bluuebunny/crossref_metadata_2025 huggingface dataset:
Beyond the Laboratory
Authors: Halcox Julian P.J. , Deanfield John E.
Published: June 2004

Results from large-scale clinical trials of lipid lowering with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have led to a revolution in the management of atherosclerosis. In addition to their potent effect on serum lipid levels, statins influence several other cellular pathways, including those involving inflammatory, oxidative, and thrombotic processes. These effects clearly have the potential to beneficially modify the atherogenic process, and it has been suggested that they contribute to the impressive results seen in the clinical trials. We review the clinical evidence for benefits of statin therapy that are distinct from their effect on lipid biology. In particular, we address three key issues: the role of statins in diseases not traditionally associated with elevated cholesterol levels; whether clinical benefits are seen with statin therapy before an effect on lipid levels; and whether the magnitude of clinical benefit observed with statin therapy is unrelated to the degree of cholesterol reduction. At present, low-density–lipoprotein lowering seems to be the primary mechanism underlying the clinical benefits of statin therapy and should remain the focus of risk-reduction strategies in clinical practice.
Endothelial Function
Authors: Landmesser Ulf , Hornig Burkhard , Drexler Helmut
Published: June 2004

Common conditions predisposing to atherosclerosis, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with endothelial dysfunction. Endothelial function has largely been assessed as endothelium-dependent vasomotion, at least in part based on the assumption that impaired endothelium-dependent vasodilation also reflects the alteration of other important functions of the endothelium. An important rationale for this approach has been the observation that endothelium-derived nitric oxide (NO), a major mediator of endothelium-dependent vasodilation, has important anti-inflammatory and antithrombotic properties, ie, inhibiting leukocyte adhesion, limiting platelet adhesion and aggregation, and the expression of plasminogen activator inhibitor-1 (PAI-1), a prothrombotic protein. Accumulating data suggest that the degree of impairment of endothelium-dependent vasomotion has profound and independent prognostic implications. A common mechanism underlying endothelial dysfunction relates to increased vascular production of reactive oxygen species. Recent studies also suggest that inflammation per se and C-reactive protein in particular may directly contribute to endothelial dysfunction. These findings raise the question of whether assessment of endothelial function can be used in the clinical setting to identify patients at high risk. New insights into mechanisms of endothelial dysfunction, such as a better understanding of the regulation of important vascular sources of oxygen radicals, may lead to novel therapeutic strategies with the potential to improve prognosis.
Statins as Immunomodulatory Agents
Authors: Mach François
Published: June 2004

Statins have long been thought to exert their benefits by reducing cholesterol synthesis. However, the fact that mevalonate is the precursor of isoprenoids that regulate diverse cellular functions has led investigators to examine pleiotropic effects for these agents. Major histocompatibility complex class II (MHC-II) molecules, which affect the immune response and organ rejection after transplantation, may be induced by the proinflammatory cytokine interferon gamma (IFN-γ). An experiment was conducted to determine whether statins affect the regulation of MHC-II expression by IFN-γ in cultured human endothelial cells and monocyte/macrophages. Statins were found to repress the induction of MHC-II by IFN-γ. This may explain the immunosuppressive effects of statins seen in two clinical trials of organ transplantation and suggest a potential role for statins as immunosuppressive agents.
Effects of HMG-CoA Reductase Inhibitors on Endothelial Function
Authors: Mason R. Preston , Walter Mary F. , Jacob Robert F.
Published: June 2004

Certain pleiotropic activities reported for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are related to reductions in cellular cholesterol biosynthesis and isoprenoid levels. In endothelial cells, these metabolic changes contribute to favorable effects on nitric oxide (NO) bioavailability. Given the essential role of NO in preserving vascular structure and function, this effect of statins is of considerable therapeutic importance. Statins have been demonstrated to restore endothelial NO production by several mechanisms, including upregulating endothelial NO synthase (eNOS) protein expression and blocking formation of reactive oxygen species. In this article, we will discuss additional ways in which statins restore endothelial NO production and improve endothelial function. (1) Statins modulate membrane microdomain formation, resulting in reduced expression of proteins that specifically inhibit eNOS activation. (2) Statins reduce sterol biosynthesis, thus interfering with the formation of pathologic microdomains, including cholesterol crystalline structures. This observation has important implications for plaque stabilization, as these microdomains contribute to cholesterol crystal formation and endothelial apoptosis. Finally, (3) statins improve endothelial function by interfering with oxidative stress pathways through both enzymatic and nonenzymatic mechanisms. The relationships between membrane microdomains, cholesterol biosynthesis, and endothelial function will be discussed.
Inflammation, Immunity, and HMG-CoA Reductase Inhibitors
Authors: Schönbeck Uwe , Libby Peter
Published: June 2004

According to traditional thinking, atherosclerosis results from passive lipid deposition in the vascular wall. Thus, therapies predominantly targeted lipid metabolism. The contemporary view of atherosclerosis, however, has broadened to include an active and complex role for inflammation, orchestrated in part by mediators of the immune system. This recognition prompted the question of whether antiinflammatory interventions might provide a novel avenue for the treatment of atherosclerosis. Uncertainties about the type of antiinflammatory regimen and appropriate patient selection currently hamper clinical investigation. Yet cardiovascular scientists have begun to address these questions at the bench, in experimental models, and indirectly in humans. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A HMG-CoA reductase (statins) have emerged as promising tools with dual functions. Originally designed to target elevated lipids, the “traditional” cause of atherosclerosis, statins might also confer cardiovascular benefit by directly or indirectly modulating the inflammatory component of this prevalent disease. Yet controversy persists regarding the (clinical) relevance of these potential non–LDL-lowering “pleiotropic” functions of statins. This overview addresses the controversy by reviewing in vitro and in vivo evidence regarding statins as antiinflammatory agents.
CRP as a Mediator of Disease
Authors: Yeh Edward T.H.
Published: June 2004

