bluuebunny/crossref_metadata_2025 huggingface dataset:
Sexual dimorphism in oxidant status in spontaneously hypertensive rats
Authors: Sullivan Jennifer C. , Sasser Jennifer M. , Pollock Jennifer S.
Published: August 2006

Male spontaneously hypertensive rats (SHR) have a blunted pressure-natriuresis relationship and enhanced oxidative stress compared with female SHR. Furthermore, oxidative stress contributes to abnormal renal Na+handling and renal damage in hypertension. The aim of this study was to determine whether a sex difference exists in renal inner medullary hydrogen peroxide (H2O2) levels and/or antioxidant systems in SHR and the influence of sex steroids on these systems. Thirteen-week-old intact and gonadectomized male and female SHR were placed in metabolic cages for 24-h urine collection. Renal inner medullas were isolated for antioxidant activity assays and Western blot analysis or for measurements of H2O2using Amplex Red. Studies verified that male SHR had greater Na+reabsorption compared with female SHR. Male SHR had enhanced urinary excretion of H2O2compared with female SHR. Gonadectomy decreased H2O2excretion in males and increased H2O2excretion in females, suggesting that testosterone stimulates total body oxidative stress and estrogen suppresses levels of total body oxidative stress. There was not a sex difference in inner medullary H2O2levels. Male SHR had a testosterone-dependent increase in inner medullary SOD activity, and both intact and gonadectomized males had high levels of inner medullary catalase activity compared with females. The results of this study showed that there was a sexual dimorphism in Na+handling and oxidant status. We hypothesize that there is a testosterone-sensitive increase in whole body reactive oxygen species production that results in a compensatory increase in the inner medullary antioxidant capability possibly to normalize Na+handling.
An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations
Authors: Kregel Kevin C. , Zhang Hannah J.
Published: August 2006

Aging is an inherently complex process that is manifested within an organism at genetic, molecular, cellular, organ, and system levels. Although the fundamental mechanisms are still poorly understood, a growing body of evidence points toward reactive oxygen species (ROS) as one of the primary determinants of aging. The “oxidative stress theory” holds that a progressive and irreversible accumulation of oxidative damage caused by ROS impacts on critical aspects of the aging process and contributes to impaired physiological function, increased incidence of disease, and a reduction in life span. While compelling correlative data have been generated to support the oxidative stress theory, a direct cause-and-effect relationship between the accumulation of oxidatively mediated damage and aging has not been strongly established. The goal of this minireview is to broadly describe mechanisms of in vivo ROS generation, examine the potential impact of ROS and oxidative damage on cellular function, and evaluate how these responses change with aging in physiologically relevant situations. In addition, the mounting genetic evidence that links oxidative stress to aging is discussed, as well as the potential challenges and benefits associated with the development of antiaging interventions and therapies.
Possible inhibitory role of prolactin-releasing peptide for ACTH release associated with running stress
Authors: Ohiwa Nao , Chang Hyukki , Saito Tsuyoshi , Onaka Tatsushi , Fujikawa Takahiko , Soya Hideaki
Published: August 2006

Exercise around the lactate threshold induces a stress response, defined as “running stress.” We have previously demonstrated that running stress is associated with activation of certain regions of the brain, e.g., the paraventricular hypothalamic nucleus (PVN) and supraoptic nucleus, that are hypothesized to play an integral role in regulating stress-related responses, including ACTH release during running. Thus we investigated the role of prolactin-releasing peptide (PrRP), found in the ventrolateral medulla and the nucleus of the solitary tract, which is known to project to the PVN during running-induced ACTH release. Accumulation of c-Fos in PrRP neurons correlated with running speeds, reaching maximal levels under running stress. Intracerebroventricular injection of neutralizing anti-PrRP antibodies led to increased plasma ACTH level and blood lactate accumulation during running stress, but not during restraint stress. Exogenous intracerebroventricular administration of low doses of PrRP had the opposite effects. Therefore, our results suggest that, during running stress, PrRP-containing neurons are activated in an exercise intensity-dependent manner, and likewise the produced endogenous PrRP attenuates ACTH release and blood lactate accumulation during running stress. Here we provide a novel perspective on understanding of PrRP in the endocrine-metabolic response associated with running stress.
Influence of photoperiod and gonadal status on food intake, adiposity, and gene expression of hypothalamic appetite regulators in a seasonal mammal
Authors: Anukulkitch Chantacha , Rao Alexandra , Dunshea Frank R. , Blache Dominique , Lincoln Gerald A. , Clarke Iain J.
Published: August 2006

We studied the effects of photoperiod on metabolic profiles, adiposity, and gene expression of hypothalamic appetite-regulating peptides in gonad-intact and castrated Soay rams. Groups of five to six animals were studied 6, 18, or 30 wk after switching from long photoperiod (LP: 16 h of light) to short photoperiod (SP: 8 h of light). Reproductive and metabolic indexes were measured in blood plasma. Expression of neuropeptide Y (NPY), proopiomelanocortin (POMC), and leptin receptor (ObRb) in the arcuate nucleus was measured using in situ hybridization. Testosterone levels of intact animals were low under LP, increased to a peak at 16 wk under SP, and then declined. Voluntary food intake (VFI) was high under LP in both intact and castrated animals, decreased to a nadir at 12–16 wk under SP, and then recovered, but only in intact rams as the reproductive axis became photorefractory to SP. NPY gene expression varied positively and POMC expression varied negatively with the cycle in VFI, with differences between intact and castrate rams in the refractory phase. ObRb expression decreased under SP, unrelated to changes in VFI. Visceral fat weight also varied between the intact and castrated animals across the cycle. We conclude that 1) photoperiodic changes in VFI reflect changes in NPY and POMC gene expression, 2) changes in ObRb gene expression are not necessarily determinants of changes in VFI, 3) gonadal status affects the pattern of VFI that changes with photoperiod, and 4) in the absence of gonadal factors, animals can eat less but gain adiposity.
Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats
Authors: Szentirmai Éva , Kapás Levente , Krueger James M.
Published: August 2006

