bluuebunny/crossref_metadata_2025 huggingface dataset:
Seasonally hibernating phenotype assessed through transcript screening
Authors: Williams Daryl R. , Epperson L. Elaine , Li Weizhong , Hughes Margaret A. , Taylor Ruth , Rogers Jane , Martin Sandra L. , Cossins Andrew R. , Gracey Andrew Y.
Published: October 2005

Hibernation is a seasonally entrained and profound phenotypic transition to conserve energy in winter. It involves significant biochemical reprogramming, although our understanding of the underpinning molecular events is fragmentary and selective. We have conducted a large-scale gene expression screen of the golden-mantled ground squirrel, Spermophilus lateralis, to identify transcriptional responses associated specifically with the summer-winter transition and the torpid-arousal transition in winter. We used 112 cDNA microarrays comprising 12,288 probes that cover at least 5,109 genes. In liver, the profiles of torpid and active states in the winter were almost identical, although we identified 102 cDNAs that were differentially expressed between winter and summer, 90% of which were downregulated in the winter states. By contrast, in cardiac tissue, 59 and 115 cDNAs were elevated in interbout arousal and torpor, respectively, relative to the summer active condition, but only 7 were common to both winter states, and during arousal none was downregulated. In brain, 78 cDNAs were found to change in winter, 44 of which were upregulated. Thus transcriptional changes associated with hibernation are qualitatively modest and, since these changes are generally less than twofold, also quantitatively modest. Unbiased Gene Ontology profiling of the transcripts suggests a winter switch to β-oxidation of lipids in liver and heart, a reduction in metabolism of toxic compounds and the urea cycle in liver, and downregulated electron transport in the brain. We identified just one strongly winter-induced transcript common to all tissues, namely an RNA-binding protein, RBM3. This analysis clearly differentiates responses of the principal tissues, identifies a large number of new genes undergoing regulation, and broadens our understanding of affected cellular processes that, in part, account for the winter-adaptive hibernating phenotype.
Differential Expression of Chemokines, Risk of Stable Coronary Heart Disease, and Correlation with Established Cardiovascular Risk Markers
Authors: Rothenbacher Dietrich , Müller-Scholze Sylvia , Herder Christian , Koenig Wolfgang , Kolb Hubert
Published: October 2005

Objective—

We investigated the association of several chemokines with the risk of stable coronary heart disease (CHD) in a large case-control study after adjustment for other established risk factors. Furthermore, we analyzed their correlation with various acute-phase proteins, inflammation-associated cytokines, and an adhesion molecule.

Methods and Results—

We included 312 patients aged 40 to 68 years with angiographically confirmed and stable CHD and 472 age- and gender-matched controls in this study. The main outcome measure was the odds ratio (OR) for CHD associated with increased levels of interferon (INF)-inducible protein of 10 kd (IP-10), interleukin (IL)-8, regulated on activation normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammation protein 1α (MIP-1α), or eotaxin determined by rigidly evaluated sandwich ELISAs. Serum levels of IP-10 and IL-8 were higher, and serum levels of RANTES were lower in CHD patients when compared with age- and gender-matched controls. In addition, values in the second and top tertile of IP-10 and IL-8 were associated with an increased OR for CHD when compared with values in the bottom tertile [OR for IP-10 (top tertile) was 2.62 (95% CI, 1.79 to 3.85) in the age- and gender-adjusted model and 1.93 (95% CI, 1.23 to 3.04) in the fully adjusted model, and for IL-8, the OR was 1.77 (95% CI, 1.20 to 2.59) and 1.53 (95% CI, 0.98 to 2.39), respectively]; increased RANTES values were associated with a lower OR for CHD [OR, 0.67 (95% CI, 0.47 to 0.96) and 0.61 (95% CI, 0.40 to 0.94)]. Furthermore, positive correlations of IP-10 and IL-8 with several acute-phase proteins or inflammation-associated cytokines were evident, and positive correlations for IP-10 plasma viscosity and intercellular adhesion molecule 1 were also present.

Conclusions—

The current study suggests that there may be no universal upregulation of chemokines in CHD-associated inflammation but different upregulation of IP-10 and IL-8 versus downregulation of RANTES; there was no clear disease association for MCP-1, MIP-1α, or eotaxin.
Curcumin Inhibits Platelet-Derived Growth Factor–Stimulated Vascular Smooth Muscle Cell Function and Injury-Induced Neointima Formation
Authors: Yang Xiaoping , Thomas D. Paul , Zhang Xiaochun , Culver Bruce W. , Alexander Brenda M. , Murdoch William J. , Rao Mysore N.A. , Tulis David A. , Ren Jun , Sreejayan Nair
Published: October 2005

Objective—

Vascular smooth muscle cell (VSMC) migration, proliferation, and collagen synthesis are key events involved in the pathogenesis of cardiovascular disease. Growth factors, such as platelet-derived growth factor (PDGF) and fibroblast growth factor, released during vascular injury plays a pivotal role in regulating these events. Curcumin (diferuloyl methane), a major component of the spice turmeric (
Curcuma longa
), has been shown recently to have beneficial effects in chronic conditions, such as inflammation, cancer, cystic fibrosis, and Alzheimer’s disease. The objective of this study was to investigate the ability of curcumin to inhibit PDGF-stimulated migration, proliferation, and collagen synthesis in cultured VSMCs and neointima formation after carotid artery injury in rats.

Methods and Results—

Curcumin (1 to 25 μM) produced a concentration-dependent inhibition of PDGF-elicited VSMC migration, proliferation, and collagen synthesis assessed by chemotaxis, [
3
H]thymidine incorporation, and [
3
H]-
l
-proline incorporation, respectively. Curcumin blocked PDGF-induced VSMC actin-cytoskeleton reorganization, attenuated PDGF signal transduction, and inhibited the binding of PDGF to its receptors. Carotid artery neointima formation was significantly attenuated by perivascular curcumin compared with vehicle controls 14 days after injury, characterized by reduced DNA synthesis, collagen synthesis, and PDGF receptor phosphorylation.

