bluuebunny/crossref_metadata_2025 huggingface dataset:
Purification and Partial Characterization of a
Paracoccidioides brasiliensis
Protein with Capacity To Bind to Extracellular Matrix Proteins
Authors: González Angel , Gómez Beatriz L. , Diez Soraya , Hernández Orville , Restrepo Angela , Hamilton Andrew J. , Cano Luz E.
Published: March 2005

Microorganisms adhere to extracellular matrix proteins by means of their own surface molecules.
Paracoccidioides brasiliensis
conidia have been shown to be capable of interacting with extracellular matrix proteins. We aimed at determining the presence of fungal proteins that could interact with extracellular matrix protein and, if found, attempt their purification and characterization. Various extracts were prepared from
P. brasiliensis
mycelial and yeast cultures (total homogenates, β-mercaptoethanol, and sodium dodecyl sulfate [SDS] extracts) and analyzed by ligand affinity assays with fibronectin, fibrinogen and laminin. Two polypeptides were detected in both fungal forms. SDS extracts that interacted with all the extracellular matrix protein were tested; their molecular masses were 19 and 32 kDa. Analysis of the N-terminal amino acid sequence of the purified 32-kDa mycelial protein showed substantial homology with
P. brasiliensis
,
Histoplasma capsulatum
, and
Neurospora crassa
hypothetical proteins. Additionally, a monoclonal antibody (MAb) produced against this protein recognized the 32-kDa protein in the SDS extracts of both fungal forms for immunoblot. Immunofluorescence analysis revealed that this MAb reacted not only with mycelia and yeast cells, but also with conidia, indicating that this protein was shared by the three fungal propagules. By immunoelectron microscopy, this protein was detected in the cell walls and in the cytoplasm. Both the 32-kDa purified protein and MAb inhibited the adherence of conidia to the three extracellular matrix proteins in a dose-dependent manner. These findings demonstrate the presence of two polypeptides capable of interacting with extracellular matrix proteins on the surface of
P. brasiliensis
propagules, indicating that there may be common receptors for laminin, fibronectin, and fibrinogen. These proteins would be crucial for initial conidial adherence and perhaps also in dissemination of paracoccidioidomycosis.
Role of Endothelin 1 in the Pathogenesis of Chronic Chagasic Heart Disease
Authors: Tanowitz Herbert B. , Huang Huan , Jelicks Linda A. , Chandra Madhulika , Loredo Maria L. , Weiss Louis M. , Factor Stephen M. , Shtutin Vitaliy , Mukherjee Shankar , Kitsis Richard N. , Christ George J. , Wittner Murray , Shirani Jamshid , Kisanuki Yaz Y. , Yanagisawa Masashi
Published: March 2005

On the basis of previous observations, endothelin 1 (ET-1) has been suggested as contributing to the pathogenesis of Chagasic cardiomyopathy. Therefore, ET-1
flox/flox
;α-MHC-Cre(+) mice in which the ET-1 gene was deleted from cardiac myocytes and ET-1
flox/flox
;Tie 2 Cre(+) mice in which the ET-1 gene was deleted from endothelial cells were infected with
Trypanosoma cruzi
. Genetic controls for these cell-specific ET-1 knockout mice were used. Ninety percentage of all mice survived acute infection with the Brazil strain and were evaluated 130 days postinfection. Inflammation and fibrosis were observed in all infected mice; however, fibrosis was reduced in ET-1
flox/flox
;α-MHC-Cre(+) mice. Cardiac magnetic resonance imaging revealed that infection resulted in a significant increase in right ventricular internal diameter (RVID) in all mice except ET-1
flox/flox
;α-MHC-Cre(+) mice; i.e., RVID was not changed in infected ET-1
flox/flox
;α-MHC-Cre(+) mice. Echocardiography of the left ventricle demonstrated increased left ventricular end-diastolic diameter, reduced fractional shortening, and decreased relative wall thickness in infected mice. However, the magnitude of the changes was significantly less in ET-1
flox/flox
;α-MHC-Cre(+) mice compared to other groups. These data provide further evidence of a role for ET-1, particularly cardiac myocyte-derived ET-1, in the pathogenesis of chronic Chagasic cardiomyopathy.
Novel Mouse Model of ChronicPseudomonas aeruginosaLung Infection Mimicking Cystic Fibrosis
Authors: Hoffmann Nadine , Rasmussen Thomas Bovbjerg , Jensen PeterØstrup , Stub Charlotte , Hentzer Morten , Molin Søren , Ciofu Oana , Givskov Michael , Johansen Helle Krogh , Høiby Niels
Published: March 2005

Pseudomonas aeruginosacauses a chronic infection in the lungs of cystic fibrosis (CF) patients by establishing an alginate-containing biofilm. The infection has been studied in several animal models; however, most of the models required artificial embedding of the bacteria. We present here a new pulmonary mouse model without artificial embedding. The model is based on a stable mucoid CF sputum isolate (NH57388A) with hyperproduction of alginate due to a deletion inmucAand functionalN-acylhomoserine lactone (AHL)-based quorum-sensing systems. Chronic lung infection could be established in both CF mice (CftrtmlUnc−/−) and BALB/c mice, as reflected by the detection of a high number ofP. aeruginosaorganisms in the lung homogenates at 7 days postinfection and alginate biofilms, surrounded by polymorphonuclear leukocytes in the alveoli. In comparison, both an AHL-producing nonmucoid revertant (NH57388C) from the mucoid isolate (NH57388A) and a nonmucoid isolate (NH57388B) deficient in AHL were almost cleared from the lungs of the mice. This model, in whichP. aeruginosais protected against the defense system of the lung by alginate, is similar to the clinical situation. Therefore, the mouse model provides an improved method for evaluating the interaction between mucoidP. aeruginosa, the host, and antibacterial therapy.
Shiga Toxin Is Transported from the Endoplasmic Reticulum following Interaction with the Luminal Chaperone HEDJ/ERdj3
Authors: Yu Min , Haslam David B.
Published: March 2005

