bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathophysiological basis of liver disease in cystic fibrosis employing a ΔF508 mouse model
Authors: Freudenberg Folke , Broderick Annemarie L. , Yu Bian B. , Leonard Monika R. , Glickman Jonathan N. , Carey Martin C.
Published: April 2008

The molecular pathogenesis of cystic fibrosis (CF) liver disease is unknown. This study investigates its earliest pathophysiological manifestations employing a mouse model carrying ΔF508, the commonest human CF mutation. We hypothesized that, if increased bile salt spillage into the colon occurs as in the human disease, then this should lead to a hydrophobic bile salt profile and to “hyperbilirubinbilia” because of induced enterohepatic cycling of unconjugated bilirubin. Hyperbilirubinbilia may then lead to an increased bile salt-to-phospholipid ratio in bile and, following hydrolysis, precipitation of divalent metal salts of unconjugated bilirubin. We document in CF mice elevated fecal bile acid excretion and biliary secretion of more hydrophobic bile salts compared with control wild-type mice. Biliary secretion rates of bilirubin monoglucuronosides, bile salts, phospholipids, and cholesterol are increased significantly with an augmented bile salt-to-phospholipid ratio. Quantitative histopathology of CF livers displays mild early cholangiopathy in ≈53% of mice and multifocal divalent metal salt deposition in cholangiocytes. We conclude that increased fecal bile acid loss leads to more hydrophobic bile salts in hepatic bile and to hyperbilirubinbilia, a major contributor in augmenting the bile salt-to-phospholipid ratio and endogenous β-glucuronidase hydrolysis of bilirubin glucuronosides. The confluence of these perturbations damages intrahepatic bile ducts and facilitates entrance of unconjugated bilirubin into cholangiocytes. This study of the earliest stages of CF liver disease provides a framework for investigating the molecular pathophysiology of more advanced disease in murine models and in humans with CF.
Cholangiocyte expression of α2β1-integrin confers susceptibility to rotavirus-induced experimental biliary atresia
Authors: Jafri Mubeen , Donnelly Bryan , Allen Steven , Bondoc Alex , McNeal Monica , Rennert Paul D. , Weinreb Paul H. , Ward Richard , Tiao Greg
Published: April 2008

Inoculation of BALB/c mice with rhesus rotavirus (RRV) in the newborn period results in biliary epithelial cell (cholangiocyte) infection and the murine model of biliary atresia. Rotavirus infection of a cell requires attachment, which is governed in part by cell-surface expression of integrins such as α2β1. We hypothesized that cholangiocytes were susceptible to RRV infection because they express α2β1. RRV attachment and replication was measured in cell lines derived from cholangiocytes and hepatocytes. Flow cytometry was performed on these cell lines to determine whether α2β1was present. Cholangiocytes were blocked with natural ligands, a monoclonal antibody, or small interfering RNA against the α2-subunit and were infected with RRV. The extrahepatic biliary tract of newborn mice was screened for the expression of the α2β1-integrin. Newborn mice were pretreated with a monoclonal antibody against the α2-subunit and were inoculated with RRV. RRV attached and replicated significantly better in cholangiocytes than in hepatocytes. Cholangiocytes, but not hepatocytes, expressed α2β1in vitro and in vivo. Blocking assays led to a significant reduction in attachment and yield of virus in RRV-infected cholangiocytes. Pretreatment of newborn pups with an anti-α2monoclonal antibody reduced the ability of RRV to cause biliary atresia in mice. Cell-surface expression of the α2β1-integrin plays a role in the mechanism that confers cholangiocyte susceptibility to RRV infection.
Effects of the selective EET antagonist, 14,15-EEZE, on cardioprotection produced by exogenous or endogenous EETs in the canine heart
Authors: Gross Garrett J. , Gauthier Kathryn M. , Moore Jeannine , Falck John R. , Hammock Bruce D. , Campbell William B. , Nithipatikom Kasem
Published: April 2008

Previously, we demonstrated ( 17 ) that 11,12- and 14,15-epoxyeicosatrienoic acids (EETs) produce marked reductions in myocardial infarct size. Although it is assumed that this cardioprotective effect of the EETs is due to a specific interaction with a membrane-bound receptor, no evidence has indicated that novel EET antagonists selectively block the EET actions in dogs. Our goals were to investigate the effects of 11,12- and 14,15-EET, the soluble epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), and the putative selective EET antagonist, 14,15-epoxyeicosa-5( Z)-enoic acid (14,15-EEZE), on infarct size of barbital anesthetized dogs subjected to 60 min of coronary artery occlusion and 3 h of reperfusion. Furthermore, the effect of 14,15-EEZE on the cardioprotective actions of the selective mitochondrial ATP-sensitive potassium channel opener diazoxide was investigated. Both 11,12- and 14,15-EET markedly reduced infarct size [expressed as a percentage of the area at risk (IS/AAR)] from 21.8 ± 1.6% (vehicle) to 8.7 ± 2.2 and 9.4 ± 1.3%, respectively. Similarly, AUDA significantly reduced IS/AAR from 21.8 ± 1.6 to 14.4 ± 1.2% (low dose) and 9.4 ± 1.8% (high dose), respectively. Interestingly, the combination of the low dose of AUDA with 14,15-EET reduced IS/AAR to 5.8 ± 1.6% ( P < 0.05), further than either drug alone. Diazoxide also reduced IS/AAR significantly (10.2 ± 1.9%). In contrast, 14,15-EEZE had no effect on IS/AAR by itself (21.0 ± 3.6%), but completely abolished the effect of 11,12-EET (17.8 ± 1.4%) and 14,15-EET (19.2 ± 2.4%) and AUDA (19.3 ± 1.6%), but not that of diazoxide (10.4 ± 1.4%). These results suggest that activation of the EET pathway, acting on a putative receptor, by exogenous EETs or indirectly by blocking EET metabolism, produced marked cardioprotection, and the combination of these two approaches resulted in a synergistic effect. These data also suggest that 14,15-EEZE is not blocking the mitochondrial ATP-sensitive potassium channel as a mechanism for antagonizing the cardioprotective effects of the EETs.
Intramuscular β2-agonist administration enhances early regeneration and functional repair in rat skeletal muscle after myotoxic injury
Authors: Ryall James G. , Schertzer Jonathan D. , Alabakis Tammy M. , Gehrig Stefan M. , Plant David R. , Lynch Gordon S.
Published: April 2008