Conclusions—

These data suggest that curcumin is a potent inhibitor of key PDGF-stimulated VSMC functions and may play a critical role in regulating these events after vascular injury.
Genetic Variations in the Tissue Factor Gene Are Associated With Clinical Outcome in Acute Coronary Syndrome and Expression Levels in Human Monocytes
Authors: Mälarstig Anders , Tenno Taavo , Johnston Nina , Lagerqvist Bo , Axelsson Tomas , Syvänen Ann-Christine , Wallentin Lars , Siegbahn Agneta
Published: October 2005

Objective—

Tissue factor (TF) has, among other factors, a prominent role in acute coronary syndrome (ACS). Our goal was to investigate whether single nucleotide polymorphisms (SNP) in the TF gene (F3) are associated with plasma TF, risk, and outcome in patients with ACS. Moreover, we wanted to investigate the impact of associated TF SNPs on mRNA production in human monocytes.

Methods and Results—

In 725 patients with ACS [Fragmin and Fast Revascularization during Instability in Coronary Artery Disease II (FRISC-II) study] and 376 controls, 13 SNPs were genotyped and plasma TF measured. Thereafter, the 5466 A>G and the −1812 C>T were genotyped among all of the FRISC-II participants (n=3143) and assessed concerning clinical outcome. Associated SNPs were genotyped in 92 healthy blood donors for comparison of TF activity and TF mRNA expression. None of the SNPs were associated with patient/control status. The 5466 A>G SNP was associated with cardiovascular death (odds ratio, 1.8;
P
=0.025). The CG haplotype by −1812 C>T and 5466 A>G was associated with a 3-fold increased risk of death (
P
<0.001). TF mRNA and basal TF activity was significantly lower among 5466 AG carriers, whereas the increase in monocyte TF activity on lipopolysaccharide stimulation was significantly stronger (
P
=0.04).

Conclusions—

The 5466 AG genotype is a novel predictor of cardiovascular death in ACS and may act through a high TF response.
Dynein–Dynactin Complex Mediates Protein Kinase A–Dependent Clustering of Weibel-Palade Bodies in Endothelial Cells
Authors: Rondaij Mariska G. , Bierings Ruben , Kragt Astrid , Gijzen Karina A. , Sellink Erica , van Mourik Jan A. , Fernandez-Borja Mar , Voorberg Jan
Published: October 2005

Objective—

Perinuclear clustering is observed for several different organelles and illustrates dynamic regulation of the secretory pathway and organelle distribution. Previously, we observed that a subset of Weibel-Palade bodies (WPBs), endothelial cell–specific storage organelles, undergo centralization when endothelial cells are stimulated with cAMP-raising agonists of von Willebrand factor (vWF) secretion. In this study, we investigated this phenomenon of WPB clustering in more detail.

Methods and Results—

Our results demonstrate that the clustered WPBs are localized at the microtubule organizing center and that cluster formation depends on an intact microtubule network. Disruption of the microtubules by nocodazole completely abolished clustering, whereas treatment with the actin depolymerizing compound cytochalasin B had no effect on WPB clustering. Interfering with the dynein–dynactin interaction by overexpression of the p50 dynamitin subunit or the CC1 domain of the p150
glued
subunit of the dynactin complex completely inhibited perinuclear clustering of WPBs, suggesting that dynein activity mediates this process. Furthermore, we found that inhibition of dephosphorylation resulted in an increase in clustering, whereas inhibition of protein kinase A (PKA) markedly reduced WPB clustering.

Conclusions—

These results suggest that perinuclear clustering of WPBs involves PKA-dependent regulation of the dynein–dynactin complex. Endothelial cell stimulation with epinephrine results in retrograde movement of a subset of WPBs to the microtubule organizing center. This minus-end directed transport requires an intact microtubular network and is mediated by the motor protein dynein. Together, our results suggest that epinephrine-induced clustering of WPBs involves PKA-dependent regulation of the dynein–dynactin complex.
Reticulocyte 15-Lipoxygenase-I Is Important in Acetylcholine-Induced Endothelium-Dependent Vasorelaxation in Rabbit Aorta
Authors: Tang Xin , Holmes Blythe B. , Nithipatikom Kasem , Hillard Cecilia J. , Kuhn Hartmut , Campbell William B.
Published: October 2005

Objective—

Aortic 15-lipoxygenase (15-LO) metabolizes arachidonic acid (AA) to 15-hydroperoxyeicosatetraenoic acid, which is then converted to the vasodilators 15-hydroxy-11,12-epoxyeicosatrienoic acid and 11,12,15-trihydroxyeicosatrienoic acid. These metabolites contribute to endothelium-dependent relaxations of rabbit aorta to AA and acetylcholine. We investigated the identity of rabbit aortic 15-LO and studied its importance in the regulation of vascular tone.

Methods and Results—

RT-PCR using 12-lipoxygenase/15-LO specific primers resulted in a 572-bp product with a sequence identical to 15-LO-I from rabbit aorta. A RT-PCR/restriction digest strategy excluded expression of 12-lipoxygenase. Immunoblotting revealed 15-LO-I expression in rabbit endothelial and smooth muscle cells. Aortic homogenates and cytosolic fractions metabolize AA to 15(S)-hydroxyeicosatetraenoic acid and linoleic acid to 13(S)-hydroxyoctadecadienoic acid. This activity was blocked by LO inhibitors. The kinetic characteristics (Michaelis constant of aortic 15-LO is 2.2±0.3 μmol/L for AA and 23.5±3.3 μmol/L for linoleic acid) of aortic 15-LO were similar to those of the purified 15-LO-I. An antisense oligonucleotide inhibited 15-LO-I expression in rabbit aorta. Indomethacin and nitro-
l
-arginine-resistant relaxations to acetylcholine were inhibited by 15-LO-I antisense oligonucleotide but not by the scrambled oligonucleotide.