Ghrelin, a gut-brain peptide, is best known for its role in the stimulation of feeding and growth hormone release. In the brain, orexin, neuropeptide Y (NPY), and ghrelin are parts of a food intake regulatory circuit. Orexin and NPY are also implicated in maintaining wakefulness. Previous experiments in our laboratory revealed that intracerebroventricular injections of ghrelin induce wakefulness in rats. To further elucidate the possible role of ghrelin in the regulation of arousal, we studied the effects of microinjections of ghrelin into hypothalamic sites, which are implicated in the regulation of feeding and sleep, such as the lateral hypothalamus (LH), medial preoptic area (MPA), and paraventricular nucleus (PVN) on sleep in rats. Sleep responses, motor activity, and food intake after central administration of 0.04, 0.2, or 1 μg (12, 60, or 300 pmol) ghrelin were recorded. Microinjections of ghrelin into the LH had strong wakefulness-promoting effects lasting for 2 h. Wakefulness was also stimulated by ghrelin injection into the MPA and PVN; the effects were confined to the first hour after the injection. Ghrelin's non-rapid-eye-movement sleep-suppressive effect was accompanied by attenuation in the electroencephalographic (EEG) slow-wave activity and changes in the EEG power spectrum. Food consumption was significantly stimulated after microinjections of ghrelin into each hypothalamic site. Together, these results are consistent with the hypothesis that forebrain ghrelinergic mechanisms play a role in the regulation of vigilance, possibly through activating the components of the food intake- and arousal-promoting network formed by orexin and NPY.
Is the osmotically inactive sodium storage pool fixed or variable?
Authors: Nguyen Minhtri K. , Kurtz Ira
Published: August 2006

Recently, there is renewed interest in the role of osmotically inactive Na+ storage during Na+ retention. Although it is well accepted that a portion of the total exchangeable Na+ reservoir is osmotically inactive, there is current controversy as to whether the osmotically inactive Na+ storage pool is fixed or variable during Na+ retention. In this article, we analyze the current scientific evidence to assess whether the osmotically inactive Na+ storage pool can be dynamically regulated. Our analysis supports the assertion that the osmotically inactive Na+ storage pool is fixed rather than variable.
In vivo effects of lipopolysaccharide and TLR4 on platelet production and activity: implications for thrombotic risk
Authors: Jayachandran Muthuvel , Brunn Gregory J. , Karnicki Krzysztof , Miller Randall S. , Owen Whyte G. , Miller Virginia M.
Published: August 2006

Gram-negative bacteria release LPS, which activates Toll-like-receptor-4 (TLR4) in the host, initiating an inflammatory response to infection. Infection increases risk for thrombosis. Platelets contribute to defense from infection and to thrombosis. Experiments were designed to determine whether LPS, through TLR4 signaling, affects platelet phenotype. Platelet responses in wild-type (WT) mice and mice that lack the TLR4 gene (dTLR4) were compared following a single nonlethal injection of LPS (0.2 mg/kg iv). Compared with WT mice, mice without TLR4 had fewer circulating platelets with lower RNA content and were less responsive to thrombin-activated expression of P-selectin but were equally sensitive to aggregation or ATP secretion. One week following the LPS injection, the time it takes for the circulating platelet pool to turnover, the number of circulating platelets, thrombin-induced expression of P-selectin, and collagen-activated aggregation were increased comparably in both groups of mice. Therefore, the change of the platelet pool to an activated phenotype 1 wk after a single exposure to LPS appears to arise from a process that is independent of TLR4. The persistence of the effect 1 wk after the injection suggests that the changes reflect an action of LPS on megakaryocytes and their platelet progeny rather than on circulating platelets, which would have been cleared.
C-Reactive Protein Decreases Interleukin-10 Secretion in Activated Human Monocyte-Derived Macrophages via Inhibition of Cyclic AMP Production
Authors: Singh Uma , Devaraj Sridevi , Dasu Mohan R. , Ciobanu Dana , Reusch Jane , Jialal Ishwarlal
Published: August 2006

Objective—C-Reactive protein (CRP), a cardiovascular risk marker, could also participate in atherosclerosis. Atherosclerotic plaques express CRP and interleukin (IL)-10, a major antiinflammatory cytokine. IL-10 deficiency results in increased lesion formation, whereas IL-10 delivery attenuates lesions. We tested the effect of CRP on lipopolysaccharide (LPS)-induced IL-10 secretion in human monocyte-derived macrophages (HMDMs).

