality, cardiovascular disease remains the leading cause of death in the West. Another approach may rest with exploiting naturally occurring regulators of maladaptive cardiac hypertrophy that have been identified in the past few years. These endogenous negative regulators can be grouped, for the most part, into those constitutively active but whose activity is decreased by hypertrophic stimulation, and those with little or no baseline activity that are activated by hypertrophic stimulation. Spanning both groups are 4 systems that converge on cyclic guanosine 3′, 5′-monophosphate (cGMP) generation, namely natriuretic peptides (ANP and BNP), kinins, nitric oxide (NO), and the angiotensin II type 2 receptor (AT
2
). Although holding promise as a means for restricting hypertrophy, each of these signaling molecules has certain limitations that need to be overcome. What follows is an overview of research over the past 2 years, much of it published in
Hypertension
, which has dealt with the antihypertrophic action of this particular group of endogenous signaling molecules. Understanding the function and regulation of the antihypertrophic NO–cGMP system offers the promise of novel therapeutic strategies for treating cardiac hypertrophy and heart failure.
Eplerenone Shows Renoprotective Effect by Reducing LOX-1–Mediated Adhesion Molecule, PKCε-MAPK-p90RSK, and Rho-Kinase Pathway
Authors: Kobayashi Naohiko , Hara Kazuyoshi , Tojo Akihiro , Onozato Maristela Lika , Honda Takeaki , Yoshida Kohtaro , Mita Shin-ichiro , Nakano Shigefumi , Tsubokou Yusuke , Matsuoka Hiroaki
Published: February 2005

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) may play an important role in atherosclerosis by inducing leukocyte adhesion molecules, such as intercellular and vascular cell adhesion molecule-1 (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]). We hypothesized that eplerenone, a novel selective aldosterone blocker, produces inhibition of LOX-1–mediated adhesion molecules, suppresses mitogen-activated protein (MAP) kinase and its downstream effector p90 ribosomal S6 kinase (p90RSK) through the protein kinase Cε (PKCε) pathway, and improves endothelial function by inhibition of Rho-kinase in the renal cortex of Dahl salt-sensitive hypertensive (DS) and salt-resistant (DR) rats. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of 6 weeks to the left ventricular hypertrophy stage (11 weeks) for 5 weeks. At 11 weeks, expression levels of LOX-1, ICAM-1, VCAM-1, and Rho-kinase were higher in DS rats than in DR rats and were decreased by eplerenone. Similarly, upregulated phosphorylation of PKCε, MAP kinase, and p90RSK in DS rats was also inhibited by eplerenone. In contrast, downregulated endothelial nitric oxide synthase mRNA was increased by eplerenone to a similar degree as after treatment with Y-27632, a selective Rho-kinase inhibitor. Eplerenone administration resulted in significant improvement in glomerulosclerosis (eplerenone 10 mg, −61%; 30 mg, −78%; and 100 mg, −84% versus DS;
P
<0.01, respectively) and urinary protein (10 mg, −78%; 30 mg, −87%; and 100 mg, −88% versus DS;
P
<0.01, respectively). These results suggest that the renoprotective effects of eplerenone may be partly caused by inhibition of LOX-1–mediated adhesion molecules and PKCε–MAP kinase–p90RSK pathway, and improvement in endothelial function.
Aortic Stiffness Is an Independent Predictor of Progression to Hypertension in Nonhypertensive Subjects
Authors: Dernellis John , Panaretou Maria
Published: February 2005

Aortic stiffness may predict progression to hypertension beyond classic risk factors. In a longitudinal study, we assessed the predictive value of aortic stiffness on future hypertension in nonhypertensive subjects with blood pressure (BP) <140/90. Aortic stiffness was determined by echocardiography at baseline in 2512 subjects. The follow-up time was 4 years. A stepwise increase in hypertension incidence occurred across the male and older participants: 3.8% of young female individuals, 11.5% of young male, 26.1% of old female, and 58.8% of old male subjects progressed to hypertension over 4 years. In multivariate analysis, aortic stain, distensibility, and stiffness index (β) remained significantly associated with the progression to future hypertension after adjustment to classic risk factors in men and women and in young and old populations. This study provides the first direct evidence to our knowledge in a longitudinal study that aortic stiffness is an independent predictor of progression to hypertension in nonhypertensive individuals.
Hyperadrenergic Postural Tachycardia Syndrome in Mast Cell Activation Disorders
Authors: Shibao Cyndya , Arzubiaga Carmen , Roberts L. Jackson , Raj Satish , Black Bonnie , Harris Paul , Biaggioni Italo
Published: February 2005