Conclusions—

15-LO-I is expressed in rabbit aortic endothelium and is important in endothelium-dependent regulation of vascular tone.
Fatty Acids Cause Alterations of Human Arterial Smooth Muscle Cell Proteoglycans That Increase the Affinity for Low-Density Lipoprotein
Authors: Rodríguez-Lee Mariam , Östergren-Lundén Gunnel , Wallin Boel , Moses Jonatan , Bondjers Göran , Camejo Germán
Published: October 2005

Objective—

The dyslipidemia of insulin resistance, with high levels of albumin-bound fatty acids, is a strong cardiovascular disease risk. Human arterial smooth muscle cell (hASMC) matrix proteoglycans (PGs) contribute to the retention of apoB lipoproteins in the intima, a possible key step in atherogenesis. We investigated the effects of high NEFA levels on the PGs secreted by hASMCs and whether these effects might alter the PG affinity for low-density lipoprotein.

Methods and Results—

hASMC exposed for 72 hours to high concentrations (800 μmol/L) of linoleate (LO) or palmitate upregulated the core protein mRNAs of the major PGs, as measured by quantitative PCR. Insulin (1 nmol/L) and the PPARγ agonist rosiglitazone (10 μmol/L) blocked these effects. In addition, high LO increased the mRNA levels of enzymes required for glycosaminoglycan (GAG) synthesis. Exposure to NEFA increased the chondroitin sulfate:heparan sulfate ratio and the negative charge of the PGs. Because of these changes, the GAGs secreted by LO-treated cells had a higher affinity for human low-density lipoprotein than GAGs from control cells. Insulin and rosiglitazone inhibited this increase in affinity.

Conclusions—

The response of hASMC to NEFA could induce extracellular matrix alterations favoring apoB lipoprotein deposition and atherogenesis.
Uric Acid Is as Important as Proteinuria in Identifying Fetal Risk in Women With Gestational Hypertension
Authors: Roberts James M. , Bodnar Lisa M. , Lain Kristine Y. , Hubel Carl A. , Markovic Nina , Ness Roberta B. , Powers Robert W.
Published: October 2005

Gestational hypertension is differentiated into higher and lower risk by the presence or absence of proteinuria. We asked if hyperuricemia, a common finding in pregnancy hypertension, might also be an indicator of increased risk. We examined fetal outcome data from 972 pregnancies collected from 1997 to 2002 in a nested case-control study. Participants were nulliparous with no known medical complications. The frequency of preterm birth, the duration of pregnancy, frequency of small-for-gestational-age infants, and birth weight centile were determined for pregnancies assigned to 8 categories by the presence or absence of combinations of hypertension, hyperuricemia, and proteinuria. In women with gestational hypertension, hyperuricemia was associated with shorter gestations and smaller birth weight centiles and increased risk of preterm birth and small-for-gestational-age infants. Hyperuricemia increased the risk of these outcomes in the presence or absence of proteinuria. Risk was also increased in a small group of women with hyperuricemia and proteinuria without hypertension. Women with only hypertension and hyperuricemia have similar or greater risk as women with only hypertension and proteinuria. Those with hypertension, proteinuria, and hyperuricemia have greater risk than those with hypertension and proteinuria alone. The risk of these outcomes increased with increasing uric acid. Hyperuricemia is at least as effective as proteinuria at identifying gestational hypertensive pregnancies at increased risk. Uric acid should be reexamined for clinical and research utility.
Hydrolysis of Angiotensin Peptides by Human Angiotensin I–Converting Enzyme and the Resensitization of B
2
Kinin Receptors
Authors: Chen Zhenlong , Tan Fulong , Erdös Ervin G. , Deddish Peter A.
Published: October 2005

We measured the cleavage of angiotensin I (Ang I) metabolites by angiotensin I–converting enzyme (ACE) in cultured cells and examined how they augment actions of bradykinin B
2
receptor agonists. Monolayers of Chinese hamster ovary cells transfected to stably express human ACE and bradykinin B
2
receptors coupled to green fluorescent protein (B
2
GFP) or to express only coupled B
2
GFP receptors. We used 2 ACE-resistant bradykinin analogues to activate the B
2
receptors. We used high-performance liquid chromatography to analyze the peptides cleaved by ACE on cell monolayers and found that Ang 1-9 was hydrolyzed 18× slower than Ang I and &30% slower than Ang 1-7. Ang 1-7 was cleaved to Ang 1-5. Although μmol/L concentrations of slowly cleaved substrates Ang 1-7 and Ang 1-9 inhibit ACE, they resensitize the desensitized B
2
GFP receptors in nmol/L concentration, independent of ACE inhibition. This is reflected by release of arachidonic acid through a mechanism involving cross-talk between ACE and B
2
receptors. When ACE was not expressed, the Ang 1-9, Ang 1-7 peptides were inactive. Inhibitors of protein kinase C-α, phosphatases and Tyr-kinase blocked this resensitization activity, but not basal B
2
activation by bradykinin. Ang 1-9 and Ang 1-7 enhance bradykinin activity, probably by acting as endogenous allosteric modifiers of the ACE and B
2
receptor complex. Consequently, when ACE inhibitors block conversion of Ang I, other enzymes can still release Ang I metabolites to enhance the efficacy of ACE inhibitors.
Thrombophilia Is Significantly Associated With Severe Preeclampsia
Authors: Mello Giorgio , Parretti Elena , Marozio Luca , Pizzi Cristina , Lojacono Andrea , Frusca Tiziana , Facchinetti Fabio , Benedetto Chiara
Published: October 2005