Of the various hypotheses offered to explain atherosclerosis, inflammation now appears to provide a key to this pathological process. Inflammation has been shown to play a major role in precipitating a cascade of events from formation of the atheromatous lesion in response to vascular injury through lipid ingestion by macrophages, to subsequent rupture of the lesion, and myocardial infarction. Atherosclerosis shares many inflammatory features with rheumatoid arthritis (RA), an autoimmune disease, and drugs that block the inflammatory cytokine pathway now provide effective treatment for RA. In animal models, blockers of the inflammatory cytokine pathway appear to block mononuclear cell binding to arterial plaque. C-reactive protein (CRP), an inflammatory marker, may also play a proinflammatory role in activating monocyte chemotactic protein. Antiatherosclerotic drugs may be exerting some of their beneficial effects by inhibiting the harmful effects of CRP.
Inflammation as a Cardiovascular Risk Factor
Authors: Willerson James T. , Ridker Paul M.
Published: June 2004

Inflammation occurs in the vasculature as a response to injury, lipid peroxidation, and perhaps infection. Various risk factors, including hypertension, diabetes, and smoking, are amplified by the harmful effects of oxidized low-density–lipoprotein cholesterol, initiating a chronic inflammatory reaction, the result of which is a vulnerable plaque, prone to rupture and thrombosis. Epidemiological and clinical studies have shown strong and consistent relationships between markers of inflammation and risk of future cardiovascular events. Inflammation can potentially be detected locally by imaging techniques as well as emerging techniques, such as identification of temperature or pH heterogeneity. It can be detected systemically by measurement of inflammatory markers. Of these, the most reliable and accessible for clinical use is currently high-sensitivity C-reactive protein. A combination of methods may provide the best identification of persons at risk for cardiovascular events who would benefit from treatment. In randomized, controlled trials, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, in the form of statins, have been shown to provide effective therapy for lowering CRP, in conjunction with their lipid-lowering effects. Although the magnitude of risk reduction associated with statin use appears to be largest for those with the highest serum levels of CRP, whether CRP reduction per se lowers cardiovascular risk is unknown.
Contribution of Fluid Shear Response in Leukocytes to Hemodynamic Resistance in the Spontaneously Hypertensive Rat
Authors: Fukuda Shunichi , Yasu Takanori , Kobayashi Nobuhiko , Ikeda Nahoko , Schmid-Schönbein Geert W.
Published: June 2004

The mechanisms for elevation of peripheral vascular resistance in spontaneously hypertensive rats (SHR), a glucocorticoid-dependent form of hypertension, are unresolved. An increase in hemodynamic resistance caused by circulating blood may be a factor. Physiological fluid shear stress induces a variety of responses in circulating leukocytes, including pseudopod retraction. Due to high rigidity, leukocytes with pseudopods have greater difficulty to pass through capillaries. Because SHR have more circulating leukocytes with pseudopods, we hypothesize that inhibition of the leukocyte shear response by glucocorticoids in SHR impairs normal leukocyte passage through capillaries and causes enhanced resistance in capillary channels. Fluid shear leads to retraction of pseudopods in normal leukocytes, whereas shear induces pseudopod projection in SHR and dexamethasone-treated Wistar rats. The high incidence of circulating leukocytes with pseudopods results in slower cell passage through capillaries under normal blood flow and during reduced flow enhanced capillary plugging both in vivo and in vitro. SHR blood requires higher pressure (90.0±8.2 mm Hg) than Wistar Kyoto rat (WKY, 69.6±6.5 mm Hg;
P
<0.0001) or adrenalectomized SHR (73.5±2.1 mm Hg;
P
=0.0009) at the same flow rate in the resting hemodynamically isolated skeletal muscle microcirculation. Intravenous injection of blood from SHR, but not WKY, causes blood pressure increase in normal rats, which depends on pseudopod formation. We conclude that in addition to enhanced vascular tone, pseudopod formation with lack of normal fluid shear response may serve as mechanisms for an elevated hemodynamic resistance in SHR.
Mechanisms of Cardiac Nerve Sprouting After Myocardial Infarction in Dogs
Authors: Zhou Shengmei , Chen Lan S. , Miyauchi Yasushi , Miyauchi Mizuho , Kar Saibal , Kangavari Simon , Fishbein Michael C. , Sharifi Behrooz , Chen Peng-Sheng
Published: June 2004