Methods and Results—Incubation of HMDMs with CRP significantly decreased LPS-induced IL-10 mRNA and intracellular and secreted IL-10 protein and destabilized IL-10 mRNA. Also, CRP alone increased secretion of IL-8, IL-6, and tumor necrosis factor from HMDMs and did not inhibit LPS-induced secretion of these cytokines. Fc γ receptor I antibodies significantly reversed CRP-mediated IL-10 inhibition. CRP significantly decreased intracellular cAMP, phospho-cAMP response element binding protein (pCREB), and adenyl cyclase activity. cAMP agonists reversed CRP-mediated IL-10 inhibition. Overexpression of wild-type and constitutively active CREB in THP-1 cells revealed attenuation of the inhibitory effect of CRP on LPS-induced IL-10 levels. CRP also inhibited hemoglobin:haptoglobin-induced IL-10 and heme oxygenase-1. Furthermore, administration of human CRP to rats significantly decreased IL-10 levels.

Conclusions—This study provides novel evidence that CRP, by decreasing IL-10 alters the antiinflammatory/proinflammatory balance, accentuating inflammation, which is pivotal in atherothrombosis.
Altered Fibrin Architecture Is Associated With Hypofibrinolysis and Premature Coronary Atherothrombosis
Authors: Collet J.P. , Allali Y. , Lesty C. , Tanguy M.L. , Silvain J. , Ankri A. , Blanchet B. , Dumaine R. , Gianetti J. , Payot L. , Weisel J.W. , Montalescot G.
Published: August 2006

Objective—

Hypofibrinolysis promotes atherosclerosis progression and recurrent ischemic events in premature coronary artery disease. We investigated the role of fibrin physical properties in this particular setting.

Methods and Results—

Biomarkers of recurrent thrombosis and premature coronary artery disease (CAD) were measured in 33 young post–myocardial infarction patients with angiographic-proven CAD and in 33 healthy volunteers matched for age and sex. Ex vivo plasma fibrin physical properties were assessed by measuring fibrin rigidity and fibrin morphological properties using a torsion pendulum and optical confocal microscopy. The fibrinolysis rate was derived from continuous monitoring of the viscoelastic properties after addition of lytic enzymes. Young CAD patients had a significant increase in plasma concentration of fibrinogen, von Willebrand factor, plasminogen activator inhibitor type 1, and lipoprotein(a) as compared with controls (
P
<0.05). Fibrin of young CAD patients was stiffer (
P
=0.002), made of numerous (
P
=0.002) and shorter fibers (
P
=0.04), and lysed at a slower rate than that of controls (
P
=0.03). Fibrin stiffness was an independent predictor for both premature CAD and hypofibrinolysis.

Conclusions—

This first detailed study of clot properties in such a group of patients demonstrated that abnormal plasma fibrin architecture is an important feature of both premature CAD and fibrinolysis rate. The determinants of this particular phenotype warrant further investigation.
Direct and Indirect Effects of Alloantibodies Link Neointimal and Medial Remodeling in Graft Arteriosclerosis
Authors: Thaunat Olivier , Louedec Liliane , Dai Jianping , Bellier Florence , Groyer Emilie , Delignat Sandrine , Gaston Anh-Thu , Caligiuri Giuseppina , Joly Etienne , Plissonnier Didier , Michel Jean-Baptiste , Nicoletti Antonino
Published: August 2006

Objective—Chronic vascular rejection, the main cause of allograft failure, is characterized by the destruction of smooth muscle cells (SMCs) in the media concomitantly with the proliferation of SMCs in the adjacent neointima. We hypothesized that alloantibodies might be responsible for these 2 opposite but coordinated events.

Methods and Results—We used the rat aortic interposition model of chronic vascular rejection. During the rejection process, a neointima composed of proliferating SMCs from the recipient developed, whereas the SMCs in the media, all of donor origin, underwent apoptosis. Alloantibody deposition was detected only in the media. Using in vitro cultures experiments, we observed that alloantibody binding to donor SMCs exerts (1) a rapid upregulation of the transcription of growth factors genes, followed by (2) the induction of apoptosis after 24 hours. The transient production of growth factors by donor SMCs in response to the binding of alloantibodies induced the proliferation of recipient SMCs in culture supernatant transfer experiments. Additional data suggest that among the repertoire of alloantibodies, those directed against major histocompatibility complex I might carry the remodeling effect.

Conclusions—Our data suggest that during chronic vascular rejection, alloantibody binding to donor medial SMCs is a crucial event that links neointimal and medial remodeling.
Inhibition of Smooth Muscle Proliferation by Urea-Based Alkanoic Acids via Peroxisome Proliferator-Activated Receptor α–Dependent Repression of Cyclin D1
Authors: Ng Valerie Y. , Morisseau Christophe , Falck John R. , Hammock Bruce D. , Kroetz Deanna L.
Published: August 2006

Objective—

Proliferation of smooth muscle cells is implicated in cardiovascular complications. Previously, a urea-based soluble epoxide hydrolase inhibitor was shown to attenuate smooth muscle cell proliferation. We examined the possibility that urea-based alkanoic acids activate the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) and the role of PPARα in smooth muscle cell proliferation.

Methods and Results—

Alkanoic acids transactivated PPARα, induced binding of PPARα to its response element, and significantly induced the expression of PPARα-responsive genes, showing their function as PPARα agonists. Furthermore, the alkanoic acids attenuated platelet-derived growth factor–induced smooth muscle cell proliferation via repression of cyclin D1 expression. Using small interfering RNA to decrease endogenous PPARα expression, it was determined that PPARα was partially involved in the cyclin D1 repression. The antiproliferative effects of alkanoic acids may also be attributed to their inhibitory effects on soluble epoxide hydrolase, because epoxyeicosatrienoic acids alone inhibited smooth muscle cell proliferation.