Systemic administration of β2-adrenoceptor agonists (β2-agonists) can improve skeletal muscle regeneration after injury. However, therapeutic application of β2-agonists for muscle injury has been limited by detrimental cardiovascular side effects. Intramuscular administration may obviate some of these side effects. To test this hypothesis, the right extensor digitorum longus (EDL) muscle from rats was injected with bupivacaine hydrochloride to cause complete muscle fiber degeneration. Five days after injury, half of the injured muscles received an intramuscular injection of formoterol (100 μg). Muscle function was assessed at 7, 10, and 14 days after injury. A single intramuscular injection of formoterol increased muscle mass and force-producing capacity at day 7 by 17 and 91%, respectively, but this effect was transient because these values were not different from control levels at day 10. A second intramuscular injection of formoterol at day 7 prolonged the increase in muscle mass and force-producing capacity. Importantly, single or multiple intramuscular injections of formoterol did not elicit cardiac hypertrophy. To characterize any potential cardiovascular effects of intramuscular formoterol administration, we instrumented a separate group of rats with indwelling radio telemeters. Following an intramuscular injection of formoterol, heart rate increased by 18%, whereas systolic and diastolic blood pressure decreased by 31 and 44%, respectively. These results indicate that intramuscular injection can enhance functional muscle recovery after injury without causing cardiac hypertrophy. Therefore, if the transient cardiovascular effects associated with intramuscular formoterol administration can be minimized, this form of treatment may have significant therapeutic potential for muscle-wasting conditions.
Doublet stimulation protocol to minimize musculoskeletal stress during paralyzed quadriceps muscle testing
Authors: Dudley-Javoroski Shauna , Littmann Andrew E. , Iguchi Masaki , Shields Richard K.
Published: April 2008

With long-term electrical stimulation training, paralyzed muscle can serve as an effective load delivery agent for the skeletal system. Muscle adaptations to training, however, will almost certainly outstrip bone adaptations, exposing participants in training protocols to an elevated risk for fracture. Assessing the physiological properties of the chronically paralyzed quadriceps may transmit unacceptably high shear forces to the osteoporotic distal femur. We devised a two-pulse doublet strategy to measure quadriceps physiological properties while minimizing the peak muscle force. The purposes of the study were 1) to determine the repeatability of the doublet stimulation protocol, and 2) to compare this protocol among individuals with and without spinal cord injury (SCI). Eight individuals with SCI and four individuals without SCI underwent testing. The doublet force-frequency relationship shifted to the left after SCI, likely reflecting enhancements in the twitch-to-tetanus ratio known to exist in paralyzed muscle. Posttetanic potentiation occurred to a greater degree in subjects with SCI (20%) than in non-SCI subjects (7%). Potentiation of contractile rate occurred in both subject groups (14% and 23% for SCI and non-SCI, respectively). Normalized contractile speed (rate of force rise, rate of force fall) reflected well-known adaptations of paralyzed muscle toward a fast fatigable muscle. The doublet stimulation strategy provided repeatable and sensitive measurements of muscle force and speed properties that revealed meaningful differences between subjects with and without SCI. Doublet stimulation may offer a unique way to test muscle physiological parameters of the quadriceps in subjects with uncertain musculoskeletal integrity.
Influence of hypercapnic vasodilation on cerebrovascular autoregulation and pial arteriolar bed resistance in piglets
Authors: Narayanan Nithya , Leffler Charles W. , Daley Michael L.
Published: April 2008

Changes in both pial arteriolar resistance (PAR) and simulated arterial-arteriolar bed resistance (SimR) of a physiologically based biomechanical model of cerebrovascular pressure transmission, the dynamic relationship between arterial blood pressure and intracranial pressure, are used to test the hypothesis that hypercapnia disrupts autoregulatory reactivity. To evaluate pressure reactivity, vasopressin-induced acute hypertension was administered to normocapnic and hypercapnic ( N = 12) piglets equipped with closed cranial windows. Pial arteriolar diameters were used to compute arteriolar resistance. Percent change of PAR (%ΔPAR) and percent change of SimR (%ΔSimR) in response to vasopressin-induced acute hypertension were computed and compared. Hypercapnia decreased cerebrovascular resistance. Indicative of active autoregulatory reactivity, vasopressin-induced hypertensive challenge resulted in an increase of both %ΔPAR and %ΔSimR for all normocapnic piglets. The hypercapnic piglets formed two statistically distinct populations. One-half of the hypercapnic piglets demonstrated a measured decrease of both %ΔPAR and %ΔSimR to pressure challenge, indicative of being pressure passive, whereas the other one-half demonstrated an increase in these percentages, indicative of active autoregulation. No other differences in measured variables were detectable between regulating and pressure-passive piglets. Changes in resistance calculated from using the model mirrored those calculated from arteriolar diameter measurements. In conclusion, vasodilation induced by hypercapnia has the potential to disrupt autoregulatory reactivity. Our physiologically based biomechanical model of cerebrovascular pressure transmission accurately estimates the changes in arteriolar resistance during conditions of active and passive cerebrovascular reactivity.
Flufenamic Acid Affects Multiple Currents and Causes Intracellular Ca2+Release inAplysiaBag Cell Neurons
Authors: Gardam Kate E. , Geiger Julia E. , Hickey Charlene M. , Hung Anne Y. , Magoski Neil S.
Published: April 2008