Cardiac nerve sprouting and sympathetic hyperinnervation after myocardial infarction (MI) both contribute to arrhythmogenesis and sudden death. However, the mechanisms responsible for nerve sprouting after MI are unclear. The expression of nerve growth factor (NGF), growth associated protein 43 (GAP43), and other nerve markers were studied at the infarcted site, the noninfarcted left ventricle free wall (LVFW), and the left stellate ganglion (LSG) at several time points (30 minutes to 1 month) after MI. Transcardiac (difference between coronary sinus and aorta) NGF levels were also assayed. Acute MI resulted in the immediate elevation of the transcardiac NGF concentration within 3.5 hours after MI, followed by the upregulation of cardiac NGF and GAP43 expression, which was earlier and more pronounced at the infarcted site than the noninfarcted LVFW. However, cardiac nerve sprouting and sympathetic hyperinnervation were more pronounced in the noninfarcted than the infarcted LVFW site and peaked at 1 week after MI. The NGF and GAP43 protein levels significantly increased in the LSG from 3 days (
P
<0.01 for all) after MI, without a concomitant increase in mRNA. There was persistent elevation of NGF levels in aorta and coronary sinus within 1 month after MI. We conclude MI results in immediate local NGF release, followed by upregulation of NGF and GAP43 expression at the infarcted site. NGF and GAP43 are transported retrogradely to LSG, which triggers nerve sprouting at the noninfarcted LVFW. A rapid and persistent upregulation of NGF and GAP43 expression at the infarcted site underlies the mechanisms of cardiac nerve sprouting after MI.
Cardioprotection During the Final Stage of the Late Phase of Ischemic Preconditioning Is Mediated by Neuronal NO Synthase in Concert With Cyclooxygenase-2
Authors: Wang Yang , Kodani Eitaro , Wang Jianxun , Zhang Shelley X. , Takano Hitoshi , Tang Xian-Liang , Bolli Roberto
Published: June 2004

The infarct-sparing effect of the late phase of ischemic preconditioning (late PC) lasts for 72 hours. Upregulation of both cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) has been shown to be essential to the protection in the initial stage of late PC (24 hours after PC); however, the mechanisms underlying the protection in the final stage of late PC (48 to 72 hours after PC) are unknown. Conscious rabbits were preconditioned with six cycles of 4-minute coronary occlusion/4-minute reperfusion. At 72 hours after PC, powerful protection against infarction was associated with increased myocardial levels of COX-2 mRNA, protein, and cardioprotective prostaglandins (PGI
2
and PGE
2
). The COX-2–selective inhibitor NS-398 completely blocked the protection. Surprisingly, iNOS expression was not increased at 72 hours; instead, upregulation of neuronal NO synthase (nNOS) was evident at both the mRNA (+266±20%,
P
<0.005) and the protein levels (+195±66%,
P
<0.005), which was accompanied by an increase in myocardial nitrite/nitrate (+20±4%,
P
<0.05). The nNOS-selective inhibitors
N
-propyl-
l
-arginine or
S
-ethyl
N
-[4-(trifluoromethyl)phenyl]isothiourea completely blocked the protection of late PC at 72 hours, whereas the iNOS-selective inhibitor
S
-methylisothiourea had no effect. In line with these findings, the disappearance of protection at 120 hours after PC was associated with the return of nNOS mRNA, protein, and activity to control levels. Although expression of COX-2 protein was still elevated at 120 hours, only a marginal increase in PGI
2
and PGE
2
levels was detected. In contrast to 72 hour after PC, nNOS was not upregulated at 24 hour after PC. We conclude that (1) the cardioprotection observed in the final stage of late PC (72 hour) is mediated by nNOS, not by iNOS, in concert with COX-2, and (2) nNOS-derived NO is required to drive COX-2 activity. These data identify, for the first time, a cardioprotective role of nNOS and demonstrate, surprisingly, that the mechanism of late PC differs at 72 hours (nNOS) versus 24 hours (iNOS).
Activated Protein C Induces Endothelial Cell Proliferation by Mitogen-Activated Protein Kinase Activation In Vitro and Angiogenesis In Vivo
Authors: Uchiba Mitsuhiro , Okajima Kenji , Oike Yuichi , Ito Yasuhiro , Fukudome Kenji , Isobe Hirotaka , Suda Toshio
Published: June 2004

Activated protein C (APC), a natural anticoagulant, has recently been demonstrated to activate the mitogen-activated protein kinase (MAPK) pathway in endothelial cells in vitro. Because the MAPK pathway is implicated in endothelial cell proliferation, it is possible that APC induces endothelial cell proliferation, thereby causing angiogenesis. We examined this possibility in the present study. APC activated the MAPK pathway, increased DNA synthesis, and induced proliferation in cultured human umbilical vein endothelial cells dependent on its serine protease activity. Antibody against the endothelial protein C receptor (EPCR) inhibited these events. Early activation of the MAPK pathway was inhibited by an antibody against protease-activated receptor-1, whereas neither late and complete activation of the MAPK pathway nor endothelial cell proliferation were inhibited by this antibody. APC activated endothelial nitric oxide synthase (eNOS) via phosphatidylinositol 3-kinase–dependent phosphorylation, followed by activation of protein kinase G, suggesting that APC bound to EPCR might activate the endothelial MAPK pathway by a mechanism similar to that of VEGF. APC induced morphogenetic changes resembling tube-like structures of endothelial cells, whereas DIP-APC did not. When applied topically to the mouse cornea, APC clearly induced angiogenesis in wild-type mice, but not in eNOS knockout mice. These in vitro events induced by APC might at least partly explain the angiogenic activity in vivo. This angiogenic activity of APC might contribute to maintain proper microcirculation in addition to its antithrombotic activity.
Embryonic Heart Failure in
NFATc1
−/−
Mice
Authors: Phoon Colin K.L. , Ji Rui Ping , Aristizábal Orlando , Worrad Diane M. , Zhou Bin , Baldwin H. Scott , Turnbull Daniel H.
Published: June 2004