The role of thrombophilia in the pathogenesis of preeclampsia is controversial. The aim of this case-controlled study was to determine whether thrombophilia increases the risk of preeclampsia or interferes with its clinical course. A total of 808 white patients who developed preeclampsia (cases) and 808 women with previous uneventful pregnancies (controls) matched for age and parity were evaluated for inherited and acquired thrombophilia (factor V Leiden; factor II G20210A; methylenetetrahydrofolate reductase C677T; protein S, protein C, and antithrombin III deficiency; anticardiolipin antibodies; lupus anticoagulant; and hyperhomocysteinemia). Odds ratios (ORs) with 95% confidence intervals (CIs) for risk of being carriers of thrombophilia in cases compared with controls and for risk of maternal life-threatening complications and adverse perinatal outcomes in preeclamptic patients with or without thrombophilia were calculated. Women with severe preeclampsia (406 cases) had a higher risk (OR, 4.9; 95% CI, 3.5 to 6.9) of being carriers of either an inherited or acquired thrombophilic factor, except for protein S, protein C, and antithrombin deficiency. In women with mild preeclampsia (402 cases), only prothrombin and homozygous methylenetetrahydrofolate reductase gene mutations were significantly more prevalent than in the controls. Thrombophilic patients with severe preeclampsia are at increased risk of acute renal failure (OR, 1.8; 95% CI, 1.5 to 2.2), disseminated intravascular coagulation (OR, 2.7; 95% CI, 1.1 to 6.4), abruptio placentae (OR, 2.6; 95% CI, 1.2 to 6.0) and perinatal mortality (OR, 1.7; 95% CI, 1.5 to 2.2) compared with nonthrombophilic preeclamptic patients. Our study demonstrates a significant association between maternal thrombophilia and severe preeclampsia in white women. Thrombophilia also augments the risk of life-threatening maternal complications and adverse perinatal outcomes in preeclamptic patients.
Effects of Salt Sensitivity on Neural Cardiovascular Regulation in Essential Hypertension
Authors: Coruzzi Paolo , Parati Gianfranco , Brambilla Lorenzo , Brambilla Valerio , Gualerzi Massimo , Novarini Almerico , Castiglioni Paolo , Di Rienzo Marco
Published: October 2005

Salt-sensitive hypertensive subjects, as defined by conventional categorical classification, exhibit alterations of autonomic cardiovascular control. The aim of our study was to explore whether, in hypertensive subjects, the degree of autonomic dysfunction and the level of salt sensitivity are correlated even when the latter is only mildly elevated and displays under-threshold values. Salt sensitivity of 34 essential hypertensive subjects was assessed on a continuous basis by the salt sensitivity index after low- and high-sodium diet. Beat-by-beat finger blood pressure was recorded after each diet period. Autonomic cardiovascular control was evaluated by spectral analysis of blood pressure and pulse interval and by assessment of spontaneous baroreflex sensitivity (sequence technique). Salt sensitivity and baroreflex sensitivity showed a negative relationship during low and high sodium intake, starting from low values of the salt sensitivity index. All spectral indexes of pulse interval, except the ratio between low- and high-frequency powers, were inversely related to salt sensitivity index after high sodium intake. In subjects with lower salt sensitivity, baroreflex sensitivity and pulse interval power in the high-frequency band were higher after high sodium intake than after low sodium intake. In contrast, subjects with a higher salt sensitivity index showed lower values of baroreflex sensitivity and pulse interval power in the high-frequency band, uninfluenced by salt intake. Our results provide the first demonstration of an impairment of parasympathetic cardiac control in parallel with the increase in the degree of salt sensitivity, also in subjects who were not ranked as salt-sensitive by the conventional categorical classification.
Nitric Oxide Regulates Transforming Growth Factor-β Signaling in Endothelial Cells
Authors: Saura Marta , Zaragoza Carlos , Herranz Beatrice , Griera Mercedes , Diez-Marqués Luisa , Rodriguez-Puyol Diego , Rodriguez-Puyol Manuel
Published: October 2005

Many forms of vascular disease are characterized by increased transforming growth factor (TGF)-β
1
expression and endothelial dysfunction. Smad proteins are a key step in TGF-β–initiated signal transduction. We hypothesized that NO may regulate endothelial TGF-β–dependent gene expression. We show that NO inhibits TGF-β/Smad–regulated gene transactivation in a cGMP-dependent manner. NO effects were mimicked by a soluble analogue of cGMP. Inhibition of cGMP-dependent protein kinase 1 (PKG-1) or overexpression of dominant-negative PKG-1α suppressed NO/cGMP inhibition of TGF-β–induced gene expression. Inversely, overexpression of PKG-1α catalytic subunit blocked TGF-β–induced gene transactivation. Furthermore NO delayed and reduced phosphorylated Smad2/3 nuclear translocation, an effect mediated by PKG-1, whereas
N
G
-nitro-
l
-arginine methyl ester augmented Smad phosphorylation and gene expression in response to TGF-β. Aortas from endothelial NO synthase–deficient mice showed enhanced basal TGF-β
1
and collagen type I expression; endothelial cells from these animals showed increased Smad phosphorylation and transcriptional activity. Proteasome inhibitors prevented the inhibitory effect of NO on TGF-β signaling. NO reduced the metabolic life of ectopically expressed Smad2 and enhanced its ubiquitination. Taken together, these results suggest that the endothelial NO/cGMP/PKG pathway interferes with TGF-β/Smad2 signaling by directing the proteasomal degradation of activated Smad.
Evaluation of the Paraoxonases as Candidate Genes for Stroke
Authors: Ranade Koustubh , Kirchgessner Todd G. , Iakoubova Olga A. , Devlin James J. , DelMonte Terrye , Vishnupad Priya , Hui Lester , Tsuchihashi Zenta , Sacks Frank M. , Sabatine Marc S. , Braunwald Eugene , White Thomas J. , Shaw Peter M. , Dracopoli Nicholas C.
Published: October 2005

Background and Purpose—

The paraoxonases are involved in protecting low-density lipoprotein (LDL) from lipid oxidation. Paraoxonase 1 (PON1) was implicated in susceptibility to coronary artery disease and stroke in previous studies. We evaluated, in a comprehensive way, all 3 paraoxonase genes for association with stroke observed in the Cholesterol and Recurrent Events (CARE) trial.