Flufenamic acid (FFA) is a nonsteroidal antiinflammatory agent, commonly used to block nonselective cation channels. We previously reported that FFA potentiated, rather than inhibited, a cation current in Aplysia bag cell neurons. Prompted by this paradoxical result, the present study examined the effects of FFA on membrane currents and intracellular Ca2+in cultured bag cell neurons. Under whole cell voltage clamp, FFA evoked either outward ( Iout) or inward ( Iin) currents. Iouthad a rapid onset, was inhibited by the K+channel blocker, tetraethylammonium, and was associated with both an increase in membrane conductance and a negative shift in the whole cell current reversal potential. Iindeveloped more slowly, was inhibited by the cation channel blocker, Gd3+, and was concomitant with both an increased conductance and positive shift in reversal potential. FFA also enhanced the use-dependent inactivation and caused a positive-shift in the activation curve of the voltage-dependent Ca2+current. Furthermore, as measured by ratiometric imaging, FFA produced a rise in intracellular Ca2+that persisted in the absence of extracellular Ca2+and was reduced by depleting either the endoplasmic reticulum and/or mitochondrial stores. Ca2+appeared to be involved in the activation of Iin, as strong intracellular Ca2+buffering effectively eliminated Iinbut did not alter Iout. Finally, the effects of FFA were likely not due to block of cyclooxygenase given that the general cyclooxygenase inhibitor, indomethacin, failed to evoke either current. That FFA influences a number of neuronal properties needs to be taken into consideration when employing it as a cation channel antagonist.
Perisaccadic Mislocalization of Visual Targets by Head-Free Gaze Shifts: Visual or Motor?
Authors: van Wetter Sigrid M. C. I. , van Opstal A. John
Published: April 2008

Such perisaccadic mislocalization is maximal in the direction of the saccade and varies systematically with the target-saccade onset delay. We have recently shown that under head-fixed conditions perisaccadic errors do not follow the quantitative predictions of current visuomotor models that explain these mislocalizations in terms of spatial updating. These models all assume sluggish eye-movement feedback and therefore predict that errors should vary systematically with the amplitude and kinematics of the intervening saccade. Instead, we reported that errors depend only weakly on the saccade amplitude. An alternative explanation for the data is that around the saccade the perceived target location undergoes a uniform transient shift in the saccade direction, but that the oculomotor feedback is, on average, accurate. This “ visual shift” hypothesis predicts that errors will also remain insensitive to kinematic variability within much larger head-free gaze shifts. Here we test this prediction by presenting a brief visual probe near the onset of gaze saccades between 40 and 70° amplitude. According to models with inaccurate gaze-motor feedback, the expected perisaccadic errors for such gaze shifts should be as large as 30° and depend heavily on the kinematics of the gaze shift. In contrast, we found that the actual peak errors were similar to those reported for much smaller saccadic eye movements, i.e., on average about 10°, and that neither gaze-shift amplitude nor kinematics plays a systematic role. Our data further corroborate the visual origin of perisaccadic mislocalization under open-loop conditions and strengthen the idea that efferent feedback signals in the gaze-control system are fast and accurate.
Synaptic Properties of Thalamic and Intracortical Inputs to Layer 4 of the First- and Higher-Order Cortical Areas in the Auditory and Somatosensory Systems
Authors: Lee Charles C. , Sherman S. Murray
Published: April 2008

The thalamus is an essential structure in the mammalian forebrain conveying information topographically from the sensory periphery to primary neocortical areas. Beyond this initial processing stage, “higher-order” thalamocortical connections have been presumed to serve only a modulatory role, or are otherwise functionally disregarded. Here we demonstrate that these “higher-order” thalamic nuclei share similar synaptic properties with the “first-order” thalamic nuclei. Using whole cell recordings from layer 4 neurons in thalamocortical slice preparations in the mouse somatosensory and auditory systems, we found that electrical stimulation in all thalamic nuclei elicited large, glutamatergic excitatory postsynaptic potentials (EPSPs) that depress in response to repetitive stimulation and that fail to activate a metabotropic glutamate response. In contrast, the intracortical inputs from layer 6 to layer 4 exhibit facilitating EPSPs. These data suggest that higher-order thalamocortical projections may serve a functional role similar to the first-order nuclei, whereas both are physiologically distinct from the intracortical layer 6 inputs. These results suggest an alternate route for information transfer between cortical areas via a corticothalamocortical pathway.
Advanced Age Is Associated with Endothelial Dysfunction in Healthy Elderly Subjects
Authors: Yavuz B.B. , Yavuz B. , Sener Dede D. , Cankurtaran M. , Halil M. , Ulger Z. , Nazli N. , Kabakci G. , Aytemir K. , Tokgozoglu L. , Oto A. , Ariogul S.
Published: April 2008

Background: Aging is associated with an increased risk for atherosclerosis in which endothelial dysfunction is an early marker. Objective: The purpose of this study was to determine if endothelial function is altered with increasing age in healthy subjects. Method: The study population consisted of 30 elderly and 36 younger subjects free from major cardiovascular risk factors. Transthoracic echocardiography was performed for each subject to rule out structural heart disease. Endothelial function was evaluated by flow-mediated dilation (FMD) of the brachial artery via ultrasound. Results: Baseline characteristics of the elderly and the younger group were similar, except for age (mean age: 71.3 ± 5.8 vs. 26.5 ± 7.2). Transthoracic echocardiography was normal in all subjects. FMD of the elderly group was significantly lower than the younger group (7.9 ± 3.1 in the elderly, 10.8 ± 1.9 in the younger group, p < 0.001). A negative relationship was found between FMD and age (r = –0.528, p < 0.001). Conclusion: It can be concluded that endothelial function detected by FMD declines with increasing age in healthy human subjects. Advanced age is a predictor of impaired endothelial function.
Mouse CD36 Has Opposite Effects on LDL and Oxidized LDL Metabolism In Vivo
Authors: Luangrath Vilayphone , Brodeur Mathieu R. , Rhainds David , Brissette Louise
Published: April 2008

Objective—

The cluster of differentiation-36 (CD36) is a multifunctional protein which is recognized for its in vitro ability to take up oxidized low-density lipoproteins (oxLDL) in macrophages and is therefore considered atherogenic. It also binds LDL. Our objective was to define the physiological role of CD36 in both native LDL and oxLDL metabolism in mice.