Gene targeting in the mouse has become a standard approach, yielding important new insights into the genetic factors underlying cardiovascular development and disease. However, we still have very limited understanding of how mutations affect developing cardiovascular function, and few studies have been performed to measure altered physiological parameters in mouse mutant embryos. Indeed, although in utero lethality due to embryonic heart failure is one of the most common results of gene targeting experiments in the mouse, the underlying physiological mechanisms responsible for embryonic demise remain elusive. Using in utero ultrasound biomicroscopy (UBM), we studied embryonic day (E) 10.5 to 14.5
NFATc1
−/−
embryos and control littermates.
NFATc1
−/−
mice, which lack outflow valves, die at mid-late gestation from presumed defects in forward blood flow with resultant heart failure. UBM showed increasing abnormal regurgitant flow in the aorta and extending into the embryonal–placental circulation, which was evident after E12.5 when outflow valves normally first develop. Reduced
NFATc1
−/−
net volume flow and diastolic dysfunction contributed to heart failure, but contractile function remained unexpectedly normal. Among 107
NFATc1
−/−
embryos imaged, only 2 were observed to be in acute decline with progressive bradyarrhythmia, indicating that heart failure occurs rapidly in individual
NFATc1
−/−
embryos. This study is among the first linking a specific physiological phenotype with a defined genotype, and demonstrates that
NFATc1
−/−
embryonic heart failure is a complex phenomenon not simply attributable to contractile dysfunction.
Doxycycline Suppresses Cerebral Matrix Metalloproteinase-9 and Angiogenesis Induced by Focal Hyperstimulation of Vascular Endothelial Growth Factor in a Mouse Model
Authors: Lee Chanhung Z. , Xu Bin , Hashimoto Tomoki , McCulloch Charles E. , Yang Guo-Yuan , Young William L.
Published: June 2004

Background and Purpose—

A number of central nervous system (CNS) disorders are associated with abnormalities in or activation of angiogenesis, including vascular malformations. To test the hypothesis that the nonspecific matrix metalloproteinase (MMP) inhibitor, doxycycline, suppresses vascular endothelial growth factor (VEGF)-induced cerebral angiogenesis through inhibition of MMPs, we used a mouse model with enhanced cerebral angiogenesis induced by focal hyperstimulation of VEGF from adenovirus DNA (AdVEGF) transduction.

Methods—

The time course study of MMP activity was performed at 7 and 14 days after AdVEGF transduction. MMP activity and expression were examined by zymography and immunohistochemistry, respectively. As an index of cerebral angiogenesis, microvessel counting was performed in the brains of 3 groups of mice (n=6): (1) control; (2) AdVEGF only; and (3) AdVEGF plus doxycycline (30 mg/kg per day).

Results—

Brain MMP-9 activities increased 4-fold (883±137 versus 179±179; 1-sided
P
<0.001) at 7 days after AdVEGF transduction. VEGF transduction increased vessel counts by 19% (255±27 versus 215±15, 1-sided
P
<0.01). Doxycycline treatment decreased MMP-9 activity (89±72 versus 883±137; 1-sided
P
<0.001) and cerebral microvessel number (231±17 versus 255±27; 1-sided
P
<0.05).

Conclusions—

Doxycycline is effective in decreasing stimulated cerebral MMP-9 activity and parenchymal angiogenesis. The decrease in MMP-9 activity is associated with decreased microvessel counts. Brain pathophysiological processes that involve abnormally enhanced angiogenesis may be amenable to manipulation by MMP inhibitors, including tetracycline derivatives.
Animal Protein, Animal Fat, and Cholesterol Intakes and Risk of Cerebral Infarction Mortality in the Adult Health Study
Authors: Sauvaget Catherine , Nagano Jun , Hayashi Mikiko , Yamada Michiko
Published: June 2004

Background and Purpose—

A traditional diet that is poor in animal products is thought to explain the high rate of stroke in Asian populations. The purpose of the present study was to examine the effect of a diet rich in animal protein, animal fat, and cholesterol on the risk of cerebral infarction mortality in a Japanese population.

Methods—

A prospective study of 3731 Japanese men and women aged 35 to 89 years was conducted from 1984 to 2001. Nutrient intake was estimated at baseline from the responses to a 24-hour diary. During the follow-up period, cases of cerebral infarction deaths (as entered on death certificates) were monitored.

Results—

During the follow-up period, 60 deaths were attributed to cerebral infarction. A high intake of animal fat and cholesterol was significantly associated with a reduced risk of cerebral infarction death. The risk was reduced by 62% (CI, 82% to 18%) for those in the third tertile of animal fat intake, compared with those in the first tertile, with a significant linear dose-response relationship (
P
=0.0073). The risk of death from infarction was reduced by 63% (CI, 82% to 22%) in the high cholesterol consumption group, compared with the low consumption group. A significant linear dose–response relationship was observed. Animal protein was not significantly associated with infarction mortality after adjustment for animal fat and cholesterol.

Conclusions—

This study suggests that in Japan, where animal product intake is lower than in Western countries, a high consumption of animal fat and cholesterol was associated with a reduced risk of cerebral infarction death.
Longitudinal Risk of Intracranial Hemorrhage in Patients With Arteriovenous Malformation of the Brain Within a Defined Population
Authors: Halim Alexander X. , Johnston S. Claiborne , Singh Vineeta , McCulloch Charles E. , Bennett John P. , Achrol Achal S. , Sidney Stephen , Young William L.
Published: June 2004

Background and Purpose—

Accurate estimates for risk and rates of intracranial hemorrhage (ICH) in the natural course of patients harboring brain arteriovenous malformation (BAVM) are needed to provide a quantitative basis for planning clinical trials to evaluate interventional strategies and to help guide practice management.