Methods—

Over 2500 subjects enrolled in the CARE trial were genotyped for 14 single nucleotide polymorphisms, including 7 newly identified in this study, in the 3 paraoxonase genes.

Results—

A glutamine (Gln)/arginine (Arg) polymorphism at amino acid residue 192 in PON1 was significantly associated with stroke (
P
=0.003 in multivariate analysis, including age, sex, LDL, hypertension, diabetes, smoking, and pravastatin treatment as covariates). The odds ratios were 2.28 (95% CI, 1.38 to 3.79) for Gln/Arg heterozygotes and 2.47 (95% CI, 1.18 to 5.19) for Arg/Arg homozygotes compared with Gln/Gln homozygotes. These results are consistent with 2 of 3 other published studies. In combined analysis of all 4 studies, the association between Gln192Arg SNP and stroke was highly significant (χ
2
8df
=45.58,
P
<0.000001). Sequence analysis of the PON1 gene from seventy stroke cases revealed a novel nonsense mutation at codon 32 in one stroke case, which was not detected in over 2500 unaffected individuals. Polymorphisms in the PON2 and PON3 genes were not associated with stroke.

Conclusions—

These results suggest that Gln192Arg genotype is an important risk factor for stroke.
Heritability of the Function and Structure of the Arterial Wall
Authors: Sayed-Tabatabaei F.A. , van Rijn M.J.E. , Schut A.F.C. , Aulchenko Y.S. , Croes E.A. , Zillikens M.C. , Pols H.A.P. , Witteman J.C.M. , Oostra B.A. , van Duijn C.M.
Published: October 2005

Background and Purpose—

Using 930 individuals connected in a single pedigree from an isolated population, participants of the Erasmus Rucphen Family (ERF) study, we investigated the heritability of carotid–femoral pulse wave velocity (PWV), carotid intima media thickness (IMT), and carotid plaque score.

Methods—

PWV was measured between the carotid and femoral arteries as an indicator of aortic stiffness. Common carotid IMT and plaque score, quantifying alterations in arterial wall structure, were measured by ultrasonography.

Results—

All 3 traits were significantly associated with classic cardiovascular risk factors. Age- and gender-adjusted heritability estimates were 0.36 for PWV, 0.41 for carotid IMT, and 0.28 for plaque score. After adjustment for appropriate risk factors, the heritabilities were 0.26, 0.35, and 0.21 for PWV, IMT, and plaque score, respectively. All heritability estimates were statistically significant (
P
<0.001). Taking into account different proportions of variance associated with covariates for each trait, genetic factors explained &12% of the total variability for each of the phenotypes.

Conclusions—

To our knowledge, this is the first report on the heritability of PWV. The heritability estimates of IMT and plaque score were similar to those in previous reports. We conclude that genetic factors significantly contribute to arterial structure and function in this isolated population, presenting the opportunity to locate susceptibility genes related to cardiovascular disorders.
Low-Grade Carotid Stenosis
Authors: Wasserman Bruce A. , Wityk Robert J. , Trout Hugh H. , Virmani Renu
Published: October 2005

Background and Purpose—

The management of carotid atherosclerosis is well-established for symptomatic stenosis above 69%, but the optimal approach for managing lower degrees of narrowing remains uncertain. Because the risk of stroke increases with higher grades of stenosis, we are inclined to consider low-grade disease to be low risk. This approach, however, does not take into account other factors such as plaque size or composition. Plaque may progress to a substantial size before it demonstrates significant stenosis by angiography. We know that low-grade disease can result in cerebrovascular ischemic events, but predicting vulnerable lesions has not been possible by relying on stenosis alone.

Summary of Review—

An understanding of the clinical behavior of plaque causing little to no narrowing is now possible with the advent of high-resolution black blood MRI, a modality that does not rely on luminal narrowing for detection.

Conclusion—

We present the current understanding of the clinical implications of low-grade carotid stenosis with an example of the MRI assessment of high-risk carotid plaque causing minimal narrowing that highlights the importance of looking beyond the lumen.
Vitamin Intervention for Stroke Prevention Trial
Authors: Spence J. David , Bang Heejung , Chambless Lloyd E. , Stampfer Meir J.
Published: October 2005

Background and Purpose—

The Vitamin Intervention for Stroke Prevention trial (VISP) intention-to-treat analysis did not show efficacy of combined vitamin therapy for recurrent vascular events in patients with nondisabling stroke. Reasons for lack of efficacy may have included folate fortification of grain products, inclusion of the recommended daily intake for B
12
in the low-dose arm, treatment with parenteral B
12
in patients with low B
12
levels in both study arms, a dose of B
12
too low for patients with malabsorption, supplementation with nonstudy vitamins, and failure of patients with significant renal impairment to respond to vitamin therapy. We conducted an efficacy analysis limited to patients most likely to benefit from the treatment, based on hypotheses arising from evidence developed since VISP was initiated. The criteria for this subgroup were defined before any data analysis.

Methods—

For this analysis, we excluded patients with low and very high B
12
levels at baseline (<250 and >637 pmol/L, representing the 25th and 95th percentiles), to exclude those likely to have B
12
malabsorption or to be taking B
12
supplements outside the study and patients with significant renal impairment (glomerular filtration rate <46.18; the 10th percentile).