Postural tachycardia syndrome (POTS) is a disabling condition that commonly affects otherwise normal young females. Because these patients can present with a flushing disorder, we hypothesized that mast cell activation (MCA) can contribute to its pathogenesis. Here we describe POTS patients with MCA (MCA+POTS), diagnosed by episodes of flushing and abnormal increases in urine methylhistamine, and compared them to POTS patients with episodic flushing but normal urine methylhistamine and to normal healthy age-matched female controls. MCA+POTS patients were characterized by episodes of flushing, shortness of breath, headache, lightheadedness, excessive diuresis, and gastrointestinal symptoms such as diarrhea, nausea, and vomiting. Triggering events include long-term standing, exercise, premenstrual cycle, meals, and sexual intercourse. In addition, patients were disabled by orthostatic intolerance and a characteristic hyperadrenergic response to posture, with orthostatic tachycardia (from 79±4 to 114±6 bpm), increased systolic blood pressure on standing (from 117±5 to 126±7 mm Hg versus no change in POTS controls), increased systolic blood pressure at the end of phase II of the Valsalva maneuver (157±12 versus 117±9 in normal controls and 119±7 mm Hg in POTS;
P
=0.048), and an exaggerated phase IV blood pressure overshoot (50±10 versus 17±3 mm Hg in normal controls;
P
<0.05). In conclusion, MCA should be considered in patients with POTS presenting with flushing. These patients often present with a typical hyperadrenergic response, but β-blockers should be used with great caution, if at all, and treatment directed against mast cell mediators may be required.
The Stoic Theory of Implanted Preconceptions
Authors: Jackson-McCabe Matt
Published: February 2005

A number of late Stoic sources describe either ethical concepts or a supposed universal belief in gods as being innate in the human animal. Though Chrysippus himself is known to have spoken of "implanted preconceptions" (ε¨μϕυτοιπρολν´ψειζ) of good and bad, scholars have typically argued that the notion of innate concepts of any kind would have been entirely incompatible with his theory of knowledge. Both Epictetus' notion of innate concepts of good and bad and the references to an innate belief in gods by other philosophers of the Roman era are thus generally held to be later developments, probably owing to a Platonist-Stoic syncretism. Review of the evidence, however, shows that Chrysippus, like Epictetus, held ethical concepts to represent a special category of conception in that their formation was guaranteed by oikeiôsis. Unlike other concepts, that is, these represent a formal conceptualization of an innate tendency to distinguish between things fitting for one's constitution and things not fitting that all animals, according to the Stoics, bring to their empirical experiences. While the notion that human belief in gods is similarly innate does seem to have been a later development, it too was explained with reference to oikeiôsis rather than resulting from a simple "syncretism."
The Unity of Intellect in Aristotle's De Anima
Authors: Gerson Lloyd
Published: February 2005

The perennial problem in interpreting De Anima 3.5 has produced two drastic solutions, one ancient and one contemporary. According to the first, Aristotle in 3.5 identi fies the 'agent intellect' with the divine intellect. Thus, everything Aristotle has to say about the human intellect is contained mainly in 3.4, though Aristotle returns to its treatment in 3.6. In contrast to this ancient interpretation, a more recent view holds that the divine intellect is not the subject of 3.5 and that throughout the work Aristotle is analyzing the nature of the human intellect. But this view contends that the properties Aristotle deduces for this intellect, properties that have encouraged the view that Aristotle must be speaking about a divine intellect, are in fact to be discounted or interpreted in such a way that they do not indicate the immortality and immateriality of the human intellect. In this article I argue that close attention to the text and the sequence of argument supports the conclusion that Aristotle is speaking throughout De Anima of a uni fied human intellect, possessed of the properties Aristotle explicitly attributes to it. This intellect functions diff erently when it is and when it is not separate from the hylomorphic composite. I argue further that it is Aristotle's view that if we were not ideally or essentially intellects, we could not engage in the diverse cognitive activities of this composite.
What Kind of Hedonist was Epicurus?
Authors: Woolf Raphael
Published: February 2005

This paper addresses the question of whether or not Epicurus was a psychological hedonist. Did he, that is, hold that all human action, as a matter of fact, has pleasure as its goal? Or was he just an ethical hedonist, asserting merely that pleasure ought to be the goal of human action? I discuss a recent forceful attempt by John Cooper to answer the latter question in the affirmative, and argue that he fails to make his case. There is considerable evidence in favour of a psychological reading of Epicurean hedonism, evidence that includes some of the very texts that Cooper cites in support of the ethical reading.
Embryological Models in Ancient Philosophy
Authors: Henry Devin
Published: February 2005