Methods—

We identified patients with BAVM at the Kaiser Permanente Northern California health maintenance organization and documented their clinical course. The influences of age at diagnosis, gender, race-ethnicity, ICH at presentation, venous draining pattern, and BAVM size on ICH subsequent to presentation were studied using the multivariate Cox proportional hazards model and Kaplan-Meier curves.

Results—

We identified 790 patients with BAVM (51% female; 63% white; mean age±SD at diagnosis: 38±19 years) between 1961 and 2001. Patients who presented with ICH experienced a higher rate of subsequent ICH than those who presented without ICH under multivariate analysis (hazard ratio, 3.6; 95% CI, 1.1 to 11.9;
P
<0.032). The effect was similar across race-ethnicity and gender. This difference in ICH rates was greatest in the first year (7% versus 3% per year) and converged over time. The effect of subsequent ICH on functional status was similar to that of the initial ICH.

Conclusions—

Presentation with ICH was the most important predictor of future ICH, confirming previous studies. Future ICH had similar impact on functional outcome as incident ICH. Intervention to prevent ICH would be of potentially greater benefit to patients presenting with ICH, although the advantage decreases over time.
Seizures and Epilepsy After Ischemic Stroke
Authors: Camilo Osvaldo , Goldstein Larry B.
Published: June 2004

Background—

Although a long-recognized clinical phenomenon, there remain many questions regarding the epidemiology of seizures and epilepsy after ischemic stroke, their effect on outcome, and their treatment.

Summary of Review—

Interpretation of the various studies that have been conducted of postischemic stroke seizures and epilepsy are complicated by their heterogeneous designs, inconsistent uses of terminology, small sample sizes, different periods of follow-up, and ambiguities in seizure identification and classification. Estimates of the rate of early postischemic stroke seizures range from 2% to 33%. The rates of late seizures vary from 3% to 67%. The rate of postischemic stroke epilepsy is ≈2% to 4% and is higher in those who have a late seizure. Data reflecting seizure subtypes are limited. Aside from cortical location and, possibly, stroke severity, no other risk factors for postischemic stroke seizures have been consistently demonstrated. Results regarding the impact of postischemic stroke seizures on outcome are inconsistent.

Conclusions—

Much additional work is needed to better understand the epidemiology and social impact of postischemic stroke seizures and epilepsy, their prevention, and optimal management.
In Vivo Detection of Macrophages in Human Carotid Atheroma
Authors: Trivedi Rikin A. , U-King-Im Jean-Marie , Graves Martin J. , Cross Justin J. , Horsley Jo , Goddard Martin J. , Skepper Jeremy N. , Quartey George , Warburton Elizabeth , Joubert Ilse , Wang Liqun , Kirkpatrick Peter J. , Brown John , Gillard Jonathan H.
Published: June 2004

Background—

It has been suggested that inflammatory cells within vulnerable plaques may be visualized by superparamagnetic iron oxide particle-enhanced MRI. The purpose of this study was to determine the time course for macrophage visualization with in vivo contrast-enhanced MRI using an ultrasmall superparamagnetic iron oxide (USPIO) agent in symptomatic human carotid disease.

Methods—

Eight patients scheduled for carotid endarterectomy underwent multisequence MRI of the carotid bifurcation before and 24, 36, 48, and 72 hours after Sinerem (2.6 mg/kg) infusion.

Results—

USPIO particles accumulated in macrophages in 7 of 8 patients given Sinerem. Areas of signal intensity reduction, corresponding to USPIO/macrophage-positive histological sections, were visualized in all 7 of these patients, optimally between 24 and 36 hours, decreasing after 48 hours, but still evident up to 96 hours after infusion.

Conclusions—

USPIO-enhanced MRI of carotid atheroma can be used to identify macrophages in vivo. The temporal change in the resultant signal intensity reduction on MRI suggests an optimal time window for the detection of macrophages on postinfusion imaging.
HMG-CoA Reductase Inhibitor, Atorvastatin, Promotes Sensorimotor Recovery, Suppressing Acute Inflammatory Reaction After Experimental Intracerebral Hemorrhage
Authors: Jung Keun-Hwa , Chu Kon , Jeong Sang-Wuk , Han So-Young , Lee Soon-Tae , Kim Jin-Young , Kim Manho , Roh Jae-Kyu
Published: June 2004

Background and Purpose—

Statins have neuroprotective effects on ischemic stroke. They modify the endothelial function, increase blood flow, and inhibit thrombus formation, which are independent of lipid-lowering effects. However, whether statins have a protective effect toward hemorrhagic stroke is yet unknown. To test this possibility, we attempted to determine the effect of atorvastatin on experimental intracerebral hemorrhage (ICH).

Methods—

ICH was induced using stereotaxic infusion of collagenase into the left basal ganglia in adult rats. Atorvastatin (1 mg/kg or 10 mg/kg) or phosphate-buffered saline was administered for 2 weeks. To monitor the sensorimotor deficits, limb placing and Rotorod tests were performed. Hematoma volume, brain water content, and hemispheric atrophy were analyzed. Immunohistochemical staining for myeloperoxidase (MPO), microglia (OX42), inducible nitric oxide synthase (iNOS), or endothelial nitric oxide synthase (eNOS) was performed. Perihematomal cell death was determined by TUNEL staining.

Results—

The atorvastatin-treated ICH group showed better performance on Rotorod and limb placing tests when compared with the vehicle-treated group (
P
<0.01). The hematoma volumes between groups were not different, but the brain water content and hemispheric atrophy were reduced in the atorvastatin-treated ICH group. Atorvastatin reduced TUNEL-positive cells, iNOS expression, and MPO-positive or OX42-positive cells in the perihematomal regions in a dose-dependent manner, whereas it increased eNOS expression.