Shiga toxin (Stx) follows a complex intracellular pathway in order to kill susceptible cells. After binding to cell surface glycolipids, the toxin is internalized and trafficked in retrograde fashion to the endoplasmic reticulum (ER). From the ER lumen, the toxin must gain access to the cytoplasm, where it enzymatically inactivates the 28S rRNA, inhibiting protein synthesis. The host molecules involved in this pathway and the mechanisms utilized by the toxin to access the cytoplasm from the ER are largely unknown. We found that Stx is capable of energy-dependent transport across the ER lumen, as has recently been demonstrated for the cholera and ricin toxins. Genetic screening for molecules involved in Shiga toxin trafficking yielded a cDNA encoding a prematurely truncated protein. Characterization of this cDNA revealed that it encodes a novel Hsp40 chaperone, designated HEDJ or ERdj3, localized to the ER lumen, where it interacts with BiP, a molecule known to be involved in protein retrotranslocation out of the ER. We demonstrated that within the ER lumen Stx interacts with HEDJ and other chaperones known to be involved in retrotranslocation of proteins across the ER membrane. Moreover, sequential immunoprecipitation revealed that Shiga toxin was present in a complex that included HEDJ and Sec61, the translocon through which proteins are retrotranslocated to the cytoplasm. These findings suggest that HEDJ is a component of the ER quality control system and that Stx utilizes HEDJ and other ER-localized chaperones for transport from the ER lumen to the cytosol.
Designer Arrays for Defined Mutant Analysis To Detect Genes Essential for Survival of
Mycobacterium tuberculosis
in Mouse Lungs
Authors: Lamichhane Gyanu , Tyagi Sandeep , Bishai William R.
Published: March 2005

The mechanisms by which
Mycobacterium tuberculosis
elicits disease are complex, involving a large repertoire of bacterial genes that are required for in vivo growth and survival. To identify such genes, we utilized a high-throughput microarray detection method to rapidly screen hundreds of unique, genotypically defined transposon mutants for in vivo survival with a high degree of specificity and sensitivity. Thirty-one
M. tuberculosis
genes were found to be required for in vivo survival in mouse lungs. These genes are involved in a broad range of activities, including metabolism, cell wall functions, and regulation. Our screen included 11 of the 12 known members of the mycobacterial membrane protein (mmpL) family genes, and mutation of 6 of these genes—
mmpL4
,
mmpL5
,
mmpL7
,
mmpL8
,
mmpL10
, and
mmpL11
—severely compromised the ability of the mutants to multiply in mouse lungs. Most of the 31 genes are conserved in other pathogenic mycobacteria, including
M. leprae
and
M. bovis
, suggesting that a core of basic in vivo survival mechanisms may be highly conserved despite the divergent human pathology caused by members of the mycobacterial genus. Of the 31 genes reported here, 17 have not been previously described to be involved in in vivo growth and survival of
M. tuberculosis.
Isocitrate Lyase (AceA) Is Required for Salmonella Persistence but Not for Acute Lethal Infection in Mice
Authors: Fang Ferric C. , Libby Stephen J. , Castor Margaret E. , Fung Angela M.
Published: March 2005

Isocitrate lyase is required for fatty acid utilization via the glyoxylate shunt. Although isocitrate lyase is essential for
Salmonella
persistence during chronic infection, it is dispensable for acute lethal infection in mice. Substrate availability in the phagosome appears to evolve over time, with increasing fatty acid dependence during chronic infection.
The Mannose Receptor Mediates the Cellular Immune Response in Human Coccidioidomycosis
Authors: Ampel Neil M. , Nelson Daniel K. , Li Lijin , Dionne Sara O. , Lake Douglas F. , Simmons Keira A. , Pappagianis Demosthenes
Published: March 2005

Mannose is the predominant monosaccharide in the coccidioidal antigen preparation T27K. Mannan and anti-CD206 antibody significantly decreased the surface expression of mannose receptor (MR) on adherent peripheral blood mononuclear cells and reduced the interleukin-2 (IL-2) release induced by T27K. These data suggest that MR mediates IL-2 release by T27K.
Nonopsonic Phagocytosis of Erythrocytes Infected with Ring-StagePlasmodium falciparum
Authors: Ayi Kodjo , Patel Samir N. , Serghides Lena , Smith Todd G. , Kain Kevin C.
Published: March 2005

Ring-stage parasitized erythrocytes (RPEs) were demonstrated to interact with effector cells of the innate immune system. With receptor blockade studies and CD36-null macrophages, human and murine macrophages were shown to phagocytose RPEs through the pattern recognition receptor CD36. These in vitro data implicate scavenger receptors in the clearance of RPEs.
Leishmania majorModulates Chemokine and Chemokine Receptor Expression by Dendritic Cells and Affects Their Migratory Capacity
Authors: Steigerwald Mario , Moll Heidrun
Published: March 2005

Dendritic cells (DC) both produce and respond to chemokines. We examined the profiles of chemokines and chemokine receptors expressed by DC and their chemotactic response after interaction withLeishmania major. Expression of the chemokine receptors CCR2 and CCR5 by DC and their responsiveness to the respective ligands, CCL2 and CCL3, were downregulated, while the level of CCR7 and the DC response to its ligand CCL21 were enhanced. These parasite-induced alterations were observed with DC fromL. major-resistant and -susceptible mice. In contrast, expression of the chemokine CXCL10 was elicited only in DC fromL. major-resistant mice.
The Psychobiology of Depression and Resilience to Stress: Implications for Prevention and Treatment
Authors: Southwick Steven M. , Vythilingam Meena , Charney Dennis S.
Published: March 2005