Results—

This subgroup represents 2155 patients (37% female), with a mean age of 66±10.7 years. For the combined end point of ischemic stroke, coronary disease, or death, there was a 21% reduction in the risk of events in the high-dose group compared with the low-dose group (unadjusted
P
=0.049; adjusted for age, sex, blood pressure, smoking, and B
12
level
P
=0.056). In Kaplan–Meier survival analysis comparing 4 groups, patients with a baseline B
12
level at the median or higher randomized to high-dose vitamin had the best overall outcome, and those with B
12
less than the median assigned to low-dose vitamin had the worst (
P
=0.02 for combined stroke, death, and coronary events;
P
=0.03 for stroke and coronary events).

Conclusions—

In the era of folate fortification, B
12
plays a key role in vitamin therapy for total homocysteine. Higher doses of B
12
, and other treatments to lower total homocysteine may be needed for some patients.
Coronary Stent Restenosis in Patients Treated With Cilostazol
Authors: Douglas John S. , Holmes David R. , Kereiakes Dean J. , Grines Cindy L. , Block Elizabeth , Ghazzal Ziyad M.B. , Morris Douglas C. , Liberman Henry , Parker Karen , Jurkovitz Claudine , Murrah Nancy , Foster Jovonne , Hyde Pamela , Mancini G.B. John , Weintraub William S.
Published: October 2005

Background—

Restenosis after implantation of coronary artery stents remains a significant clinical problem. We undertook a randomized, double-blind, placebo-controlled trial to determine whether cilostazol, a drug that suppresses intimal proliferation, would reduce renarrowing in patients after stent implantation in native coronary arteries.

Methods and Results—

We assigned 705 patients who had successful coronary stent implantation to receive, in addition to aspirin, cilostazol 100 mg BID or placebo for 6 months; clopidogrel 75 mg daily was administered to all patients for 30 days. Restenosis was determined by quantitative coronary angiography at 6 months. The minimal luminal diameter at 6 months for cilostazol-treated patients was 1.77 mm for the analysis segment (stent plus 5-mm borders) compared with 1.62 mm in the placebo group (
P
=0.01). Restenosis, defined as ≥50% narrowing, occurred in 22.0% of patients in the cilostazol group and in 34.5% of the placebo group (
P
=0.002), a 36% relative risk reduction. Restenosis was significantly lower in cilostazol-treated diabetics (17.7% versus 37.7%,
P
=0.01) and in those with small vessels (23.6% versus 35.2%,
P
=0.02), long lesions (29.9% versus 46.6%,
P
=0.04), and left anterior descending coronary artery site (19.3% versus 39.8%,
P
=0.001). There was no difference in bleeding, rehospitalization, target-vessel revascularization, myocardial infarction, or death.

Conclusions—

Treatment with the drug cilostazol resulted in a significantly larger minimal luminal diameter and a significantly lower binary restenosis rate compared with placebo-treated patients. These favorable effects were apparent in patients at high risk for restenosis.
Pioglitazone Reduces Neointima Volume After Coronary Stent Implantation
Authors: Marx Nikolaus , Wöhrle Jochen , Nusser Thorsten , Walcher Daniel , Rinker Angelika , Hombach Vinzenz , Koenig Wolfgang , Höher Martin
Published: October 2005

Background—

Restenosis requiring reintervention limits the long-term success after coronary stent implantation. Thiazolidinediones, like pioglitazone or rosiglitazone, are oral antidiabetic drugs with additional antirestenotic properties. In a randomized, placebo-controlled, double-blind trial, we examined the effect of 6-month pioglitazone therapy on neointima volume after coronary stenting in nondiabetic coronary artery disease patients.

Methods and Results—

Fifty nondiabetic patients after coronary stent implantation were randomly assigned to pioglitazone (30 mg daily; pio) or placebo (control) treatment in addition to standard therapy, and neointima volume was assessed by intravascular ultrasound at the 6-month follow-up. Both groups were comparable with regard to baseline characteristics, angiographic lesion morphology, target vessel, and length of the stented segment. In addition, there were no statistical differences in minimal lumen diameter before and after intervention, as well as reference diameter after stent implantation. In this study population of nondiabetic patients, pio treatment did not significantly change fasting blood glucose, fasting insulin, or glycosylated hemoglobin levels, as well as lipid parameters. In contrast, pio treatment significantly reduced neointima volume within the stented segment, with 2.3±1.1 mm
3
/mm in the pio group versus 3.1±1.6 mm
3
/mm in controls (
P
=0.04). Total plaque volume (adventitia-lumen area) was significantly lower at follow-up in the pio group (11.2±3.2 mm
3
/mm) compared with controls (13.2±4.2 mm
3
/mm;
P
=0.04). Moreover, the binary restenosis rate was 3.4% in the pio group versus 32.3% in controls (
P
<0.01).

Conclusions—

Thus, 6-month treatment with pio significantly reduced neointima volume after coronary stent implantation in nondiabetic patients. These data bolster the hypothesis that antidiabetic thiazolidinediones, in addition to their metabolic effects, exhibit direct antirestenotic effects in the vasculature.
Sildenafil Inhibits β-Adrenergic–Stimulated Cardiac Contractility in Humans
Authors: Borlaug Barry A. , Melenovsky Vojtech , Marhin Tricia , Fitzgerald Patricia , Kass David A.
Published: October 2005

Background—

Sildenafil inhibits phosphodiesterase 5 (PDE5A) to elevate intracellular cGMP and to induce vasodilation. This effect has led to its use for treating erectile dysfunction. Although its influence on rest heart function has appeared minimal, recent animal studies suggest that sildenafil can have potent effects on hearts stimulated by β-adrenergic or pressure overloads. We therefore tested whether sildenafil blunts dobutamine-stimulated cardiac function in humans.