Conclusion—

The present study shows that atorvastatin reduces the perihematomal cell death via antiinflammation, which is associated with sensorimotor recovery after experimental ICH.
II Genotype of the Angiotensin-Converting Enzyme Gene Increases the Risk for Subarachnoid Hemorrhage From Ruptured Aneurysm
Authors: Slowik Agnieszka , Borratynska Anna , Pera Joanna , Betlej Marek , Dziedzic Tomasz , Krzyszkowski Tadeusz , Czepko Ryszard , Figlewicz Denise A. , Szczudlik Andrzej
Published: June 2004

Background and Purpose—

Evidence exists in support of a role of genetic factors in susceptibility to aneurysmal subarachnoid hemorrhage (SAH) in humans. Meta-analysis of 2 previous studies showed that the I allele of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism was a weak, but significant, risk factor for aneurysmal SAH. Moreover, a recent study has shown that the local renin-angiotensin system (RAS) is involved in the development of intracranial aneurysm. The aim of this study was to investigate the association between ACE I/D polymorphism and a risk for aneurysmal SAH in a Polish population.

Methods—

Ninety patients with aneurysmal SAH (mean age: 48.9±14.0 years) and 128 healthy controls matched for age and sex were genotyped for the ACE I/D polymorphism. Aneurysmal SAH was diagnosed by cranial computed tomography and/or lumbar puncture and digital subtraction angiography. ACE gene polymorphism was detected by polymerase chain reaction amplification of the intron 16-specific I/D fragments, 490-bp and 190-bp, respectively.

Results—

The ACE genotype distribution in patients with aneurysmal SAH (II, 52.2%; ID, 15.6%; DD, 32.2%) differed significantly from controls (II, 23.4%; ID, 50.8%; DD, 25.8%) (
P
<0.001). A logistic regression model showed that the II genotype of ACE gene was independent from female sex and smoking as a risk factor for aneurysmal SAH (OR, 4.57; 95% CI, 2.35 to 8.90).

Conclusion—

Here we report that II genotype of ACE gene is a risk factor for aneurysmal SAH.
Plasma Cellular-Fibronectin Concentration Predicts Hemorrhagic Transformation After Thrombolytic Therapy in Acute Ischemic Stroke
Authors: Castellanos Mar , Leira Rogelio , Serena Joaquín , Blanco Miguel , Pedraza Salvador , Castillo José , Dávalos Antoni
Published: June 2004

Background and Purpose—

Elevated plasma levels of cellular fibronectin (c-Fn) reflect vascular damage, so c-Fn might be a marker of secondary bleeding risk in cerebral ischemia. We investigated whether high plasma levels of c-Fn were associated with hemorrhagic transformation (HT) after treatment with tissue plasminogen activator (tPA) in patients with acute stroke.

Methods—

Eighty-seven patients (mean age: 67±12) received tPA after the ECASS II criteria (mean time to infusion: 160±46 minutes; median NIHSS: 12). HT and hypodensity volume were studied on computed tomography (CT) performed 24 to 36 hours after treatment. HT was classified according to the ECASS II definitions. c-Fn and matrix metalloproteinase 9 (MMP-9) levels were determined by ELISA in blood samples obtained before treatment and in 30 healthy subjects.

Results—

HT was found in 26 patients (30%); 15 patients had hemorrhagic infarction type 1 (HI-1), 7 had HI-2, and 4 had parenchymal hemorrhage (PH). Median c-Fn concentrations were 1.3, 1.7, 4.2, 5.4, and 7.3 μg/mL in controls, non-HT, HI-1, HI-2, and PH groups, respectively (
P
<0.001); median MMP-9 values were 54, 87, 154, 176, and 225 ng/mL (
P
<0.001). Logistic regression analysis showed that only c-Fn plasma levels remained independently associated with HT after adjusting for potential confounders (OR, 2.1; 95% CI, 1.3 to 3.4;
P
=0.002). Similar results were obtained in the 71 patients treated within 3 hours.

Conclusions—

High plasma c-Fn levels are significantly associated with subsequent HT in stroke patients treated with tPA, so plasma c-Fn determinations might be useful in clinical practice to improve the risk/benefit ratio of thrombolytic treatment.
Venous Drainage in Perimesencephalic Hemorrhage
Authors: van der Schaaf Irene C. , Velthuis Birgitta K. , Gouw Alida , Rinkel Gabriel J. E.
Published: June 2004

Background and Purpose—

In perimesencephalic nonaneurysmal hemorrhage (PMH), subarachnoid blood accumulates around the midbrain. Clinical and radiological characteristics suggest a venous origin of PMH. We compared the venous drainage of the midbrain between patients with PMH and aneurysmal subarachnoid hemorrhage (aSAH) by means of computed tomography angiography (CTA).

Methods—

CTAs of 55 PMH patients and 42 aSAH patients with a posterior circulation aneurysm were reviewed. Venous drainage was classified into: (1) normal continuous: the basal vein of Rosenthal is continuous with the deep middle cerebral vein and drains mainly to the vein of Galen (VG); (2) normal discontinuous: drainage anterior to uncal veins and posterior to VG; and (3) primitive variant: drainage to other veins than VG. Additionally, we compared in PMH patients the side of the primitive variant and side of the bleeding.