This review discusses neurobiological and psychosocial factors associated with stress-induced depression and compares these factors with those believed to characterize stress resilience. Neurobiological factors that are discussed and contrasted include serotonin, the 5-HT1A receptor, polymorphisms of the 5-HT transporter gene, norepinephrine, alpha-2 adrenergic receptors, neuropeptide Y, polymorphisms of the alpha-2 adrenergic gene, dopamine, corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), cortisol, and CRH receptors. These factors are described in the context of brain regions believed to be involved in stress, depression, and resilience to stress. Psychosocial factors associated with depression and/or stress resilience include positive emotions and optimism, humor, cognitive flexibility, cognitive explanatory style and reappraisal, acceptance, religion/spirituality, altruism, social support, role models, coping style, exercise, capacity to recover from negative events, and stress inoculation. The review concludes with potential psychological, social, spiritual, and neurobiological approaches to enhancing stress resilience, decreasing the likelihood of developing stress-induced depression/anxiety, and treating stress-induced psychopathology.
Psychological Treatment of Eating Disorders
Authors: Wilson G. Terence
Published: March 2005

Manual-based cognitive behavior therapy (CBT) is presently the most effective treatment of bulimia nervosa. Its efficacy is limited, however. Different strategies for improving upon current manual-based CBT are discussed, including combining CBT with antidepressant medication, integrating CBT with alternative psychological therapies, and expanding the scope and flexibility of manual-based CBT. CBT is underutilized in clinical practice. Dissemination of evidence-based treatment is a priority. Research on anorexia nervosa is minimal. Effective treatments have yet to be developed, although the Maudsley method of family therapy has shown the most promise in the treatment of adolescents. The most commonly seen eating disorders in clinical practice are those classified as “eating disorder not otherwise specified.” With the exception of binge eating disorder (BED), however, they have been neglected by researchers. Several psychological therapies have been shown to be effective in treating BED. Controversy exists over whether treatment-specific effects have been identified. Whereas treatments have proved effective in eliminating binge eating and associated eating disorder psychopathology, achieving clinically significant weight loss remains a challenge.
Amelioration of Pulmonary Emphysema by In Vivo Gene Transfection With Hepatocyte Growth Factor in Rats
Authors: Shigemura Norihisa , Sawa Yoshiki , Mizuno Shinya , Ono Masamichi , Ohta Mitsunori , Nakamura Toshikazu , Kaneda Yasufumi , Matsuda Hikaru
Published: March 2005

Background—

Hepatocyte growth factor (HGF) is an important mitogen and morphogen that contributes to the repair process after lung injury. The goal of the present study was to characterize its role in pulmonary emphysema, which may lead to the development of new treatment strategies with HGF.

Methods and Results—

HGF mRNA and protein levels in lung tissue and plasma from elastase-induced emphysema rats transiently increased, then declined significantly to below the basal level in a time-dependent manner (
P
<0.01). Furthermore, changes in HGF were correlated with histologically progressive emphysematous changes and deterioration in pulmonary physiology. Use of the HVJ (hemagglutinating virus of Japan) envelope method resulted in successful transfection of cDNA encoding human HGF, as demonstrated by an efficient expression of HGF in alveolar endothelial and epithelial cells. Transfection of HGF resulted in a more extensive pulmonary vasculature and inhibition of alveolar wall cell apoptosis, and those effects led to improved exercise tolerance and gas exchange (
P
<0.05), which persisted for more than 1 month.

Conclusions—

Decreased HGF expression due to a failure in sustained endogenous production after injury was associated with emphysema-related histopathologic and physiological changes in the present rat model. In addition, induction of HGF expression by a gene-transfection method resulted in improved pulmonary function via inhibition of alveolar cell apoptosis, enhancement of alveolar regeneration, and promotion of angiogenesis.
Blockade of Endogenous Cytokines Mitigates Neointimal Formation in Obese Zucker Rats
Authors: Takeda Ryo , Suzuki Etsu , Satonaka Hiroshi , Oba Shigeyoshi , Nishimatsu Hiroaki , Omata Masao , Fujita Toshiro , Nagai Ryozo , Hirata Yasunobu
Published: March 2005

Background—

It is well known that diabetes mellitus is a major risk factor for vascular diseases such as atherosclerosis and restenosis after angioplasty. It has become clear that advanced glycation end products (AGE) and their receptor (RAGE) are implicated in vascular diseases, especially in diabetes mellitus. Nevertheless, the mechanisms by which diabetes mellitus is often associated with vascular diseases remain unclear.

Methods and Results—

To study the role of endogenous cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 in the development of vascular diseases and in the expression of RAGE, we used semapimod, a pharmacological inhibitor of cytokine production, and examined its effect on neointimal formation in the femoral artery of obese Zucker (OZ) rats. We also used an adenovirus construct expressing a dominant negative mutant of the receptor for TNF-α (AdTNFRΔC) to block the action of endogenous TNF-α. Semapimod significantly suppressed neointimal formation and RAGE expression in OZ rats compared with untreated OZ rats. This inhibitory effect of semapimod on neointimal formation was overcome by infection of an adenovirus expressing RAGE into the femoral artery of OZ rats. Furthermore, AdTNFRΔC infection significantly suppressed neointimal formation and RAGE expression in the femoral artery of OZ rats.