Conclusions—

These results show that attenuation of smooth muscle cell proliferation by urea-based alkanoic acids is mediated, in part, by the activation of PPARα. These acids may be useful for designing therapeutics to treat diseases characterized by excessive smooth muscle cell proliferation.
Selective Agonists of Estrogen Receptor Isoforms
Authors: Bolego Chiara , Vegeto Elisabetta , Pinna Christian , Maggi Adriana , Cignarella Andrea
Published: August 2006

The cloning of estrogen receptors (ERs) and generation of ER-deficient mice have increased our understanding of the molecular mechanisms underlying the cardiovascular effects of estrogen. It is conceivable that clinical trials of estrogens so far failed to improve cardiovascular health because of the poor ER isoform selectivity and tissue specificity of endogenous hormones as well as incorrect treatment timing and regimens. Tissue-selective ER modulators (SERMs) may be safer agents than endogenous estrogens for cardiovascular disease. Yet, designing isoform-selective ER ligands (I-SERMs) with agonist or antagonist activity is required to pursue improved pharmacological control of ERs, especially taking into account emerging evidence for the beneficial role of vascular ERα activation. Ideally, the quest for unique ER ligands targeted to the vascular wall should lead to compounds that merge the pharmacological profiles of SERM and I-SERM agents. This review highlights the current bases for and approaches to selective ER modulation in the cardiovascular system.
Increased Cyclooxygenase-2 Expression and Prostaglandin-Mediated Dilation in Coronary Arterioles of Patients With Diabetes Mellitus
Authors: Szerafin Tamás , Erdei Nóra , Fülöp Tibor , Pasztor Eniko T. , Édes István , Koller Akos , Bagi Zsolt
Published: August 2006

Based on findings of experimental models of diabetes mellitus (DM) showing increased expression of vascular cyclooxygenase-2 (COX-2), we hypothesized that in patients with DM changes in COX-2–dependent prostaglandin synthesis affect vasomotor responses of coronary arterioles. Arterioles were dissected from the right atrial appendages obtained at the time of cardiac surgery of patient with DM(+) or without documented diabetes DM(−). Isolated arterioles (89±15 μm in diameter) were cannulated and pressurized (at 80 mm Hg), and changes in diameter were measured with video microscopy. After spontaneous tone developed [DM(−): 32±7%; DM(+): 37±5%;
P
=NS], arteriolar responses to bradykinin were investigated. Dilations to bradykinin (0.1 nmol/L to 1 μmol/L) were significantly (
P
<0.05) greater in DM(+) than DM(−) patients (10 nmol/L: 77±10% versus 38±14%). In both groups, dilations were similar to the NO-donor, sodium nitroprusside. In arterioles of DM(+), but not those of DM(−), patients’ bradykinin-induced dilations were reduced by the nonselective COX inhibitor indomethacin or by the selective COX-2 inhibitor NS-398 (DM(+) at 10 nmol/L: to 20±4% and 29±7%, respectively). Correspondingly, a marked COX-2 immunostaining was detected in coronary arterioles of DM(+), but not in those of DM(−) patients. We conclude that in coronary arterioles of diabetic patients bradykinin induces enhanced COX-2–derived prostaglandin-mediated dilation. These findings are the first to show that in humans diabetes mellitus increases COX-2 expression and dilator prostaglandin synthesis in coronary arterioles, which may serve to increase dilator capacity and maintain adequate perfusion of cardiac tissues.
Adenosine Inhibits Matrix Metalloproteinase-9 Secretion By Neutrophils
Authors: Ernens Isabelle , Rouy Didier , Velot Emilie , Devaux Yvan , Wagner Daniel R.
Published: August 2006

Matrix metalloproteinases (MMPs), and in particular MMP-9 secreted by neutrophils, are capable of degrading the matrix components of the heart and are thought to be the driving force behind myocardial matrix remodeling after infarction. Adenosine, a naturally produced nucleoside, has been shown to have cardioprotective effects and to inhibit secretion of various cytokines. The aim of our study was to determine the effect of adenosine on the secretion of MMP-9 by neutrophils. Neutrophils were isolated from healthy volunteers through Ficoll and Dextran sedimentation. Neutrophils were activated by
N
-formylmethionyl-leucyl-phenylalanine (fMLP) in the presence or absence of adenosine or adenosine analogs. Zymography and enzyme linked immunosorbent assay were used to measure MMP-9 secretion. Adenosine (1 μmol/L) decreased the fMLP-induced MMP-9 secretion by 30±2% (n=8,
P
<0.001). The effect was dose-dependent and was not specific to fMLP because adenosine also inhibited MMP-9 secretion by LPS- or H
2
O
2
-stimulated neutrophils. The effect of adenosine was mimicked by the adenosine A2a receptor agonist CGS21680 and was inhibited by both the A2a antagonist SCH5826 and A2a RNA silencing. The A3 agonist IB-MECA moderately decreased fMLP-induced MMP-9 secretion. Agonists and antagonists of the other types of adenosine receptors had no significant effect. Adenosine increased intracellular cAMP concentration and accelerated the return to baseline of the intracytoplasmic calcium peak. The inhibition of MMP-9 secretion by adenosine, as well as the calcium effect, was prevented by the protein kinase A inhibitor H-89. In conclusion, we show here that adenosine inhibits MMP-9 secretion by neutrophils. Our results suggest that this effect implies the A2a receptor and is mediated through the cAMP/PKA/Ca
2+
pathway. Therefore, adenosine may represent a new approach to prevent matrix degradation and remodeling after myocardial injury.
Desmosomal Dysfunction due to Mutations in Desmoplakin Causes Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
Authors: Yang Zhao , Bowles Neil E. , Scherer Steven E. , Taylor Michael D. , Kearney Debra L. , Ge Shuping , Nadvoretskiy Vyacheslav V. , DeFreitas Gilberto , Carabello Blasé , Brandon Lois I. , Godsel Lisa M. , Green Kathleen J. , Saffitz Jeffrey E. , Li Hua , Danieli Gian Antonio , Calkins Hugh , Marcus Frank , Towbin Jeffrey A.
Published: August 2006