Methods and Results—

Thirty-five healthy volunteers underwent a randomized, double-blind, placebo-controlled study in which cardiac function was assessed in response to dobutamine before and after oral sildenafil (100 mg, n=19) or placebo (n=16). Echo Doppler and noninvasive blood pressure data yielded load-independent contractility indexes (maximal power index and end-systolic elastance), ejection fraction, and measures of diastolic function. In the initial dobutamine test, systolic and diastolic function improved similarly in both treatment groups (eg, peak power index rose 80±28% in the placebo group and 82±31% in the sildenafil group;
P
=NS). However, in subjects who then received sildenafil, their second dobutamine response was significantly blunted, with peak power, ejection fraction, and end-systolic elastance changes reduced by 32±34%, 66±64%, and 56±63%, respectively (each
P
<0.001 versus the initial response). This contrasted to the placebo group, which displayed similar functional responses with both dobutamine tests. Sildenafil treatment did not significantly alter diastolic changes induced by dobutamine compared with results with placebo.

Conclusions—

PDE5A inhibition by sildenafil blunts systolic responses to β-adrenergic stimulation. This finding supports activity of PDE5A in the human heart and its role in modifying stimulated cardiac function.
Mortality After Acute Myocardial Infarction in Hospitals That Disproportionately Treat Black Patients
Authors: Skinner Jonathan , Chandra Amitabh , Staiger Douglas , Lee Julie , McClellan Mark
Published: October 2005

Background—

African Americans are more likely to be seen by physicians with less clinical training or to be treated at hospitals with longer average times to acute reperfusion therapies. Less is known about differences in health outcomes. This report compares risk-adjusted mortality after acute myocardial infarction (AMI) between US hospitals with high and low fractions of elderly black AMI patients.

Methods and Results—

A prospective cohort study was performed for fee-for-service Medicare patients hospitalized for AMI during 1997 to 2001 (n=1 136 736). Hospitals (n=4289) were classified into approximate deciles depending on the extent to which the hospital served the black population. Decile 1 (12.5% of AMI patients) included hospitals without any black AMI admissions during 1997 to 2001. Decile 10 (10% of AMI patients) included hospitals with the highest fraction of black AMI patients (33.6%). The main outcome measures were 90-day and 30-day mortality after AMI. Patients admitted to hospitals disproportionately serving blacks experienced no greater level of morbidities or severity of the infarction, yet hospitals in decile 10 experienced a risk-adjusted 90-day mortality rate of 23.7% (95% CI 23.2% to 24.2%) compared with 20.1% (95% CI 19.7% to 20.4%) in decile 1 hospitals. Differences in outcomes between hospitals were not explained by income, hospital ownership status, hospital volume, census region, urban status, or hospital surgical treatment intensity.

Conclusions—

Risk-adjusted mortality after AMI is significantly higher in US hospitals that disproportionately serve blacks. A reduction in overall mortality at these hospitals could dramatically reduce black-white disparities in healthcare outcomes.
Ethnicity and Peripheral Arterial Disease
Authors: Criqui Michael H. , Vargas Veronica , Denenberg Julie O. , Ho Elena , Allison Matthew , Langer Robert D. , Gamst Anthony , Bundens Warner P. , Fronek Arnost
Published: October 2005

Background—

Previous studies have indicated higher rates of peripheral arterial disease (PAD) in blacks than in non-Hispanic whites (NHWs), with limited information available for Hispanics and Asians. The reason for the PAD excess in blacks is unclear.

Methods and Results—

Ethnic-specific PAD prevalence rates were determined in a randomly selected defined population that included 4 ethnic groups; NHWs, blacks, Hispanics, and Asians. A total of 2343 participants aged 29 to 91 years were evaluated. There were 104 cases of PAD (4.4%). In weighted logistic models with NHWs as the reference group and containing demographic factors only, blacks had a higher PAD prevalence than NHWs (OR=2.30,
P
<0.024), whereas PAD rates in Hispanics and Asians, although somewhat lower, were not significantly different from NHWs. Blacks had significantly more diabetes and hypertension than NHWs and a significantly higher body mass index. Inclusion of these variables and other PAD risk factors in the model did not change the effect size for black ethnicity (OR=2.34,
P
=0.048). A model containing interaction terms for black ethnicity and each of the other risk factors revealed no significant interaction terms, which indicates no evidence that blacks were more “susceptible” than NHWs to cardiovascular disease risk factors.

Conclusions—

Black ethnicity was a strong and independent risk factor for PAD, which was not explained by higher levels of diabetes, hypertension, and body mass index. There was no evidence of a greater susceptibility of blacks to cardiovascular disease risk factors as a reason for their higher PAD prevalence. Thus, the excess risk of PAD in blacks remains unexplained and requires further study.
Reduced Mitochondrial Oxidative Capacity and Increased Mitochondrial Uncoupling Impair Myocardial Energetics in Obesity
Authors: Boudina Sihem , Sena Sandra , O’Neill Brian T. , Tathireddy Prakash , Young Martin E. , Abel E. Dale
Published: October 2005

Background—

Obesity is a risk factor for cardiovascular disease and is strongly associated with insulin resistance and type 2 diabetes. Recent studies in obese humans and animals demonstrated increased myocardial oxygen consumption (MV̇
o
2
) and reduced cardiac efficiency (CE); however, the underlying mechanisms remain unclear. The present study was performed to determine whether mitochondrial dysfunction and uncoupling are responsible for reduced cardiac performance and efficiency in
ob/ob
mice.