Conclusions—

These results suggest that endogenous cytokines, especially TNF-α, were implicated in neointimal formation in OZ rats and that RAGE was a mediator of the effect of these cytokines on neointimal formation.
HMG-CoA Reductase Inhibition Reduces Monocyte CC Chemokine Receptor 2 Expression and Monocyte Chemoattractant Protein-1–Mediated Monocyte Recruitment In Vivo
Authors: Han Ki Hoon , Ryu Jewon , Hong Kyung Hee , Ko Jesang , Pak Youngmi Kim , Kim Jae-Bum , Park Seong Wook , Kim Jae Joong
Published: March 2005

Background—

The migration of circulating monocytes to the arterial wall during atherogenesis is largely modulated by activation of the CC chemokine receptor 2 (CCR2), a dominant monocyte chemotaxis receptor. The present study investigated whether 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition affects CCR2 gene expression and CCR2-dependent monocyte recruitment.

Methods and Results—

Competitive reverse transcription-polymerase chain reaction analysis and flow cytometry showed that simvastatin, an HMG-CoA reductase inhibitor, dose-dependently reduced monocyte CCR2 mRNA and protein expression. Treatment of 21 normocholesterolemic men with simvastatin (20 mg/d for 2 weeks) decreased CCR2 protein and mRNA expression in circulating monocytes. Promoter and electrophoretic mobility shift assays showed that simvastatin activated a peroxisome proliferator response element in THP-1 monocytes. Moreover, simvastatin-induced CCR2 downregulation was completely reversed by the synthetic peroxisome proliferator-activated receptor-γ antagonist GW9662. Simvastatin-treated monocytes showed little chemotaxis movement in response to monocyte chemoattractant protein-1 (MCP-1), a specific CCR2 ligand. Treatment of C57/BL6 mice with simvastatin (0.2 μg/g body weight IP, daily for 1 week) inhibited transmigration of CD80
+
monocytes to the MCP-1–injected intraperitoneal space. Moreover, few circulating inflammatory cells from simvastatin-treated Sprague-Dawley rats (0.2 μg/g body weight IP, daily for 2 weeks) were recruited to the aortic wall of hypercholesterolemic littermates.

Conclusions—

The inhibition of CCR2/MCP-1–dependent monocyte recruitment by simvastatin may prevent excessive accumulation of monocytes in the arterial wall during atherogenesis.
Overexpression of Dimethylarginine Dimethylaminohydrolase Reduces Tissue Asymmetric Dimethylarginine Levels and Enhances Angiogenesis
Authors: Jacobi Johannes , Sydow Karsten , von Degenfeld Georges , Zhang Ying , Dayoub Hayan , Wang Bingyin , Patterson Andrew J. , Kimoto Masumi , Blau Helen M. , Cooke John P.
Published: March 2005

Background—

This study was designed to determine whether overexpression of the enzyme dimethylarginine dimethylaminohydrolase (DDAH) could enhance angiogenesis by reducing levels of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA).

Methods and Results—

In DDAH1 transgenic (TG) and wild-type mice (each n=42), the role of DDAH overexpression on angiogenesis was studied by use of the disk angiogenesis system and a murine model of hindlimb ischemia (each n=21). After surgery, animals were treated with either PBS or the NOS inhibitors ADMA or
N
ω
-nitro-
l
-arginine methyl ester (L-NAME; each 250 μmol · kg
−1
· d
−1
) by use of osmotic minipumps (each n=7). L-NAME was chosen to study an inhibitor that is not degraded by DDAH. Neovascularization in the disk angiogenesis system was impaired by both NOS inhibitors; however, TG animals were resistant to the effects of ADMA on neovascularization. Similarly, TG mice were more resistant to the inhibitory effect of ADMA on angioadaptation (angiogenesis and arteriogenesis) after hindlimb ischemia, as assessed by fluorescent microsphere studies and postmortem microangiograms. Enhanced neovascularization and limb perfusion in TG mice were associated with reduced plasma and tissue ADMA levels and enhanced tissue NOS enzyme activity.

Conclusions—

We describe a novel mechanism by which DDAH regulates postnatal neovascularization. Therapeutic manipulation of DDAH expression or activity may represent a novel approach to restore tissue perfusion.
Effects of Intravenous Levosimendan on Human Coronary Vasomotor Regulation, Left Ventricular Wall Stress, and Myocardial Oxygen Uptake
Authors: Michaels Andrew D. , McKeown Barry , Kostal Michael , Vakharia Kalpesh T. , Jordan Mark V. , Gerber Ivor L. , Foster Elyse , Chatterjee Kanu
Published: March 2005

Background—

Levosimendan is a calcium-sensitizing agent and an inodilator under current investigation in the treatment of decompensated heart failure. The effects of intravenous levosimendan on the human coronary vasculature, together with myocardial wall stress and oxygen uptake, have not been adequately studied.

Methods and Results—

Ten adult patients underwent right- and left-heart catheterization. Baseline coronary blood flow was determined with quantitative coronary angiography and an intracoronary Doppler-tipped guidewire. Myocardial oxygen uptake was measured with a coronary sinus catheter. Echocardiography was performed before and 30 minutes after an intravenous infusion of levosimendan (24-μg/kg bolus over 10 minutes) was begun. Pulmonary capillary wedge decreased 37% (
P
=0.009), cardiac output increased 9% (
P
=0.04), and systemic vascular resistance decreased 18% (
P
<0.001). Left ventricular ejection fraction increased 20% (
P
=0.009), and meridional systolic wall stress decreased 48% (
P
=0.009). Coronary artery diameter increased 10% at 15 minutes (
P
=0.001) and 11% at 30 minutes (
P
=0.01). Coronary artery velocity increased 10% over baseline (
P
=0.04). Coronary blood flow increased 45% (
P
=0.02), whereas coronary resistance decreased 36% at 30 minutes (
P
=0.03). Myocardial oxygen extraction decreased 9% at 30 minutes (
P
=0.04).