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by progressive degeneration of the right ventricular myocardium, ventricular arrhythmias, fibrous-fatty replacement, and increased risk of sudden death. Mutations in 6 genes, including 4 encoding desmosomal proteins (Junctional plakoglobin (JUP), Desmoplakin (DSP), Plakophilin 2, and Desmoglein 2), have been identified in patients with ARVD/C. Mutation analysis of 66 probands identified 4 variants in DSP; V30M, Q90R, W233X, and R2834H. To establish a cause and effect relationship between those DSP missense mutations and ARVD/C, we performed in vitro and in vivo analyses of the mutated proteins. Unlike wild-type (WT) DSP, the N-terminal mutants (V30M and Q90R) failed to localize to the cell membrane in desomosome-forming cell line and failed to bind to and coimmunoprecipitate JUP. Multiple attempts to generate N-terminal DSP (V30M and Q90R) cardiac-specific transgenes have failed: analysis of embryos revealed evidence of profound ventricular dilation, which likely resulted in embryonic lethality. We were able to develop transgenic (Tg) mice with cardiac-restricted overexpression of the C-terminal mutant (R2834H) or WT DSP. Whereas mice overexpressing WT DSP had no detectable histologic, morphological, or functional cardiac changes, the R2834H-Tg mice had increased cardiomyocyte apoptosis, cardiac fibrosis, and lipid accumulation, along with ventricular enlargement and cardiac dysfunction in both ventricles. These mice also displayed interruption of DSP-desmin interaction at intercalated discs (IDs) and marked ultra-structural changes of IDs. These data suggest DSP expression in cardiomyocytes is crucial for maintaining cardiac tissue integrity, and DSP abnormalities result in ARVD/C by cardiomyocyte death, changes in lipid metabolism, and defects in cardiac development.
Assessment of Inflammatory Burden Contralateral to the Symptomatic Carotid Stenosis Using High-Resolution Ultrasmall, Superparamagnetic Iron Oxide–Enhanced MRI
Authors: Tang Tjun , Howarth Simon P.S. , Miller Sam R. , Trivedi Rikin , Graves Martin J. , King-Im Jean U. , Li Zhi Y. , Brown Andrew P. , Kirkpatrick Peter J. , Gaunt Michael E. , Gillard Jonathan H.
Published: August 2006

Background and Purpose—

It is well known that the vulnerable atheromatous plaque has a thin, fibrous cap and large lipid core with associated inflammation. This inflammation can be detected on MRI with use of a contrast medium, Sinerem, an ultrasmall superparamagnetic iron oxide (USPIO). Although the incidence of macrophage activity in asymptomatic disease appears low, we aimed to explore the incidence of MRI-defined inflammation in asymptomatic plaques in patients with known contralateral symptomatic disease.

Methods—

Twenty symptomatic patients underwent multisequence MRI before and 36 hours after USPIO infusion. Images were manually segmented into quadrants, and the signal change in each quadrant was calculated after USPIO administration. A mixed mathematical model was developed to compare the mean signal change across all quadrants in the 2 groups. Patients had a mean symptomatic stenosis of 77% compared with 46% on their asymptomatic side, as measured by conventional angiography.

Results—

There were 11 (55%) men, and the median age was 72 years (range, 53 to 84 years). All patients had risk factors consistent with severe atherosclerotic disease. All symptomatic carotid stenoses had inflammation, as evaluated by USPIO-enhanced imaging. On the contralateral sides, inflammatory activity was found in 19 (95%) patients. Contralaterally, there were 163 quadrants (57%) with a signal loss after USPIO when compared with 217 quadrants (71%) on the symptomatic side (
P
=0.007).

Conclusions—

This study adds weight to the argument that atherosclerosis is a truly systemic disease. It suggests that investigation of the contralateral side in patients with symptomatic carotid stenosis can demonstrate inflammation in 95% of plaques, despite a mean stenosis of only 46%. Thus, inflammatory activity may be a significant risk factor in asymptomatic disease in patients who have known contralateral symptomatic disease. Patients with symptomatic carotid disease should have their contralateral carotid artery followed up.
The Versican Gene and the Risk of Intracranial Aneurysms
Authors: Ruigrok Ynte M. , Rinkel Gabriël J.E. , Wijmenga Cisca
Published: August 2006

Background and Purpose—

The proteoglycan versican is an excellent candidate gene for intracranial aneurysms (IAs) because it plays an important role in extracellular matrix assembly and is localized in a previously implicated locus for IAs on chromosome 5q.

Methods—

We analyzed all the common variations using 16-tag single nucleotide polymorphisms (SNPs) and haplotypes in the versican gene using a 2-stage genotyping approach. For stage 1, 16 SNPs were genotyped in 307 cases and 639 controls. For stage 2, the two SNPs yielding the most significant associations (
P
<0.01) were genotyped in a second independent cohort of 310 cases for confirmation of the associations.