Methods and Results—

Cardiac function, MV̇
o
2
, mitochondrial respiration, and ATP synthesis were measured in 9-week-old
ob/ob
and control mouse hearts. Contractile function and MV̇
o
2
in glucose-perfused
ob/ob
hearts were similar to controls under basal conditions but were reduced under high workload. Perfusion of
ob/ob
hearts with glucose and palmitate increased MV̇
o
2
and reduced CE by 23% under basal conditions, and CE remained impaired at high workload. In glucose-perfused
ob/ob
hearts, mitochondrial state 3 respirations were reduced but ATP/O ratios were unchanged. In contrast, state 3 respiration rates were similar in
ob/ob
and control mitochondria from hearts perfused with palmitate and glucose, but ATP synthesis rates and ATP/O ratios were significantly reduced in
ob/ob
, which suggests increased mitochondrial uncoupling. Pyruvate dehydrogenase activity and protein levels of complexes I, III, and V were reduced in obese mice.

Conclusions—

These data indicate that reduced mitochondrial oxidative capacity may contribute to cardiac dysfunction in
ob/ob
mice. Moreover, fatty acid but not glucose-induced mitochondrial uncoupling reduces CE in obese mice by limiting ATP production and increasing MV̇
o
2
.
Functional Recovery of Damaged Skeletal Muscle Through Synchronized Vasculogenesis, Myogenesis, and Neurogenesis by Muscle-Derived Stem Cells
Authors: Tamaki Tetsuro , Uchiyama Yoshiyasu , Okada Yoshinori , Ishikawa Tetsuya , Sato Masahiro , Akatsuka Akira , Asahara Takayuki
Published: October 2005

Background—

Recent studies have shown that skeletal muscle–derived stem cells (MDSCs) can give rise to several cell lineages after transplantation. However, the potential therapeutic uses of MDSCs, the functional significance of the transplanted tissue, and vasculogenesis, myogenesis, and reconstitution of other tissues have yet to be investigated in detail. In addition, the relationship between MDSCs and mesenchymal bone marrow cells is of interest.

Methods and Results—

We developed a severe-damage model of mouse tibialis anterior muscle with a large deficit of nerve fibers, muscle fibers, and blood vessels. We investigated the potential therapeutic use of freshly isolated CD34
+
/45
−
(Sk-34) cells. Results showed that, after transplantation, implanted cells give rise to myogenic, vascular (pericytes, vascular smooth muscle cells, and endothelial cells), and neural (Schwann) cells, as well as contributing to the synchronized reconstitution of blood vessels, muscle fibers, and peripheral nerves, with significant recovery of both mass and contractile function after transplantation. Investigation of Sk-34 cell transplantation to the renal capsule (nonmuscle tissue) and fluorescence in situ hybridization analysis for the transplanted muscle detecting the Y chromosome revealed the intrinsic plasticity of the Sk-34 cell population. In addition, there were no donor-derived Sk-34 cells in the muscle of lethally irradiated bone marrow–transplanted animals, indicating that the Sk-34 cells were not derived from bone marrow.

Conclusions—

These findings indicate that freshly isolated skeletal muscle–derived Sk-34 cells are potentially useful for reconstitution therapy of the vascular, muscular, and peripheral nervous systems. These results provide new insights into somatic stem and/or progenitor cells with regard to vasculogenesis, myogenesis, and neurogenesis.
Nox1 Is Involved in Angiotensin II–Mediated Hypertension
Authors: Matsuno Kuniharu , Yamada Hiroyuki , Iwata Kazumi , Jin Denan , Katsuyama Masato , Matsuki Masato , Takai Shinji , Yamanishi Kiyofumi , Miyazaki Mizuo , Matsubara Hiroaki , Yabe-Nishimura Chihiro
Published: October 2005

Background—Increased production of reactive oxygen species (ROSs) by angiotensin II (Ang II) is involved in the initiation and progression of cardiovascular diseases. NADPH oxidase is a major source of superoxide generated in vascular tissues. Although Nox1 has been identified in vascular smooth muscle cells as a new homolog of gp91phox (Nox2), a catalytic subunit of NADPH oxidase, the pathophysiological function of Nox1-derived ROSs has not been fully elucidated. To clarify the role of Nox1 in Ang II–mediated hypertension, we generated Nox1-deficient (−/Y) mice.

Methods and Results—No difference in the baseline blood pressure was observed between Nox1+/Yand Nox1−/Y. Infusion of Ang II induced a significant increase in mean blood pressure, accompanied by augmented expression of Nox1 mRNA and superoxide production in the aorta of Nox1+/Y, whereas the elevation in blood pressure and production of superoxide were significantly blunted in Nox1−/Y. Conversely, the infusion of pressor as well as subpressor doses of Ang II did elicit marked hypertrophy in the thoracic aorta of Nox1−/Ysimilar to Nox1+/Y. Administration of a nitric oxide synthase inhibitor (L-NAME) to Nox1+/Ydid not affect the Ang II–mediated increase in blood pressure, but it abolished the suppressed pressor response to Ang II in Nox1−/Y. Finally, endothelium-dependent relaxation and the level of cGMP in the isolated aorta were preserved in Nox1−/Yinfused with Ang II.

Conclusions—A pivotal role for ROSs derived from Nox1/NADPH oxidase was suggested in the pressor response to Ang II by reducing the bioavailability of nitric oxide.
A Life-Course View of the Development of Crime
Authors: Sampson Robert J. , Laub John H.
Published: October 2005

In this article, the authors present a life-course perspective on crime and a critique of the developmental criminology paradigm. Their fundamental argument is that persistent offending and desistance—or trajectories of crime—can be meaningfully understood within the same theoretical framework, namely, a revised agegraded theory of informal social control. The authors examine three major issues. First, they analyze data that undermine the idea that developmentally distinct groups of offenders can be explained by unique causal processes. Second, they revisit the concept of turning points from a time-varying view of key life events. Third, they stress the overlooked importance of human agency in the development of crime. The authors' life-course theory envisions development as the constant interaction between individuals and their environment, coupled with random developmental noise and a purposeful human agency that they distinguish from rational choice. Contrary to influential developmental theories in criminology, the authors thus conceptualize crime as an emergent process reducible neither to the individual nor the environment.