Historically embryogenesis has been among the most philosophically intriguing phenomena. In this paper I focus on one aspect of biological development that was particularly perplexing to the ancients: self-organisation. For many ancients, the fact that an organism determines the important features of its own development required a special model for understanding how this was possible. This was especially true for Aristotle, Alexander, and Simplicius, who all looked to contemporary technology to supply that model. However, they did not all agree on what kind of device should be used. In this paper I explore the way these ancients made use of technology as a model for the developing embryo. I argue that their di ff erent choices of device reveal fundamental di ff erences in the way each thinker understood the nature of biological development itself. In the fi nal section of the paper I challenge the traditional view (dating back to Alexander's interpretation of Aristotle) that the use of automata in GA can simply be read o ff from their use in the de motu.
A Language of Their Own: An Interactionist Approach to Human-Horse Communication
Authors: Brandt Keri
Published: February 2005

This paper explores the process of human-horse communication using ethnographic data of in-depth interviews and participant observation. Guided by symbolic interactionism, the paper argues that humans and horses co-create a language system by way of the body to facilitate the creation of shared meaning. This research challenges the privileged status of verbal language and suggests that non-verbal communication and language systems of the body have their own unique complexities. This investigation of humanhorse communication offers new possibilities to understand the subjective and intersubjective world of non-verbal language using beings—human and nonhuman alike.
Roadkill: Between Humans, Nonhuman Animals, and Technologies
Authors: Michael Mike
Published: February 2005

This paper has two broad objectives. First, the paper aims to treat roadkill as a topic of serious social scientific inquiry by addressing it as a cultural artifact through which various identities are played out. Thus, the paper shows how the idea of roadkill-as-food mediates contradictions and ironies in American identities concerned with hunting, technology, and relationships to nature. At a second, more abstract, level, the paper deploys the example of roadkill to suggest a par ticular approach to theorizing broader relationships between humans, nonhuman animals, and technology. This paper draws on recent developments in science and technology studies, in particular, the work of Latour (1993) and Serres (1982,1985), to derive a number of prepositional metaphors. The paper puts these forward tentatively as useful tools for exploring and unpicking some of the complex connections and heterogeneous relationalities between humans, animals, and the technology from which roadkill emerges.
In It for the Nonhuman Animals: Animal Welfare, Moral Certainty, and Disagreements
Authors: Taylor Nicola
Published: February 2005

Based on three years' ethnographic research with animal sanctuary workers, this paper argues that a level of moral certainty drives and justifies many of the workers' actions and beliefs. Similar to the "missionary zeal" of nonhuman animal rights activists, this moral certainty divides the world into two neat categories: good for the animals and bad for the animals. This overriding certainty takes precedence over other concerns and pervades all aspects of sanctuary life, resulting in the breakdown of different facets of that life into good and bad homes, good and bad animals, and good and bad workers. The paper, therefore, argues that animal welfare workers may be as "radical" as animal rights activists in one respect—their adherence to the overriding principle of being "in it for the animals."
From Transitory Status to Perpetual Sententiae: Rethinking Polygamy in Islamic Traditions
Authors: Souaiaia Ahmed
Published: February 2005

Polygamy and inequity in inheritance rights are two fundamental concerns that continue to challenge the logic and practice concerning the way women are treated in Islamic society. These two subjects remain beyond the scope of critical analysis due in part to the explicit legal proof (dalīl) that is found in the Qur'ān. How explicit are such legal proofs in general and is there any scope for an alternative interpretation? The consensus that emerged on these two matters would suggest that there is none. However, in this paper, I would argue that the perceived consensus is guided and dictated by the fact that during the formative period of Islamic law, interpretive and normative disciplines were dominated by men; hence, the male bias. It can be argued, based on historical and linguistic evidence, that there is a very plausible alternative understanding that is radically different from any of those proposed by traditionalists.
The Nature and Elements of Sacrificial Ritual
Authors: McClymond Kathryn
Published: February 2005

After delineating several basic sacrificial activities in the context of the Vedic and Israelite traditions, the following essay makes three observations about the nature of sacrifice. First, despite the emphasis on death and violence in many dominant treatments, close study indicates that sacrifice is largely a non-violent activity. Therefore, it is inappropriate to focus on killing as a definitive or central element of sacrificial ritual. Second, sacrificial systems include animal, vegetal, and liquid oblations, yet vegetal and liquid substances are generally overlooked in sacrificial theorizing. Consequently, sacrificial theories that are driven by animal sacrifice need to be adjusted to address the full spectrum of sacrificial oblations and activity. Finally, sacrificial ritual is best understood as the dynamic interplay of various sacrificial elements rather than a monolithic event marked by a single, definitive activity. This paper offers an alternative polythetic approach that focuses on clusters of sacrificial activity.
Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice
Authors: Viatte Lydie , Lesbordes-Brion Jeanne-Claire , Lou Dan-Qing , Bennoun Myriam , Nicolas Gaël , Kahn Axel , Canonne-Hergaux François , Vaulont Sophie
Published: February 2005