Results—

In stage 1, we found several SNPs in strong linkage disequilibrium and haplotypes constituting these SNPs associated with IAs in the Dutch population (strongest SNP association for rs173686 with odds ratio=1.34, 95% CI=1.09 to 1.65,
P
=0.004). In stage 2, we confirmed association for the 2 SNPs with the most significant associations (strongest SNP association for rs173686 with odds ratio=1.36, 95% CI=1.11 to 1.67,
P
=0.003).

Conclusion—

SNPs in strong linkage disequilibrium and haplotypes constituting these SNPs in the versican gene are associated with IAs suggesting that variation in or near the versican gene plays a role in susceptibility to IAs.
National Institute of Neurological Disorders and Stroke–Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards
Authors: Hachinski Vladimir , Iadecola Costantino , Petersen Ron C. , Breteler Monique M. , Nyenhuis David L. , Black Sandra E. , Powers William J. , DeCarli Charles , Merino Jose G. , Kalaria Raj N. , Vinters Harry V. , Holtzman David M. , Rosenberg Gary A. , Wallin Anders , Dichgans Martin , Marler John R. , Leblanc Gabrielle G.
Published: August 2006

Background and Purpose—

One in 3 individuals will experience a stroke, dementia or both. Moreover, twice as many individuals will have cognitive impairment short of dementia as either stroke or dementia. The commonly used stroke scales do not measure cognition, while dementia criteria focus on the late stages of cognitive impairment, and are heavily biased toward the diagnosis of Alzheimer disease. No commonly agreed standards exist for identifying and describing individuals with cognitive impairment, particularly in the early stages, and especially with cognitive impairment related to vascular factors, or vascular cognitive impairment.

Methods—

The National Institute for Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) convened researchers in clinical diagnosis, epidemiology, neuropsychology, brain imaging, neuropathology, experimental models, biomarkers, genetics, and clinical trials to recommend minimum, common, clinical and research standards for the description and study of vascular cognitive impairment.

Results—

The results of these discussions are reported herein.

Conclusions—

The development of common standards represents a first step in a process of use, validation and refinement. Using the same standards will help identify individuals in the early stages of cognitive impairment, will make studies comparable, and by integrating knowledge, will accelerate the pace of progress.
A Mathematical Model of the Risk of Nuclear Terrorism
Authors: Bunn Matthew
Published: August 2006

This article presents a mathematical model for measuring the global risk of nuclear theft and terrorism. One plausible set of parameter values used in a numerical example suggests a 29 percent probability of a nuclear terrorist attack in the next decade. The expected loss over that period would be $1.17 trillion (undiscounted), or more than $100 billion per year. Historical and other evidence is used to explore the likely values of several of the key parameters, and policy options for reducing the risk are briefly assessed. The uncertainties in estimating the risk of nuclear terrorism are very large, but even a risk dramatically smaller than that estimated in the numerical example used in this article would justify a broad range of actions to reduce the threat.
Terrorist Nuclear Weapon Construction: How Difficult?
Authors: Bunn Matthew , Wier Anthony
Published: August 2006

The likelihood of a nuclear terrorist attack depends in part on the ability of terrorist groups to acquire, construct, and detonate a nuclear device. This article attempts to determine the difficulty of such an endeavor by examining the underlying physical facts about nuclear fission, nuclear materials, and nuclear weapons design. The facts bear out a simple conclusion: while the danger should not be exaggerated, a nuclear terrorist attack is potentially within the capabilities of a well-organized and sophisticated terrorist group. A nuclear attack might be one of the most difficult missions a terrorist group could hope to try, but if a highly capable group acquired a stolen nuclear bomb or enough nuclear material to make one, there can be few grounds for confidence that they would be unable to use it.
Toward a Comprehensive Safeguards System: Keeping Fissile Materials out of Terrorists' Hands
Authors: Hecker Siegfried S.
Published: August 2006

The nexus of terrorism and nuclear weapons is today’s greatest security concern. The importance of keeping fissile materials out of the hands of terrorists is now generally accepted. The difficulty of doing so is not. Lack of appreciation, especially for the technical difficulties, is hampering our ability to build a comprehensive safeguards system and prevent nuclear terrorism.
A Nuclear Response to Nuclear Terror: Ref lections of Nuclear Preemption
Authors: Kokoshin Andrei
Published: August 2006

The threat of nuclear terrorism in the United States has led its leadership to contemplate an extreme military response—namely, nuclear preemption. To some preemption proponents, nuclear weapons are no longer considered the option of last resort. This article argues that reducing the nuclear threshold for some international actors and not others is perhaps just as dangerous as the proliferation the nuclear preemption doctrine is trying counter. The nuclear “taboo” has once again ceased to exist.
Combating Nuclear Terrorism: Addressing Nonstate Actor Motivations
Authors: Jenkins Bonnie
Published: August 2006

Yesterday’s nonproliferation efforts were successful, in part, because they addressed the motives of aspiring state proliferants. Today’s efforts to prevent nuclear terrorism should take a similar approach. Understanding—and addressing—the motivations of nonstate actors should be as important as locking down nuclear weapons and materials. The international community has a variety of tools at its disposal for addressing the demand for nuclear weapons. This article suggests a multifaceted approach for understanding, and reducing, the nuclear ambitions of nonstate actors.
Averting Nuclear Catastrophe: Contemplating Extreme Responses to U.S. Vulnerability
Authors: Gallucci Robert L.
Published: August 2006