Methods and Results—

Clearance studies of labeled LDL and oxLDL were conducted in wild-type, CD36 knockout (KO), scavenger receptor class B, type I (SR-BI) KO, and SR-BI/CD36 double KO mice. We found that CD36 impedes the disappearance of native LDL and favors that of oxLDL. This was confirmed by association and degradation assays with primary cultures of hepatic cells from wild-type and CD36 KO mice. In addition, our in vivo work indicates that neither SR-BI nor CD36 plays a significant role in cholesteryl esters (CE) selective uptake (SU) from oxLDL, whereas CD36, in absence of SR-BI, can selectively take CE from LDL.

Conclusion—

Our investigation showed for the first time that CD36 plays a significant role in oxLDL uptake in vivo in the mouse. As CD36 also retards LDL clearance, its atherogenic character may also relate to its negative effect on LDL catabolism.
Thrombocytopenia and Platelet Abnormalities in High-Density Lipoprotein Receptor–Deficient Mice
Authors: Dole Vandana S. , Matuskova Jana , Vasile Eliza , Yesilaltay Ayce , Bergmeier Wolfgang , Bernimoulin Michael , Wagner Denisa D. , Krieger Monty
Published: April 2008

Objective—

High-density lipoprotein (HDL) receptor, scavenger receptor class B, type I (SR-BI), mediated cellular uptake of lipoprotein cholesterol controls HDL structure and plasma HDL and biliary cholesterol levels. In SR-BI knockout (KO) mice, an unusually high plasma unesterified-to-total cholesterol ratio (UC:TC) and abnormally large HDL particles apparently contribute to pathology, including female infertility, susceptibility to atherosclerosis and coronary heart disease, and anemia. Here we examined the influence of SR-BI deficiency on platelets.

Methods and Results—

The high plasma UC:TC ratio in SR-BI KO mice was correlated with platelet abnormalities, including high cholesterol content, abnormal morphologies, high clearance rates, and thrombocytopenia. One day after platelets from wild-type mice were infused into SR-BI KO mice, they exhibited abnormally high cholesterol content and clearance rates similar to those of endogenous platelets. Platelets from SR-BI KO mice exhibited in vitro a blunted aggregation response to the agonist ADP but a normal response to PAR4.

Conclusions—

In SR-BI KO mice abnormal circulating lipoproteins, particularly their high UC:TC ratio—rather than the absence of SR-BI in platelets themselves—induce defects in platelet structure and clearance, together with a mild defect in function.
Alpha2-Antiplasmin Is a Critical Regulator of Angiotensin II–Mediated Vascular Remodeling
Authors: Hou YongZhong , Okada Kiyotaka , Okamoto Chikako , Ueshima Shigeru , Matsuo Osamu
Published: April 2008

Objective—

Alpha2-antiplasmin (α2-AP) is the major circulating inhibitor of plasmin, which plays a determining role in the regulation of intravascular fibrinolysis. We investigated the role of α
2
-AP on vascular remodeling in response to angiotensin II (Ang II).

Methods and Results—

α2-AP–deficient mice were performed. Ang II and
N
ω
-nitro- L-arginine methyl ester (L-NAME)–induced perivascular fibrosis was significantly decreased in α2-AP
−/−
mice compared with wild-type mice. In situ gelatinolytic activity analysis shows that perivascular gelatinolytic activity was increased in α2-AP
−/−
mice, which was responsible for decreased perivascular fibrosis in response to Ang II and L-NAME. Ang II–induced arterial wall thickening, vascular cell proliferation, apoptosis, c-Myc, and collagen Ι expression were significantly decreased in α2-AP
−/−
mice compared with wild-type mice. Further analysis shows that increased p53 and p21 expression were responsible for inhibition of Ang II–induced vascular remodeling in α2-AP
−/−
mice.

Conclusion—

The results show that α2-AP is a critical regulator for vascular remodeling by inhibiting p53/p21 pathway, suggesting that α2-AP is proposed to be a potential therapeutic target for vascular remodeling.
Urokinase Plasminogen Activator Upregulates Paraoxonase 2 Expression in Macrophages Via an NADPH Oxidase-Dependent Mechanism
Authors: Fuhrman Bianca , Khateeb Jasmin , Shiner Maayan , Nitzan Orna , Karry Rachel , Volkova Nina , Aviram Michael
Published: April 2008

Objective—

Macrophage foam cells are characterized by increased oxidative stress. Macrophage urokinase plasminogen activator (uPA) was shown to contribute to atherosclerosis progression. We hypothesized that uPA atherogenicity is related to its ability to increase macrophage oxidative stress. Increased macrophage oxidative stress in turn was shown to enhance PON2 expression. In the present study we investigated the effect of uPA on macrophage PON2 expression in relation to cellular oxidative stress.