Conclusions—

Levosimendan given intravenously exerts vasodilator effects on human coronary conductance and resistance arteries. Despite a decrease in coronary perfusion pressure, coronary blood flow is increased. A reduction in coronary vascular resistance and a decrease in coronary venous oxygen content indicate primary coronary vasodilation by levosimendan. Improved left ventricular systolic function and decreased myocardial oxygen extraction suggest improved myocardial efficiency.
Limited Exercise Capacity in Heterozygous Manganese Superoxide Dismutase Gene–Knockout Mice
Authors: Kinugawa Shintaro , Wang Ziping , Kaminski Pawel M. , Wolin Michael S. , Edwards John G. , Kaley Gabor , Hintze Thomas H.
Published: March 2005

Background—

We have reported that there is a limitation of exercise capacity in mice with defects in the expression of endothelial nitric oxide (NO) synthase, which is associated with a greater increase in whole-body oxygen consumption (V̇
o
2
). We hypothesized that in states in which superoxide anion (O
2
−
) is increased, especially in the mitochondria, whole-body V̇
o
2
will be increased because of the inactivation of NO, and consequently, exercise capacity will be reduced.

Methods and Results—

Heterozygous manganese superoxide anion dismutase (SOD2) gene–knockout mice (SOD2
+/−
), in which SOD2 activity is reduced by 30% to 80%, and wild-type control mice (SOD2
+/+
) were treadmill-tested to measure indices defining exercise capacity. Tempol was given to each mouse for 7 days by an intraperitoneal injection to scavenge O
2
−
before a second treadmill testing. V̇
o
2
and carbon dioxide production (V̇
co
2
) at rest were increased in SOD2
+/−
. The work (vertical distance run × body weight) to exhaustion was decreased in SOD2
+/−
. When the maximum V̇
o
2
and V̇
co
2
were corrected to per work unit, they were increased in SOD2
+/−
. Tempol normalized basal V̇
o
2
and V̇
co
2
and improved the work to exhaustion and corrected V̇
o
2
and V̇
co
2
in SOD2
+/−
. V̇
o
2
of skeletal muscle was measured in vitro. Bradykinin-induced reduction in V̇
o
2
in vitro was attenuated in SOD2
+/−
, and was acutely restored by Tempol. There was a decrease in SOD2 protein level and a concomitant increase in lucigenin-detectable O
2
−
production in skeletal muscle from SOD2
+/−
.

Conclusions—

These results suggest that exercise capacity is reduced in conditions in which superoxide anion is increased, and this is associated with a greater increase in whole-body oxygen consumption in SOD2
+/−
compared with SOD2
+/+
.
Lipoprotein(a) and Apolipoprotein(a) Isoforms
Authors: Guerra Rudy , Yu Zhaoxia , Marcovina Santica , Peshock Ronald , Cohen Jonathan C. , Hobbs Helen H.
Published: March 2005

Background—

Elevated plasma levels of lipoprotein(a) [Lp(a)] are an independent risk factor for cardiovascular disease in whites. Blacks have 2- to 3-fold higher plasma levels of Lp(a) than whites and yet do not have a correspondingly higher rate of coronary events. It remains unclear whether elevated plasma levels of Lp(a) are an independent risk factor for coronary atherosclerosis in individuals of African descent.

Methods and Results—

The relationship between plasma levels of Lp(a), apolipoprotein(a) isoform sizes, and the presence of coronary calcium was examined in 761 blacks and 527 whites (men aged >40 years, women aged >45 years) from a population-based sample. No relationship was found between plasma levels of Lp(a), apolipoprotein(a) isoform size, or a combination of these 2 variables and coronary artery calcium (CAC) in whites or blacks. No correlation was observed between plasma levels of Lp(a) and coronary calcium scores in any group, although all black men with very high plasma levels of Lp(a) (>300 μmol/L; n=7) were CAC-positive. Whites with high plasma levels of Lp(a) plus elevated plasma levels of LDL cholesterol (men) or reduced levels of HDL cholesterol (men and women) or who smoked (women) had a higher prevalence of CAC. In contrast, no joint effects between plasma levels of Lp(a) and other cardiovascular risk factors on coronary calcium were found in blacks.

Conclusions—

No consistent independent relationship between plasma levels of Lp(a) or apolipoprotein(a) isoform size and coronary calcium was found in whites or blacks.
Adenovirus-Mediated Overexpression of Diacylglycerol Kinase-ζ Inhibits Endothelin-1–Induced Cardiomyocyte Hypertrophy
Authors: Takahashi Hiroki , Takeishi Yasuchika , Seidler Tim , Arimoto Takanori , Akiyama Hideyuki , Hozumi Yasukazu , Koyama Yo , Shishido Tetsuro , Tsunoda Yuichi , Niizeki Takeshi , Nozaki Naoki , Abe Jun-ichi , Hasenfuss Gerd , Goto Kaoru , Kubota Isao
Published: March 2005

Background—

Diacylglycerol (DAG) is a lipid second messenger that transiently accumulates in cells stimulated by endothelin-1 (ET-1) and other Gαq protein-coupled receptor agonists. Diacylglycerol kinase (DGK) is thought to be an enzyme that controls the cellular levels of DAG by converting it to phosphatidic acid; however, the functional role of DGK has not been examined in cardiomyocytes. Because DGK inactivates DAG, a strong activator of protein kinase C (PKC), we hypothesized that DGK inhibited ET-1–induced activation of a DAG-PKC signaling cascade and subsequent cardiomyocyte hypertrophy.