Traditional deterrence is not an effective approach toward terrorist groups bent on causing a nuclear catastrophe. Preventive strategies, which call for the elimination of an enemy before it is able to attack, are highly risky and often difficult to implement. The United States should instead consider a policy of expanded deterrence, which focuses not on the would-be nuclear terrorists but on those states that may deliberately transfer or inadvertently leak nuclear weapons and materials to them. By threatening retaliation against those states, the United States may be able to deter that which it cannot physically prevent.
Proliferation on the Peninsula: Five North Korean Nuclear Crises
Authors: Perry William J.
Published: August 2006

To reduce the risk of nuclear terrorism, we must prevent terrorists from obtaining nuclear weapons or materials. This will require, among other things, a sustained effort to keep dangerous nations from going nuclear—in particular North Korea. This article reviews the efforts the United States has undertaken through the years to keep North Korea from building a nuclear arsenal, arguing that the history of proliferation on the Korean Peninsula is marked by five nuclear crises. A sixth could be on the horizon, further compromising American efforts to lessen the likelihood of a nuclear attack on U.S. soil.
Intelligence Estimates of Nuclear Terrorism
Authors: Zenko Micah
Published: August 2006

Nuclear terrorism is not a post-9/11 or even post-cold war phenomenon. In fact, this review of declassified intelligence estimates spanning the past five decades reveals that the prospect of a clandestine nuclear attack on the United States—be it from the Soviet Union, China, or al Qaeda—has been a regular concern for U.S. officials since the advent of nuclear weapons. Although the estimates themselves have been a mixed bag of quiet successes and failures, this article’s key findings suggest that the threat of nuclear terrorism is very real and that the U.S. government remains ill prepared to counter that treat.
The Race between Cooperation and Catastrophe: Reducing the Global Nuclear Threat
Authors: Nunn Sam
Published: August 2006

Nuclear terrorism is the greatest national security threat facing the United States. This is a point on which few disagree, yet the effort to reduce the global nuclear threat falls short in terms of speed, resources, and level of effort. This article presents four hypothetical nuclear crises to illustrate this point and suggests a series of steps that, if taken, could help prevent each crisis. We are in a race between cooperation and catastrophe, and the global threat is outpacing our response. We must act now.
Denying Armageddon: Preventing Terrorist Use of Nuclear Weapons
Authors: Hynes Michael V. , Peters John E. , Kvitky Joel
Published: August 2006

The United States can significantly reduce the likelihood of a nuclear terrorist attack if it pursues a vigorous, multilayered approach. Such an approach involves controlling nuclear technology and materials, manipulating the black market, and monitoring the behavior of aspiring nuclear actors. After analyzing each of these components, this article outlines the broad contours of a national preventative strategy that should give the nonproliferation community some cause for optimism.
Russia: Grasping the Reality of Nuclear Terror
Authors: Saradzhyan Simon
Published: August 2006

Radical separatists based in the North Caucasus have the motive and are seeking the means to commit an act of nuclear terrorism as well as allies to help them carry it out. Their proximity to insufficiently secured Russian nuclear facilities and their contents makes the prospect of nuclear terror in Russia very real. This article assesses the magnitude of this threat, considers possible attack scenarios, and suggests ways to reduce the likelihood of a catastrophic attack on Russian soil.
Inter-provincial Disparities in Rural ‘People's Livelihood’ in China
Authors: Natrajan Sriram
Published: August 2006

This article presents an empirical study of the evolution of income disparities in rural China across 24 provinces for 1980–2004. Provincial data on rural net incomes, rural living expenditures and rural expenditures on food are used to study the trends in inter-provincial disparities. Direct statistical measures of dispersion estimated from this data and adjusted for price differentials across provinces and across time, reveal an uneven but sustained increase in inter-provincial rural inequalities. With rural economic growth positively associated with overall provincial growth in the entire period as well as most sub-periods, the gaps in per capita incomes as well as consumption expenditure including expenditures on food across provinces have widened. Divergences across provinces, however, are fewer and show tendencies of reduction during phases of income growth. The findings, placed against the background of the large literature on the subject of inequality in China, provide support to the view that the implications of sustained increases in inequality could not only effect future economic growth but prove to be destabilising as well.
Korea's New Techno-Scientific State
Authors: Uttam Jitendra
Published: August 2006

The article aims to map the process of transformation in the Korean ‘developmental state’ which is evolving into a new ‘techno-scientific state’. In the past, the Korean ‘developmental state’ directed national economic development by decisively controlling the entire financial system. However, after successfully leading economic change for half a century, the role of the Korean state appears to be drastically diminished.

The literature that deals with this issue tends to focus on the demise of the ‘developmental state’ and discusses the ‘post-developmental minimalist state’. However, it clearly ignores the strategic role of the state in creating a distinct ‘techno-scientific’ ethos, which has been critical in enhancing Korea's industrial competitiveness in the face of the established Japanese and the emerging Chinese challenges.

The hypothesis is that the linkages between techno-scientific and techno-industrial progress can be firmly established only by state power because (a) market forces can push innovation in the same or similar techno-industrial sector but not in a distinct techno-scientific sphere; (b) high uncertainty and high-risk factors constrain the ability of market actors to invent new techno-scientific frontiers.