Methods and Results—

uPA increased PON2 expression in THP-1 macrophages in a dose-dependent manner. This effect required uPA/uPAR interaction and was abolished by cell treatment with antioxidants. uPA increased macrophage oxidative stress, measured by increased lipid peroxides, reactive oxygen species formation, superoxide anion release, and cell-mediated LDL oxidation. These effects were related to uPA-mediated activation of NADPH oxidase, and could not be reproduced in mouse peritoneal macrophages (MPM) harvested from p47

phox

−/− mice, suggesting a causal relationship between NADPH oxidase activation and the effects of uPA on macrophage oxidative stress and PON2 expression. Finally, MPM from PON2
−/−
mice were more susceptible to uPA-induced cellular oxidative stress than wild-type MPM, suggesting that PON2 protects against uPA-stimulated macrophage oxidative stress.

Conclusions—

Upregulation of macrophage PON2 may provide a compensatory protective mechanism against uPA-stimulation of macrophage oxidative stress during atherogenesis.
Do Psychological Factors Affect Inflammation and Incident Coronary Heart Disease
Authors: Nabi Hermann , Singh-Manoux Archana , Shipley Martin , Gimeno David , Marmot Michael G. , Kivimaki Mika
Published: April 2008

Objectives—

The purpose of this study was to test whether psychological factors affect inflammation processes to an extent that increases the risk of coronary heart disease (CHD).

Methods and Results—

We used data from 6396 civil servants (4453 men, 1943 women) from the Whitehall II Study, aged 35 to 55 years and free from clinically validated CHD at the start of the follow-up period. Two psychological factors were assessed at phase 1 (1985 to 1988) and phase 2 (1989 to 1990): negative affect and psychological distress. Inflammatory biomarkers (fibrinogen, high-sensitivity C-reactive- protein, interleukin-6) and 12 baseline covariates including biological and behavioral CHD risk factors, sociodemographic variables, and work stress were measured at phase 3 (1991 to 1993). Follow-up for CHD death, first nonfatal myocardial infarction, or definite angina occurring between phase 3 and phase 7 (2003 to 2004) was based on clinical records. Higher levels of inflammatory markers were associated with higher CHD incidence, with hazard ratios (HR) ranging from 1.31 to 2.37 in age-and sex-adjusted models. Higher levels of negative affectivity and psychological distress were not associated with greater concentrations of inflammatory markers. Negative affectivity (relative index of inequality=1.68, 95% confidence interval [CI] 1.20 to 2.36) and higher psychological distress exposure (HR=1.66, 95% CI 1.28 to 2.14) were associated with higher CHD incidence and these associations remained unchanged after adjustment for inflammatory markers.

Conclusions—

Our findings suggest that psychological factors do not affect inflammation although they predict incident CHD.
Stroke Disparities in Older Americans
Authors: Avendano Mauricio , Glymour M. Maria
Published: April 2008

Background and Purpose—

This study examines the independent effect of wealth, income, and education on stroke and how these disparities evolve throughout middle and old age in a representative cohort of older Americans.

Methods—

Stroke-free participants in the Health and Retirement Study (n=19 565) were followed for an average of 8.5 years. Total wealth, income, and education assessed at baseline were used in Cox proportional hazards models to predict time to stroke. Separate models were estimated for 3 age-strata (50 to 64, 65 to 74, and ≥75), and incorporating risk factor measures (smoking, physical activity, body mass index, hypertension, diabetes, and heart disease).

Results—

1542 subjects developed incident stroke. Higher education predicted reduced stroke risk at ages 50 to 64, but not after adjustment for wealth and income. Wealth and income were independent risk factors for stroke at ages 50 to 64. Adjusted hazard ratios comparing the lowest decile with the 75th-90th percentiles were 2.3 (95% CI 1.6, 3.4) for wealth and 1.8 (95% CI 1.3, 2.6) for income. Risk factor adjustment attenuated these effects by 30% to 50%, but coefficients for both wealth (HR=1.7, 95% CI 1.2, 2.5) and income (HR=1.6, 95% CI 1.2, 2.3) remained significant. Wealth, income, and education did not consistently predict stroke beyond age 65.

Conclusions—

Wealth and income are independent predictors of stroke at ages 50 to 64 but do not predict stroke among the elderly. This age patterning might reflect buffering of the negative effect of low socioeconomic status by improved access to social and health care programs at old ages, but may also be an artifact of selective survival.
Temporary Pretreatment With the Angiotensin II Type 1 Receptor Blocker, Valsartan, Prevents Ischemic Brain Damage Through an Increase in Capillary Density
Authors: Li Jian-Mei , Mogi Masaki , Iwanami Jun , Min Li-Juan , Tsukuda Kana , Sakata Akiko , Fujita Teppei , Iwai Masaru , Horiuchi Masatsugu
Published: April 2008

Background and Purpose—We investigated the effect of temporary treatment with a nonhypotensive dose of valsartan on ischemic brain damage in C57BL/6 mice.

Methods—We separated the mice into 3 groups of valsartan treatment before middle cerebral artery (MCA) occlusion: (1) for 4 weeks:Val (2W, 2W); (2) for 2 weeks followed by its cessation for 2 weeks:Val (2W, -); and (3) no treatment for 4 weeks:Val (-, -).

Results—Ischemic volume, DNA damage, superoxide production, and mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-α on the ipsilateral side after 24 hours of MCA occlusion were significantly reduced in bothVal (2W, 2W)andVal (2W, -)mice compared with those inVal (-, -)mice, whereas these parameters were larger inVal (2W, -)mice than inVal (2W, 2W)mice. Moreover, mice in both theVal (2W, 2W)andVal (2W, -)groups exhibited an increase in cerebral blood flow in the peripheral territory of the MCA 1 hour after MCA occlusion, with increases in endothelial nitric oxide synthase activation and nitric oxide production. Before MCA occlusion, treatment with valsartan did not influence superoxide production or mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-α in the brain. However, the capillary density in the brain in bothVal (2W, 2W)andVal (2W, -)mice was increased before MCA occlusion.