Methods and Results—

Real-time reverse transcription-polymerase chain reaction demonstrated a significant increase of DGK-ζ mRNA by ET-1 in cardiomyocytes. To determine the functional role of DGK-ζ, we overexpressed DGK-ζ in cardiomyocytes using a recombinant adenovirus encoding rat DGK-ζ (Ad-DGKζ). ET-1–induced translocation of PKC-ε was blocked by Ad-DGKζ (
P
<0.01). Ad-DGKζ also inhibited ET-1–induced activation of extracellular signal-regulated kinase (
P
<0.01). Luciferase reporter assay revealed that ET-1–mediated increase of activator protein-1 (AP1) DNA-binding activity was significantly inhibited by DGK-ζ (
P
<0.01). In cardiomyocytes transfected with DGK-ζ, ET-1 failed to cause gene induction of atrial natriuretic factor, increases in [
3
H]-leucine uptake, and increases in cardiomyocyte surface area.

Conclusions—

We demonstrated for the first time that DGK-ζ blocked ET-1–induced activation of the PKC-ε–ERK-AP1 signaling pathway, atrial natriuretic factor gene induction, and resultant cardiomyocyte hypertrophy. DGK-ζ might act as a negative regulator of hypertrophic program in response to ET-1, possibly by controlling cellular DAG levels.
Risk of Worsening Renal Function With Nesiritide in Patients With Acutely Decompensated Heart Failure
Authors: Sackner-Bernstein Jonathan D. , Skopicki Hal A. , Aaronson Keith D.
Published: March 2005

Background—

Renal function is an important prognostic factor for patients with acutely decompensated heart failure (ADHF). We investigated the renal effects of nesiritide as treatment for ADHF.

Methods and Results—

Randomized clinical trials comparing nesiritide with either placebo or active control for ADHF were identified by electronic and manual searches and thorough review of US Food and Drug Administration files available via the website. Worsening renal function was defined as an increase in serum creatinine >0.5 mg/dL. Relative risk across all studies was determined by meta-analysis with Mantel-Haenszel fixed-effects models (RR
MH
). Risk of dialysis and medical intervention for worsening renal function were compared between therapies. Frequency of worsening renal function was determined from 5 randomized studies that included 1269 patients. Use of Food and Drug Administration–approved doses of nesiritide (≤0.03 μg · kg
−1
· min
−1
) significantly increased the risk of worsening renal function compared with non–inotrope-based control (RR
MH
, 1.52; 95% CI, 1.16 to 2.00;
P
=0.003) or any control therapy, including non–inotrope- and inotrope-based therapies (RR
MH
, 1.54; 95% CI, 1.19 to 1.98;
P
=0.001). Even low-dose nesiritide (≤0.015 μg · kg
−1
· min
−1
) significantly increased risk (
P
=0.012 and
P
=0.006 compared with non–inotrope- and inotrope-based controls, respectively), as did nesiritide administered at any dose up to 0.06 μg · kg
−1
· min
−1
(
P
=0.002 and
P
=0.001, respectively). There was no difference in the need for dialysis between therapies.

Conclusions—

Nesiritide significantly increases the risk of worsening renal function in patients with ADHF. Whether worsening renal function reflects hemodynamic effect or renal injury is unknown, but the prognostic importance of worsening renal function suggests the need for further investigation in appropriately powered clinical trials.
Long-Term Serotonin Administration Induces Heart Valve Disease in Rats
Authors: Gustafsson Björn I. , Tømmerås Karin , Nordrum Ivar , Loennechen Jan P. , Brunsvik Anders , Solligård Erik , Fossmark Reidar , Bakke Ingunn , Syversen Unni , Waldum Helge
Published: March 2005

Background—

The purpose of this study was to investigate whether rats dosed with serotonin develop changes similar to those seen in human carcinoid heart disease.

Methods and Results—

Ten Sprague-Dawley rats were given serotonin injections subcutaneously once daily for 3 months; controls were given saline. A long-lasting hyperserotoninemia with a >10-fold increase in both platelet-poor plasma and dialysate from the femoral muscles appeared. The animals developed clinical signs such as flushing and loose stools. After 3 months, 6 of 10 rats given serotonin had pathological echocardiographs. Two animals had a combination of aortic and pulmonary valve insufficiency, 1 had isolated aortic valve insufficiency, and 3 had isolated pulmonary valve insufficiency. Histopathological examination revealed shortened and thickened aortic cusps and carcinoidlike plaques characterized by a collection of myofibroblasts within an extracellular matrix of collagen ground substance. Immunostaining for Ki-67 demonstrated an increased number of proliferating subendocardial cells. In the control group, no pathological changes were seen. With the use of reverse-transcription polymerase chain reaction, normal rat aortic cusps were shown to express mRNA for serotonin receptors 5-HT
1A
, 5-HT
2A
, and 5-HT
2B
and the serotonin transporter 5-HTT.

Conclusions—

For the first time, long-term serotonin administration was performed in rats. Morphological and echocardiographic changes similar to those seen in human carcinoid heart disease developed. This study demonstrates that serotonin most likely is involved in the pathogenesis of carcinoid heart disease.
Renin-Aldosterone Paradox and Perturbed Blood Volume Regulation Underlying Postural Tachycardia Syndrome
Authors: Raj Satish R. , Biaggioni Italo , Yamhure Paula C. , Black Bonnie K. , Paranjape Sachin Y. , Byrne Daniel W. , Robertson David
Published: March 2005

Background—

Patients with postural tachycardia syndrome (POTS) experience considerable disability, but in most, the pathophysiology remains obscure. Plasma volume disturbances have been implicated in some patients. We prospectively tested the hypothesis that patients with POTS are hypovolemic compared with healthy controls and explored the role of plasma renin activity and aldosterone in the regulation of plasma volume.