Results—

A primitive variant was present on one or both hemispheres in 53% of PMH patients with PMH (95% CI, 40% to 65%) and in 19% of aSAH patients (95% CI, 10% to 33%). In all 16 PMH patients with a unilateral primitive drainage, blood was seen on the side of the primitive drainage (100%; 95% CI, 81% to 100%); blood was never found mainly on the side with normal drainage.

Conclusions—

Patients with PMH have a primitive venous drainage directly into dural sinuses instead of via the vein of Galen more often than do controls. Moreover, the side of the perimesencephalic hemorrhage relates to the side of the primitive drainage. These results further support a venous origin of PMH.
Cigarette Smoking as a Risk Factor for Stroke Death in Japan
Authors: Ueshima Hirotsugu , Reza Choudhury Sohel , Okayama Akira , Hayakawa Takehito , Kita Yoshikuni , Kadowaki Takashi , Okamura Tomonori , Minowa Masumi , Iimura Osamu
Published: June 2004

Background and Purpose—

Some previous Japanese cohort studies failed to show an association between smoking and stroke risk. Because such an association has been noted in other populations, this issue should be re-examined in a recent representative Japanese cohort with a higher total cholesterol level.

Methods—

A total of 9638 men and women aged 30 years and older without a history of cardiovascular disease (CVD) at baseline in 1980 were followed-up for 14 years.

Results—

We observed 203 stroke deaths (107 cerebral infarctions, 45 cerebral hemorrhages, and 51 others), 191 heart disease deaths, and 413 CVD deaths. The average serum total cholesterol level was ≈4.91 mmol/L. Cox proportional hazard ratios were calculated adjusting for age, systolic blood pressure, and other conventional risk factors. The hazard ratios for men who smoked 1 to 20 cigarettes/day for all strokes, cerebral infarction, and cerebral hemorrhage were 1.60 (95% CI, 0.91 to 2.79), 2.97 (CI, 1.27 to 6.98), and 0.42 (CI, 0.16 to 1.09), respectively, and for those who smoked ≥21 cigarettes/day, they were 2.17 (CI, 1.09 to 4.30), 3.26 (CI, 1.11 to 9.56), and 0.68 (CI, 0.20 to 2.33), respectively. For women who smoked ≥21 cigarettes/day, the hazard ratio for all strokes was 3.91 (CI, 1.18 to 12.90). For CVD, all heart disease, and ischemic heart disease, the hazard risks of smoking were significant (1.49 to 4.25) for men but not significant for women.

Conclusions—

Smoking in a cohort with moderate serum total cholesterol level was a potent risk factor for stroke, especially cerebral infarction, for both men and women, and for CVD and ischemic heart disease for men.
Effect of Perindopril on Cerebral Vasomotor Reactivity in Patients With Lacunar Infarction
Authors: Walters Matthew , Muir Scott , Shah Imtiaz , Lees Kennedy
Published: June 2004

Background and Purpose—

There is growing evidence that pharmacologic interference with the renin-angiotensin system may reduce risk of stroke, although the mechanism is unclear. Impaired reactivity of cerebral vessels has recently been recognized as a risk factor for stroke. We examined the effect of the angiotensin-converting enzyme (ACE) inhibitor perindopril on cerebral vasomotor reactivity to acetazolamide in patients with lacunar cerebral infarction.

Methods—

We studied a cohort of male patients between 3 and 12 months after lacunar infarction confirmed on computed tomography. Each patient received perindopril 4 mg daily or matching placebo for 2 weeks in a randomized, double-blind, placebo-controlled crossover fashion. A 1-week washout period was observed between dosing periods. Cerebral vasomotor reactivity (increase in middle cerebral artery mean flow velocity in response to intravenous injection of 15 mg/kg acetazolamide) was measured before and after each dosing period using standard Doppler ultrasound techniques.

Results—

Twelve patients (mean age 63.2±2.3 years) completed the protocol. There was no treatment order effect. Cerebral vasomotor reactivity was significantly greater after perindopril treatment (percent change from baseline +18.8±10.1% after perindopril, −4.6±4.1% after placebo;
P
=0.032). Dosing with perindopril did not affect resting cerebral blood flow velocity (percent change from baseline +3.1±9.5% after perindopril, −0.6±5.4% after placebo), nor was there a change in resting blood pressure (+1.8 mm Hg±3.1 after perindopril, +1.4 mm Hg±2.5 after placebo).

Conclusions—

This study provides evidence of a significant improvement in cerebral vasomotor reactivity induced by perindopril, beyond any effect on blood pressure. The results suggest a possible mechanism for the beneficial effect of ACE inhibition on stroke risk observed in recent clinical trials, and suggest a role for the renin-angiotensin axis in the pathophysiology of subcortical small vessel disease.
Association Between Cerebral Ischemia and Cytotoxin-Associated Gene-A–Bearing Strains of
Helicobacter pylori
Authors: Preusch Michael R. , Grau Armin J. , Buggle Florian , Lichy Christoph , Bartel Jan , Black Carmen , Rudi Jochen
Published: June 2004

Background and Purpose—

Studies on
Helicobacter pylori
infection and risk of ischemic stroke yielded variable results. Infection with more virulent
H. pylori
strains, such as cytotoxin-associated gene-A (CagA)–bearing strains, may be of particular relevance for ischemic diseases. We investigated whether
H. pylori
and CagA seropositivity are independent risk factors for cerebral ischemia or its etiologic subtypes.

Methods—

We determined IgG antibodies against
H. pylori
and CagA protein (enzyme immunoassays) in 190 patients with acute cerebral ischemia and in 229 age- and sex-matched control subjects selected randomly from the general population.