Theoretically, this article is sceptical about the rationale of the neo-liberal ‘minimalist state’ and argues for an enhanced but transformed role of the state in supporting the techno-scientific regime formation. It provides empirical evidence from the experiences of the transforming Korean state. This article argues that the vast policy experience of the Korean State in engineering the ‘economic miracle on the Han River’ can be utilised to establish a distinct techno-scientific regime that can help create a new techno-industrial sector.
The Building of the China-ASEAN Free Trade Area
Authors: Hongfang Shen
Published: August 2006

This article examines Philippine perspectives on the CAFTA and explores the reasons why Philippine official and business circles are not willing to accept the CAFTA concept. It makes a brief assessment of Sino-Philippine economic relations in the context of the CAFTA, and also illustrates the changing attitudes of Philippine official and business sectors toward the CAFTA.
The United States' Discriminatory Protectionism against China
Authors: Noh Yooyeon , Mah Jai S.
Published: August 2006

The article examines the characteristics of the United States’ (US) discriminatory protection measures, especially the antidumping (AD) duties, against China. China has been the most significant target of US trade protectionism in terms of the absolute number as well as the intensity of measures. There exists a positive relationship between the US bilateral trade deficit and the increase in the number of its discriminatory trade protection measures against China. US AD decisions against China have been led by the chemical industry, followed by the iron and steel industry. It is expected that the number of US discriminatory trade protection measures against the Chinese textile products will increase in the coming years, since the ten-year phase-out of the Multi-Fibre Arrangement (MFA) was completed at the end of 2004. Since discriminatory trade restrictions are costly in terms of the welfare of the concerned countries, it would be necessary for them to apply stricter regulations regarding the discriminatory protection measures.
Impersistence of Depression in Youth: Implications for Drug Study Design
Authors: Malone Richard P. , Bennett David S. , Delaney Mary Anne , Choudhury Muniya S. , Luebbert James F. , Cater Jacqueline
Published: August 2006

Food and Drug Administration data show that most antidepressant studies in youth do not show drug effect. The few positive studies used rigorous diagnostic screening procedures, suggesting major depressive disorder (MDD) may not be a persistent condition in a subgroup of youth. To investigate persistence of MDD, we serially assessed a cohort of inpatients admitted to the hospital with a clinical diagnosis of MDD. Assessments included a structured diagnostic interview, the Diagnostic Interview for Children and Adolescents‐Revised (DICA‐R), and measures of depressive symptomatology. Of 66 subjects (40 girls; mean age, 14.4 ± 2.2 years), 34 (51.5%) met DICA‐R criteria for MDD at the initial postadmission assessment. Of these, only 8 (23.5%) met DICA‐R criteria for MDD at any subsequent assessment. Similar reductions were found on other ratings of depression. In conclusion, MDD did not persist in this sample. The findings suggest a multigated assessment procedure should be employed before randomization in antidepressant clinical trials.
Food Does Not Affect the Pharmacokinetics of Tesaglitazar, a Novel Dual Peroxisome Proliferator‐Activated Receptor α/γ Agonist
Authors: Samuelsson S. , Johansson S. , Halldórsdóttir S. , Stenhoff H. , Öhman K. P.
Published: August 2006

Tesaglitazar is a dual peroxisome proliferator‐activated receptor (PPAR) α/γ agonist in development to treat lipid and glucose abnormalities associated with type 2 diabetes. This study evaluated the effects of food on tesaglitazar pharmacokinetics. In an open, randomized, 2‐way crossover study, 20 healthy men received tesaglitazar 1 mg during fasting and after a high‐fat, high‐calorie breakfast. Blood samples were taken to assess pharmacokinetic variables. Systemic exposure to tesaglitazar was unaffected by food intake. Estimated ratios were 0.99 (90% confidence interval [CI], 0.94–1.04) for fed/fasted area under plasma concentration‐time curve and 0.82 (90% CI, 0.78–0.86) for fed/fasted maximum plasma concentration (Cmax). Mean Cmaxwas ∼18% lower (0.41 [95% CI, 0.38–0.43] versus 0.50 [95% CI, 0.47–0.53] μmol/L), and median time to Cmaxwas increased (2.00 vs 0.75 h) in fed versus fasted state. The median difference of tmaxwas 1.25 h (P = .0001, signed‐rank test). Tesaglitazar was well tolerated. Tesaglitazar pharmacokinetics is unaffected by food intake, allowing once‐daily administration of tesaglitazar with or without food in clinical practice.
Pediatric Licensing Status and the Availability of Suitable Formulations for New Medical Entities Approved in the United States Between 1998 and 2002
Authors: Balakrishnan Komathi , Grieve Joanne , Tordoff June , Norris Pauline , Reith David
Published: August 2006

The availability of new medical entities for children in the United States was examined at the time of marketing approval and 3 years later. New medical entities approved in the United States in each of the years 1998 to 2002 were identified using the Center for Drug Evaluation and Research Web site. Each Physicians’ Desk Reference published in the years 1998 to 2005 was examined to determine formulations and licensing information. For the 133 new medical entities licensed to be marketed in the period 1998 to 2002, the number licensed for children increased from 5 (4%) to 39 (29%) in the 3 years after registration. After 3 years’ marketing, 79 (59%) drugs were in formulations suitable for children, and 27 (20%) of the new medical entities were licensed and had a suitable formulation for children. Incentives to improve access for children to medicines should focus more on demonstration of improved access.