Methods and Results—

Patients with POTS (n=15) and healthy controls (n=14) underwent investigation. Heart rate (HR), blood pressure (BP), plasma renin activity, and aldosterone were measured with patients both supine and upright. Blood volumes were measured with
131
I-labeled albumin and hematocrit. Patients with POTS had a higher orthostatic increase in HR than controls (51±18 versus 16±10 bpm,
P
<0.001). Patients with POTS had a greater deficit in plasma volume (334±187 versus 10±250 mL,
P
<0.001), red blood cell volume (356±128 versus 218±140 mL,
P
=0.010), and total blood volume (689±270 versus 228±353 mL,
P
<0.001) than controls. Despite the lower plasma volume in patients with POTS, there was not a compensatory increase in plasma renin activity (0.79±0.58 versus 0.79±0.74 ng · mL
−1
· h
−1
,
P
=0.996). There was a paradoxically low level of aldosterone in the patients with POTS (190±140 pmol/L versus 380±230 pmol/L;
P
=0.017).

Conclusions—

Patients with POTS have paradoxically unchanged plasma renin activity and low aldosterone given their marked reduction in plasma volume. These patients also have a significant red blood cell volume deficit, which is regulated by the renal hormone erythropoietin. These abnormalities suggest that the kidney may play a key role in the pathophysiology of POTS.
Adenovirus-Mediated Expression of β-Adrenergic Receptor Kinase C-Terminus Reduces Intimal Hyperplasia and Luminal Stenosis of Arteriovenous Polytetrafluoroethylene Grafts in Pigs
Authors: Luo Zhengyu , Akita Geoffrey Y. , Date Taro , Treleaven Christopher , Vincent Karen A. , Woodcock Denise , Cheng Seng H. , Gregory Richard J. , Jiang Canwen
Published: March 2005

Background—

Hemodialysis vascular access dysfunction is the single most important cause of morbidity in kidney hemodialysis patients. Failure of an arteriovenous polytetrafluoroethylene (PTFE) graft, the most common form of hemodialysis access, is primarily due to intimal hyperplasia and thrombosis at the venous anastomosis.

Methods and Results—

This study was aimed at evaluating the efficacy and safety of an adenoviral vector (Ad2/βARKct) encoding the carboxyl terminus of β-adrenergic receptor kinase (βARKct) in a pig model of arteriovenous PTFE graft failure. Transduction of the external jugular vein with Ad2/βARKct (5E9, 5E10, or 5E11 particles per vein) did not result in systemic toxicity, as measured by clinical and pathological assessments. Ad2/βARKct significantly reduced neointimal hyperplasia in the graft/vein anastomosis. It also improved the graft patency rate and angiographic score, as measured histologically and angiographically, compared with vehicle or empty viral vector controls.

Conclusions—

Our results suggest that local administration of adenoviral vectors encoding βARKct into the jugular vein represents a viable strategy to treat AV graft hemodialysis vascular access failure.
Serum Uric Acid and Target Organ Damage in Primary Hypertension
Authors: Viazzi Francesca , Parodi Denise , Leoncini Giovanna , Parodi Angelica , Falqui Valeria , Ratto Elena , Vettoretti Simone , Bezante Gian Paolo , Del Sette Massimo , Deferrari Giacomo , Pontremoli Roberto
Published: March 2005

The role of serum uric acid as an independent risk factor for cardiovascular and renal morbidity is controversial. A better understanding of its relationship with preclinical organ damage may help clarify the mechanism(s) implicated in the development of early cardiovascular disease. We evaluated the association between uric acid and the presence and degree of target organ damage in 425 (265 males, 160 females) middle-aged, untreated patients with essential hypertension. Left ventricular mass index and carotid intima-media thickness were assessed by ultrasound scan. Albuminuria was measured as the albumin to creatinine ratio in 3 nonconsecutive first morning urine samples. Overall, patients with target organ damage had significantly higher levels of serum uric acid as compared with those without it (presence versus absence of left ventricular hypertrophy,
P
=0.04; carotid abnormalities,
P
<0.05; microalbuminuria,
P
<0.004; and at least 1 versus no organ damage,
P
<0.03). In women, the occurrence and severity of each target organ damage we examined increased progressively from the lower to the upper serum uric acid tertiles (
P
<0.01). After adjustment for body mass index, age, creatinine clearance, and high-density lipoprotein cholesterol, each standard deviation increase in serum uric acid entailed a 75% higher risk of having cardiac hypertrophy and a 2-times greater risk of having carotid abnormalities. These results support the role of serum uric acid as an independent, modifiable marker of cardiovascular damage.
Intermediate Realms of Law: Corporate Groups and Rulers in Medieval India
Authors: Davis Donald
Published: March 2005

The laws of corporate groups such as merchants, traders, religious specialists, soldiers, etc. are examined on the basis of both the normative Hindu legal texts and epigraphical sources from various parts of India. Other recent studies arguing that medieval India experienced an increasing integration of polity and society over larger core areas are corroborated from the perspective of law and legal institutions. Methodological and theoretical propositions are also raised to argue that Hindu legal texts, known as Dharmaśastra, are essential to any history of law and society in medieval India, but only when their nature and purpose are properly understood. Les lois des corps sociaux, comme les marchands, les négociants, les experts religieux, ou les soldats, sont examinées d'après les textes normatifs du droit hindou ancien, et aussi selon des sources épigraphiques venant des diverses régions de l'Inde. D'autres études récentes qui affirment que l'Inde médiévale a connu une intégration croissante entre régime et société dans des domaines centralisés plus étendus sont ici con firmées par le biais du droit et des institutions légales. Des arguments méthodologiques et théoriques sont aussi soulevés pour soutenir que les textes légals hindous, connus sous le nom de Dharmaśastra, sont fondamentals à toute histoire du droit et de la société dans l'Inde médiévale, mais seulement quand leur nature et leur objet sont bien compris.
Do the Determinants of Promotion Differ for White Men Versus Women and Minorities? An Exploration of Intersectionalism Through Sponsored and Contest Mobility Processes
Authors: Smith Ryan A.
Published: March 2005