Conclusions—Our results suggest that temporary valsartan treatment could protect against ischemic brain damage even after its cessation, at least in part due to an increase in capillary density.
Asymmetric Vascular Stent
Authors: Ionita Ciprian N. , Paciorek Ann M. , Hoffmann Kenneth R. , Bednarek Daniel R. , Yamamoto Junichi , Kolega John , Levy Elad I. , Hopkins L. Nelson , Rudin Stephen , Mocco J
Published: April 2008

Background and Purpose—

Intracranial aneurysm (IA) treatment through hemodynamic modification with novel stent designs is a burgeoning area of research. We present a feasibility study for a new low-porosity patch-containing stent designed to treat intracranial aneurysms. The device is deployed so the patch covers the aneurysm neck ensuring strong flow diversion away from the aneurysm while keeping a low probability of occlusion of perforating vessels.

Methods—

We created 17 side-wall aneurysms in 6 dogs, 2 per carotid artery if animal size permitted. Twelve proximal aneurysms were treated with AVSs: 5 distal aneurysms were untreated, serving as controls against self-thrombosis; 7 treated aneurysms were fully-covered; and 5 were partially-covered. After 4 weeks, a final angiogram was performed and aneurysms were explanted. Angiograms acquired pre- and posttreatment and at 4-week follow-up were analyzed quantitatively using normalized time-density curves (NTDC). Cone-beam micro-CT and histological specimen analysis were then performed.

Results—

Posttreatment, NTDC average peaks dropped to 45% of initial values for the partially-covered aneurysms and 78% for the fully-covered aneurysms. Cone-beam micro-CT imaging performed at 4 weeks posttreatment showed partial thrombosis in 4 of 5 partially-covered aneurysms and complete thrombosis in all fully-covered aneurysms. Histology revealed neointimal coverage of all asymmetrical patch regions and thrombus formation in both fully- and partially-covered aneurysms. Four-week follow-up was not done for 1 animal (2 controls, 2 treated) that expired because of groin hemorrhage and for another animal (1 aneurysm) with an occluded carotid.

Conclusions—

We demonstrate aneurysmal blood flow diversion using a new low-porosity patch-containing asymmetrical vascular stent in a canine side-wall aneurysm model. Overall results are encouraging and support continued AVS development.
Common CCR5-del32 Frameshift Mutation Associated With Serum Levels of Inflammatory Markers and Cardiovascular Disease Risk in the Bruneck Population
Authors: Afzal Ali R. , Kiechl Stefan , Daryani Yousef P. , Weerasinghe Arusha , Zhang Yang , Reindl Markus , Mayr Agnes , Weger Siegfried , Xu Qingbo , Willeit Johann
Published: April 2008

Background and Purpose—

Atherosclerosis is a progressive inflammatory disease and can develop in large arteries such as carotid and femoral arteries or medium-sized muscular arteries of the heart. Previous predominantly experimental studies suggested an important role of chemokines in the development of atherosclerosis. The main aim of this study was to examine potential effect of the CCR5-del32 mutation on systemic inflammation, intima-media thickness in carotid and femoral arteries, and on the indices of cardiovascular disease.

Methods—

In the present study, we have examined the association of a common functional 32-bp frameshift deletion mutation in a chemokine receptor (CCR5) in relation to inflammation and atherosclerosis. CCR5 is a G protein-coupled receptor involved in inflammatory response and regulation of leukocytes activation and migration. Genetic screening of this mutation was carried out on a well-known and previously described cohort of Bruneck (n=826) using polymerase chain reaction.

Results—

Screening was successful in 810 subjects of whom 7 were homozygous, 102 were heterozygous, and 701 were normal. The mutation was associated with significantly lower levels of C-reactive protein in a dose-dependent manner. Moreover, CCR5-del32 was associated with a significantly lower carotid intima-media thickness in the common carotid artery (del32/del32, 837±8 μm; wt/del32, 909±21 μm; wt/wt, 958±8 μm;
P
=0.007 after multivariable adjustment). Furthermore, incident cardiovascular disease (1995 to 2005) was markedly reduced in del32 homozygotes and heterozygotes subjects compared with wild-type homozygotes (del32/del32=0%, wt/del32=7.8%, wt/wt=14.8%,
P
=0.020). Findings equally applied to coronary artery and cerebrovascular disease.

Conclusions—

The chemokine receptor CCR5-del32 frameshift mutation is associated with low levels of C-reactive protein, decreased intima-media thickness, and cardiovascular disease risk. These findings are consistent with the hypothesis that the chemokine receptor CCR5 is involved in the mediation of low-grade systemic inflammation and may play a role in human atherosclerosis and cardiovascular disease.
Performance of Comorbidity Measures to Predict Stroke and Death in a Community-Dwelling, Hypertensive Medicaid Population
Authors: Tang Jun , Wan Jim Y. , Bailey James E.
Published: April 2008

Background and Purpose—

The Charlson and Elixhauser comorbidities are widely used to control for differences in comorbidity in epidemiological studies but have not been validated for outpatient studies of hypertension. This study sought that validation using death and stroke outcomes.

Methods—

Using Cox models in a retrospective cohort study of 49 479 hypertensive patients, Modified Charlson Index was compared with 6 alternative approaches to assessing comorbidity: individual Charlson comorbidities, Elixhauser comorbidities, prior major cardiovascular disease event, traditional risk factors for cerebrovascular accident, healthcare utilization, and antihypertensive medication utilization. Comorbidity measures were calculated at baseline and for a period before occurrence of the study outcome of interest or study conclusion.