Evidence is accumulating that hepcidin, a liver regulatory peptide, could be the common pathogenetic denominator of all forms of iron overload syndromes including HFE-related hemochromatosis, the most prevalent genetic disorder characterized by inappropriate iron absorption. To understand the mechanisms whereby hepcidin controls iron homeostasis in vivo, we have analyzed the level of iron-related proteins by Western blot and immunohistochemistry in hepcidin-deficient mice, a mouse model of severe hemochromatosis. These mice showed important increased levels of duodenal cytochrome b (Dcytb), divalent metal transporter 1 (DMT1), and ferroportin compared with control mice. Interestingly, the level of ferroportin was coordinately up-regulated in the duodenum, the spleen, and the liver (predominantly in the Kupffer cells). Finally, we also evidenced a decrease of ceruloplasmin in the liver of hepcidin-deficient mice. We hypothesized that the deregulation of these proteins might be central in the pathogenesis of iron overload, providing key therapeutic targets for iron disorders. (Blood. 2005;105:4861-4864)
Sea urchin vault structure, composition, and differential localization during development
Authors: Stewart Phoebe L , Makabi Miriam , Lang Jennifer , Dickey-Sims Carrie , Robertson Anthony J , Coffman James A , Suprenant Kathy A
Published: February 2005

Background

Vaults are intriguing ribonucleoprotein assemblies with an unknown function that are conserved among higher eukaryotes. The Pacific coast sea urchin, Strongylocentrotus purpuratus, is an invertebrate model organism that is evolutionarily closer to humans than Drosophila and C. elegans, neither of which possesses vaults. Here we compare the structures of sea urchin and mammalian vaults and analyze the subcellular distribution of vaults during sea urchin embryogenesis.

Results

The sequence of the sea urchin major vault protein (MVP) was assembled from expressed sequence tags and genome traces, and the predicted protein was found to have 64% identity and 81% similarity to rat MVP. Sea urchin MVP includes seven ~50 residue repeats in the N-terminal half of the protein and a predicted coiled coil domain in the C-terminus, as does rat MVP. A cryoelectron microscopy (cryoEM) reconstruction of isolated sea urchin vaults reveals the assembly to have a barrel-shaped external structure that is nearly identical to the rat vault structure. Analysis of the molecular composition of the sea urchin vault indicates that it contains components that may be homologs of the mammalian vault RNA component (vRNA) and protein components (VPARP and TEP1). The sea urchin vault appears to have additional protein components in the molecular weight range of 14–55 kDa that might correspond to molecular contents. Confocal experiments indicate a dramatic relocalization of MVP from the cytoplasm to the nucleus during sea urchin embryogenesis.

Conclusions

These results are suggestive of a role for the vault in delivering macromolecules to the nucleus during development.
Evolution of the relaxin-like peptide family
Authors: Wilkinson Tracey N , Speed Terence P , Tregear Geoffrey W , Bathgate Ross AD
Published: February 2005

Background

The relaxin-like peptide family belongs in the insulin superfamily and consists of 7 peptides of high structural but low sequence similarity; relaxin-1, 2 and 3, and the insulin-like (INSL) peptides, INSL3, INSL4, INSL5 and INSL6. The functions of relaxin-3, INSL4, INSL5, INSL6 remain uncharacterised. The evolution of this family has been contentious; high sequence variability is seen between closely related species, while distantly related species show high similarity; an invertebrate relaxin sequence has been reported, while a relaxin gene has not been found in the avian and ruminant lineages.

Results

Sequence similarity searches of genomic and EST data identified homologs of relaxin-like peptides in mammals, and non-mammalian vertebrates such as fish. Phylogenetic analysis was used to resolve the evolution of the family. Searches were unable to identify an invertebrate relaxin-like peptide. The published relaxin cDNA sequence in the tunicate, Ciona intestinalis was not present in the completed C. intestinalis genome. The newly discovered relaxin-3 is likely to be the ancestral relaxin. Multiple relaxin-3-like sequences are present in fugu fish (Takifugu rubripes) and zebrafish (Danio rerio), but these appear to be specific to the fish lineage. Possible relaxin-1 and INSL5 homologs were also identified in fish and frog species, placing their emergence prior to mammalia, earlier than previously believed. Furthermore, estimates of synonymous and nonsynonymous substitution rates (dN/dS) suggest that the emergence of relaxin-1, INSL4 and INSL6 during mammalia was driven by positive Darwinian selection, hence these peptides are likely to have novel and in the case of relaxin-1, which is still under positive selection in humans and the great apes, possibly still evolving functions. In contrast, relaxin-3 is constrained by strong purifying selection, demonstrating it must have a highly conserved function, supporting its hypothesized important neuropeptide role.

Conclusions

We present a phylogeny describing the evolutionary history of the relaxin-like peptide family and show that positive selection has driven the evolution of the most recent members of the family.