Results—

CagA seropositivity was more common in patients (114/190; 60.0%) than in control subjects (99/229; 43.2%; odds ratio, 1.97; 95% CI, 1.33 to 2.91;
P
<0.001). This result remained significant after adjustment for age, sex, vascular risk factors and diseases, and childhood and adult social status (odds ratio, 1.84; 95% CI, 1.13 to 3.00;
P
=0.015). Subgroup analyses yielded similar results in all etiologic stroke subtypes. In contrast,
H. pylori
seropositivity in general was not associated with increased risk of stroke or its etiologic subtypes.

Conclusions—

Our results support the hypothesis of an association between infection with CagA-positive
H. pylori
strains and acute cerebral ischemia.
Remote Evaluation of Acute Ischemic Stroke in Rural Community Hospitals in Georgia
Authors: Wang Sam , Gross Hartmut , Lee Sung Bae , Pardue Carol , Waller Jennifer , Nichols Fenwick T. , Adams Robert J. , Hess David C.
Published: June 2004

Background and Purpose—

Despite Food and Drug Administration approval of tissue-type plasminogen activator (tPA) for stroke, obstacles in the US health care system prevent widespread use. The Remote Evaluation for Acute Ischemic Stroke (REACH) program was developed to address these obstacles in rural settings. We have previously shown the reliability of the REACH system in performing a valid National Institutes of Health Stroke Scale (NIHSS) evaluation at the Medical College of Georgia (MCG). We now report on the performance of the system since its deployment in 5 rural hospitals in east Georgia.

Methods—

The rural emergency department (ED) staff can activate a Code REACH protocol 24 hours per day, 7 days per week by calling the Emergency Communications Center (ECC, an in-house dispatch center) at MCG, who pages the on-call consultant. The consultant calls back the ECC and is connected to the waiting ED. Simultaneously, using any broadband-connected workstation, the consultant logs in to the REACH system, allowing performance of an NIHSS evaluation, review of the computerized tomography (CT) images transmitted by the local radiology staff, and then the consultant can speak to the patient and family to verify time of onset.

Results—

The REACH system has evaluated 75 patients from March 2003 to April 2004, and 12 have received tPA, all without intracranial hemorrhage complications. NIHSS scores ranged from 0 to 30, with a mean of 14.3 (SD=8.7, median 11.5). The mean onset to door time was 70.9 minutes (SD=70.8, median 50), the mean door to consult time was 45.1 minutes (SD=39.8, median 34), and the mean door to NIHSS completion was 62.9 minutes (SD=50.8, median 51). The mean onset to needle time was 135.33 minutes (SD=51.45, median 134.5).

Conclusion—

The REACH system enables remote stroke physicians to direct the local ED staff to administer tPA in rural settings where thrombolytics were not previously used. REACH may be used as a rapid consult tool to provide the same quality of stroke care to patients in rural hospitals as is given in tertiary stroke centers. This supports our endeavor to bring stroke expertise to rural community hospitals.
Taking the Sanctuary to the Streets: Religion, Race, and Community Development in Columbus, Ohio
Authors: Alex-Assensoh Yvette M.
Published: June 2004

This study focuses on how institutional, organizational, and political contexts structure the involvement of black churches in the politics of local community development. Interviews with black Baptist clergy in the city of Columbus, Ohio, and analysis of census data are the basis for the discussion. The study shows that despite a general context of exclusion from Columbus mainstream politics, a group of black Baptist ministers have created a strong organizational association used to share information, resources, and expertise necessary to participate collectively in housing, welfare, and community banking issues. The results of this study demonstrate the continuing relevance of the black urban church in helping to ameliorate inner-city problems associated with community development.
Community Development and the Politics of Deracialization: The Case of Denver, Colorado, 1991-2003
Authors: George Hermon
Published: June 2004

This article examines the mayoralty of Wellington Webb, 1991 to 2003, the first black mayor of Denver, Colorado, as a case study for testing the idea that “deracialization” produces benefits for the black community. Deracialization is essentially a political current within neoliberalism that argues black leaders should deemphasize race in favor of certain political styles and symbols. Upon examining Mayor Webb’s administrations—from the perspective of community development—municipal employment, public schools, police accountability, and affordable housing are found to have worsened, or reflected ambiguous change, for Denver’s poor and working-class neighborhoods. Supported with social and economic data, as well as interviews with community activists, the study concludes that race remains a significant issue for understanding how community development is pursued in black neighborhoods in some cities.
Empowered Culture? New York City’s Empowerment Zone and the Selling of El Barrio
Authors: Dávila Arlene
Published: June 2004

This article explores the implementation of empowerment zone (EZ) legislation in East Harlem, or what some describe as El Barrio in New York City. The EZ is used as a case study for a critique of tourism as an urban development strategy. El Barrio is difficult to market within a framework of tourism defined by EZ standards, especially the heightened conflicts that ensue as minority communities attempt to reconstitute their cultures for tourist aims. Ultimately, this article shows a growing contradiction between the disavowal of ethnicity and race as grounds for equity and empowerment and the fact that ethnicity and race are the bases on which urban spatial transformations are taking place. Furthermore, the case study suggests that the politicization (and mobilization) of race and ethnicity are not the greatest perils to intra-Latino and interracial alliances in U.S. cities or to people’s aspirations regarding urban space at the local level. Rather, the ascendancy of neoliberal tenets presents obstacles to multiethnic and multiracial coalitions on behalf of livable and enjoyable communities for all people.