Results—

The Charlson comorbidities had the smallest Akaike information criterion value for both the stroke and death outcomes when baseline data were used. The Elixhauser comorbidities had the smallest Akaike information criterion value for both the stroke and death outcomes when follow-up data were used. Modified Charlson Index also predicted stroke and death, but alternative models were more robust.

Conclusion—

This study indicates that both the Charlson and Elixhauser comorbidities are valid prediction tools that could enable clinicians and health systems to better assess risk for stroke and death in patients with hypertension. However, the Charlson comorbidities perform better when comorbidities are assessed using baseline data, whereas the Elixhauser comorbidities perform better for short follow-up periods when comorbidities are assessed proximal to events of interest.
Influence of Socioeconomic Status and Gender on Stroke Treatment and Diagnostics
Authors: Arrich Jasmin , Müllner Marcus , Lalouschek Wolfgang , Greisenegger Stefan , Crevenna Richard , Herkner Harald
Published: April 2008

Background and Purpose—

Female patients and patients with a lower level socioeconomic status (SES) often experience less favorable health outcomes. We aimed to investigate whether gender and socioeconomic status of patients with acute ischemic stroke or transient ischemic attack are associated with different diagnostic and treatment strategies.

Methods—

The risk factors of interest were gender and SES. We predefined our diagnostic and treatment end points according to current stroke guidelines and used multivariate models to adjust for age, stroke severity, and comorbidities.

Results—

A total of 2606 patients were included in the analysis. Women were less likely to receive antiplatelet agents within the first 48 hours after admission (OR: 0.59, 95% CI: 0.53 to 0.89) and more likely to have their blood glucose measured on admission than men (OR: 1.52, 95% CI: 1.1 to 2.1). With higher SES patients were more likely to receive a TTE or TTE during hospital stay. Women were almost twice as likely to receive a prescription for antidepressants at discharge OR of 1.96 (95% CI: 1.48 to 2.59).

Conclusion—

Socioeconomic status and gender are associated with some diagnostic and treatment differences of acute ischemic stroke. Most pronounced were a reduced chance for women to receive antiplatelet therapy on admission and a reduced chance for a TTE and TEE with a lower level of SES, whereas the rate of thrombolysis was unbiased by gender and SES.
Multimodal MRI in Cerebral Small Vessel Disease
Authors: Nitkunan Arani , Barrick Tom R. , Charlton Rebecca A. , Clark Chris A. , Markus Hugh S.
Published: April 2008

Background and Purpose—

Cerebral small vessel disease is the most common cause of vascular dementia. Interest in using MRI parameters as surrogate markers of disease to assess therapies is increasing. In patients with symptomatic sporadic small vessel disease, we determined which MRI parameters best correlated with cognitive function on cross-sectional analysis and which changed over a period of 1 year.

Methods—

Thirty-five patients with lacunar stroke and leukoaraiosis were recruited. They underwent multimodal MRI (brain volume, fluid-attenuated inversion recovery lesion load, lacunar infarct number, fractional anisotropy, and mean diffusivity from diffusion tensor imaging) and neuropsychological testing. Twenty-seven agreed to reattend for repeat MRI and neuropsychology at 1 year.

Results—

An executive function score correlated most strongly with diffusion tensor imaging (fractional anisotropy histogram,
r
=−0.640,
P
=0.004) and brain volume (
r
=0.501,
P
=0.034). Associations with diffusion tensor imaging were stronger than with all other MRI parameters. On multiple regression of all imaging parameters, a model that contained brain volume and fractional anisotropy, together with age, gender, and premorbid IQ, explained 74% of the variance of the executive function score (
P
=0.0001). Changes in mean diffusivity and fractional anisotropy were detectable over the 1-year follow-up; in contrast, no change in other MRI parameters was detectable over this time period.

Conclusion—

A multimodal MRI model explains a large proportion of the variation in executive function in cerebral small vessel disease. In particular, diffusion tensor imaging correlates best with executive function and is the most sensitive to change. This supports the use of MRI, in particular diffusion tensor imaging, as a surrogate marker in treatment trials.
Nonaspirin NSAIDs, Cyclooxygenase 2 Inhibitors, and the Risk for Stroke
Authors: Roumie Christianne L. , Mitchel Edward F. , Kaltenbach Lisa , Arbogast Patrick G. , Gideon Patricia , Griffin Marie R.
Published: April 2008

Background and Purpose—

There is limited information regarding the cerebrovascular safety of cyclooxygenase 2 inhibitors (coxibs) and noncoxib nonsteroidal antiinflammatory drugs (NSAIDs). We determined whether specific NSAIDs, including coxibs, are associated with risk of stroke.

Methods—

Retrospective cohort study among Tennessee Medicaid enrollees aged 50 to 84 years between January 1, 1999 and December 31, 2004. Noninstitutionalized persons with continuous enrollment in Medicaid and no stroke or other serious medical illness in the year before cohort entry were included. The 7 most common NSAIDs were examined: celecoxib, rofecoxib, valdecoxib, ibuprofen, naproxen, diclofenac, and indomethacin. Nonuse of NSAIDs was the reference group. Because new use is less susceptible to bias, we conducted a similar analysis confined to new users. The outcome was hospitalization for an incident cerebrovascular event: ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.

Results—

The cohort included 336 906 persons, with 989 826 person-years of follow-up, and 4354 stroke hospitalizations. There were 4.51 strokes per 1000 person years in the nonuse group, 5.15 strokes per 1000 person years (adjusted HR 1.28, 95% CI 1.06, 1.53) with rofecoxib use, and 5.95 strokes per 1000 person years (adjusted HR 1.41, 95% CI 1.04, 1.91) with valdecoxib use. New use of rofecoxib and valdecoxib led to 6.06 (adjusted HR 1.46 95% CI 1.08, 1.98) and 6.19 (adjusted HR 1.39, 95% CI 0.74, 2.59) strokes per 1000 person years respectively. No other NSAID significantly increased the risk of incident stroke.