This article uses survey data to address two previously unanswered questions: What explains the gap in promotion between women and minorities relative to White men? and Are the processes that determine promotions for White men the same for minorities and women? Overall, race and gender intersect to produce unique promotion outcomes for all groups. Specifically, promotion gaps between White men and their female and minority counterparts are largely a function of group differences in performance indicators and work commitment. Also, relative to White men, before receiving a promotion, Black men must work longer periods of time after leaving school and Latinos must accrue more years with their current employer. Finally, the processes that lead to promotion do not differ between White men and White women, but relative to White men, Black women and Latinas must have more prior job-specific experience and more overall work experience before receiving a promotion—allelse equal.
Race and Job Dismissal
Authors: Wilson George
Published: March 2005

This study combines data from 8 years (1991 to 1997 and 1999) of the Panel Study of Income Dynamics to assess predictions from the compositional and particularistic perspectives concerning the determinants of job dismissal among African American and White males during 3 years of the early work career. The findings from logistic regression analyses provide most support for the particularistic perspective. Specifically, dismissal for African Americans, relative to Whites, is widespread. Compared to Whites, African Americans are susceptible to dismissal across categories of traditional stratification-based causal factors—namely, human capital credentials (e.g., education, job absences), background socioeconomic status, and job/labor market characteristics (e.g., union status, economic sector, industry). In addition, analyses indicate that particularism as a determinant of dismissal is more pronounced in working-class than middle-class occupations.
Race and Workplace Integration
Authors: Stainback Kevin , Robinson Corre L. , Tomaskovic-Devey Donald
Published: March 2005

The Civil Rights Act of 1964 stands as one of the greatest achievements in U.S. history. Although the law made discrimination illegal, its effectiveness, especially Title VII covering the employment domain, remains highly contested. The authors argue that legal shifts produce workplace racial integration only to the extent that there are additional political pressures on firms to desegregate. They examine fluctuating national political pressure to enforce equal employment opportunity law and affirmative action mandates as key influences on the pace of workplace racial desegregation and explore trajectories of Black-White integration in U.S. workplaces since 1966. Their results show that although federal and state equal employment opportunity pressures had initial successes in reducing racial segregation in workplaces, little progress has been made since the early 1980s. They conclude that racial desegregation is an ongoing politically mediated process, not a natural or inevitable outcome of early civil rights movement victories.
Black-White Differences in Occupational Prestige
Authors: Conley Dalton , Yeung W. Jean
Published: March 2005

This article examines whether differences in parental occupational prestige mediate or moderate race differences in four indicators of child development—reading scores, math scores, Behavior Problems Index, and health status—using data from the Panel Study of Income Dynamics Child Development Supplement. The authors find that although for behavioral problems there is no impact of parental occupational prestige, for reading, math, and health there are significant academic returns to parental occupational prestige, but only for White families. The authors hypothesize that this racially distinct dynamic may be a result of ongoing discrimination in the labor market, thereby reducing the association between ability (job and parenting) and prestige; or it may be a result of the difficulty of Blacks to translate occupational prestige gains into other benefits as a result of discrimination outside the labor market; or finally, it may be the result of a generational lag between occupational status and parenting practices.
Statistical Discrimination in Employment
Authors: Baumle Amanda K. , Fossett Mark
Published: March 2005

The phenomenon of statistical discrimination may take on increasing importance in the future as “traditional” prejudice-based discrimination slowly fades. This article considers how statistical discrimination compares with perspectives on discrimination in sociology, economics, and law. Statistical discrimination fits well with mainstream perspectives in economics, suggesting it is likely to be a common practice and endure even as racial prejudice declines. Statistical discrimination is less central in sociological perspectives on discrimination because they tend to focus on prejudice-based discrimination, ethnic conflict and stratification, and how ethnic group interests are embedded in social institutions. In the area of law, statistical discrimination is treated differently in different situations—sometimes allowable, other times prohibited. The authors note some characteristics of statistical discrimination that set it apart from other forms of discrimination and consider whether standard policies aimed at reducing racial discrimination in employment are likely to be effective in combating statistical discrimination.
Race, Ethnicity, and Wage Inequality Among Women
Authors: Browne Irene , Askew Rachel
Published: March 2005

This article examines trends in Black-White and Latina-White wage inequality among women from 1989 to 2003. Building on Bound and Dresser’s conclusion that the Black-White earnings gap widened in the 1980s, the authors find that in the 1990s and early 21st century, the Black-White earnings differential remained fairly constant and that education plays a pivotal role in the Latina-White earnings gap. In every year, Latinas show larger wage differences with Whites than Black women; however, when controlling education and experience, Black women see the greatest earnings disadvantage in comparison to White women. Although the Latina-White earnings differential stood at parity in 1989, a wage gap opened and steadily increased through the 1990s and into the 21st century. This trend was not the result of an influx of Latinas with few years of schooling entering the labor force; the largest opening in relative wages occurred among Latinas with a college degree.
The Church at the Centre of the City
Authors: Ballard Paul
Published: March 2005

The Church has always been in the city centre. At this time this means having to adjust to the latest process of rapid renovation that is overtaking the central business district of many of the older industrial cities and towns. The city centre has always been the hub of power and commerce. It is now also the focus for consumerism and leisure in the twenty-four hour city. Yet little or no attention has been given to debate this challenge to the Church’s ministry and mission. This is briefly described and discussed theologically and some models for ministry are offered.