Conclusions—

Our results indicate an increased risk of stroke with current use of two highly selective coxibs, rofecoxib and valdecoxib, also shown to increase cardiovascular risk. These results also provide some reassurance about other specific NSAIDs regarding stroke risk.
Oxyhemoglobin-Induced Expression of R-Type Ca
2+
Channels in Cerebral Arteries
Authors: Link Timothy E. , Murakami Kentaro , Beem-Miller Micah , Tranmer Bruce I. , Wellman George C.
Published: April 2008

Background and Purpose—

Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a major contributor to mortality and morbidity after aneurysm rupture. Recently, R-type voltage-dependent Ca
2+
channel (VDCC) expression has been associated with increased cerebral artery constriction in a rabbit model of SAH. The goal of the present study was to examine whether the blood component oxyhemoglobin (oxyHb) can mimic the ability of SAH to cause R-type VDCC expression in the cerebral vasculature.

Methods—

Rabbit cerebral arteries were organ cultured in serum-free media for up to 5 days in the presence or absence of purified oxyHb (10 μmol/L). Diameter changes in response to diltiazem, (L-type VDCC antagonist) and SNX-482 (R-type VDCC antagonist) were recorded at day 1, 3, or 5 in arteries constricted by elevated extracellular potassium. RT-PCR was performed on RNA extracted from arteries cultured for 5 days (±oxyHb) to assess VDCC expression.

Results—

After 5 days, oxyHb-treated arteries were less sensitive and partially resistant to diltiazem compared to similar arteries organ cultured in the absence of oxyHb. Further, SNX-482 dilated arteries organ cultured for 5 days in the presence, but not in the absence, of oxyHb. RT-PCR revealed that oxyHb treated arteries expressed R-type VDCCs (Ca
V
2.3) in addition to L-type VDCCs (Ca
V
1.2), whereas untreated arteries expressed only Ca
V
1.2.

Conclusions—

These results demonstrate that oxyhemoglobin exposure for 5 days induces the expression of Ca
V
2.3 in cerebral arteries. We propose that oxyhemoglobin contributes to enhanced cerebral artery constriction after SAH via the emergence of R-type VDCCs.
Effect of Statins on Intracerebral Hemorrhage Outcome and Recurrence
Authors: FitzMaurice Emilie , Wendell Lauren , Snider Ryan , Schwab Kristin , Chanderraj Rishi , Kinnecom Cathrine , Nandigam Kaveer , Rost Natalia S. , Viswanathan Anand , Rosand Jonathan , Greenberg Steven M. , Smith Eric E.
Published: April 2008

Background and Purpose—

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been associated with improved outcome after ischemic stroke and subarachnoid hemorrhage but an increased risk of incident intracerebral hemorrhage (ICH). We investigated (1) whether statin use before ICH was associated with functional independence at 90 days, and (2) whether survivors exposed to statins after ICH had an increased risk of recurrence.

Methods—

We analyzed 629 consecutive ICH patients with 90-day outcome data enrolled in a prospective cohort study between 1998 to 2005. Statin use was determined by patient interview at the time of ICH and supplemented by medical record review. Independent status was defined as Glasgow Outcome Scale 4 or 5. ICH survivors were followed by telephone interview every 6 months.

Results—

Statins were used by 149/629 (24%) before ICH. There was no effect of pre-ICH statin use on the rates of functional independence (28% versus 29%,
P
=0.84) or mortality (46% versus 45%,
P
=0.93). Medical comorbidities and warfarin use were more common in statin users. Hematoma volumes were similar (median 28 cm
3
in pre-ICH statin users compared to 22 cm
3
in nonusers,
P
=0.18). The multivariable-adjusted odds ratio for independent status in pre-ICH statin users was 1.16 (95% CI 0.65 to 2.10,
P
=0.62). ICH survivors treated with statins after discharge did not have a higher risk of recurrence (adjusted HR 0.82, 95% CI 0.34 to 1.99,
P
=0.66).

Conclusions—

Pre-ICH statin use is not associated with improved ICH functional outcome or mortality. Post-ICH statin use is not associated with an increased risk of ICH recurrence.
Fever After Aneurysmal Subarachnoid Hemorrhage
Authors: Dorhout Mees Sanne M. , Luitse Merel J.A. , van den Bergh Walter M. , Rinkel Gabriel J.E.
Published: April 2008

Background and Purpose—

Fever after aneurysmal subarachnoid hemorrhage is associated with poor outcome. Because hydrocephalus and extravasated blood may influence thermoregulation, we determined whether these factors increase the risk for fever after subarachnoid hemorrhage.

Methods—

Fever within 14 days (subdivided into infectious and noninfectious) was defined as a mean daily body temperature above 38.0°C for at least 2 consecutive days in a prospectively collected cohort of 194 patients with subarachnoid hemorrhage. Hazard ratios were calculated to assess the impact of hydrocephalus (bicaudate index) and cisternal and intraventricular blood (Hijdra score) on the occurrence of fever. Adjusted hazard ratios were calculated in one multivariate model, including other possible confounding factors.

Results—

Infectious fever occurred in 34% of patients and noninfectious fever in 9%. Adjusted hazard ratios of intraventricular blood were 2.2 (95% CI, 1.3 to 3.8) for any fever, 2.4 (95% CI, 1.3 to 4.4) for infectious fever, and 2.0 (95% CI, 0.7 to 5.9) for noninfectious fever. Adjusted hazard ratios of cisternal blood and hydrocephalus for infectious and noninfectious fever ranged from 0.6 to 1.5, all with wide CIs.

Conclusion—

Intraventricular blood is an independent risk factor for the development of fever. In this study, noninfectious fever was rare and not related to extravasated blood or hydrocephalus.