bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of load carrying on metabolic cost and hindlimb muscle dynamics in guinea fowl (Numida meleagris)
Authors: McGowan C. P. , Duarte H. A. , Main J. B. , Biewener A. A.
Published: June 2006

The goal of this study was to test whether the contractile patterns of two major hindlimb extensors of guinea fowl are altered by load-carrying exercise. We hypothesized that changes in contractile pattern, specifically a decrease in muscle shortening velocity or enhanced stretch activation, would result in a reduction in locomotor energy cost relative to the load carried. We also anticipated that changes in kinematics would reflect underlying changes in muscle strain. Oxygen consumption, muscle activation intensity, and fascicle strain rate were measured over a range of speeds while animals ran unloaded vs. when they carried a trunk load equal to 22% of their body mass. Our results showed that loading produced no significant ( P > 0.05) changes in kinematic patterns at any speed. In vivo muscle contractile strain patterns in the iliotibialis lateralis pars postacetabularis and the medial head of the gastrocnemius showed a significant increase in active stretch early in stance ( P < 0.01), but muscle fascicle shortening velocity was not significantly affected by load carrying. The rate of oxygen consumption increased by 17% ( P < 0.01) during loaded conditions, equivalent to 77% of the relative increase in mass. Additionally, relative increases in EMG intensity (quantified as mean spike amplitude) indicated less than proportional recruitment, consistent with force enhancement via stretch activation, in the proximal iliotibialis lateralis pars postacetabularis; however, a greater than proportional increase in the medial gastrocnemius was observed. As a result, when averaged for the two muscles, EMG intensity increased in direct proportion to the fractional increase in load carried.
Endocytosis of Extracellular Superoxide Dismutase Into Endothelial Cells
Authors: Chu Yi , Piper Robert , Richardson Simon , Watanabe Yoshimasa , Patel Pragnesh , Heistad Donald D.
Published: June 2006

Objective—

Extracellular superoxide dismutase (EC-SOD) is a secreted antioxidant enzyme that binds to the outer plasma membrane and extracellular matrix through its heparin-binding domain (HBD). Carriers of a common genetic variant of EC-SOD (EC-SOD
R213G
, within the HBD) have higher plasma concentration of EC-SOD and increased risk for vascular disease. In the present study, we used confocal fluorescence microscopy to examine mechanisms of endocytosis of EC-SOD to determine whether EC-SOD translocates to the nucleus of endothelial cells, and to test the hypothesis that EC-SOD, but not EC-SOD
R213G
, is endocytosed into endothelial cells.

Methods and Results—

Mouse endothelial cells (MS-1) were incubated with EC-SOD, EC-SOD
R213G
, or HBD-deleted EC-SOD (EC-SODΔHBD). Binding to MS-1 was observed only with EC-SOD, but not EC-SOD
R213G
or EC-SODΔHBD. Endocytosis of EC-SODs was monitored after coincubation of MS-1 cells with EC-SODs and BSA-Texas Red (BSA-TR), which marks endosomes and lysosomes. Only EC-SOD was endocytosed, colocalizing with BSA-TR. EC-SOD also colocalized with early endosome antigen 1 (EEA-1), a specific marker for endocytosis. Endocytosis of EC-SOD was inhibited by chlorpromazine, but not by methyl-β-cyclodextrin or nystatin, which suggests that endocytosis of EC-SOD is mediated by clathrin but not by caveolae. Minimal or no localization of EC-SOD in the nucleus of MS-1 cells was detected.

Conclusions—

Our findings indicate that EC-SOD, but not EC-SOD
R213G
, is endocytosed into endothelial cells through clathrin-mediated pathway, but does not translocate to the nucleus. We speculate that impairment of endocytosis may contribute to high plasma levels of EC-SOD
R213G
in R213G carriers.
Fibroblast Growth Factor-2 Failed to Induce Angiogenesis in Junctional Adhesion Molecule-A-Deficient Mice
Authors: Cooke Vesselina G. , Naik Meghna U. , Naik Ulhas P.
Published: June 2006

Objective—

We have previously shown that JAM-A regulates fibroblast growth factor-2 (FGF-2)–induced endothelial cell morphology, proliferation, and migration. Whether JAM-A is involved in FGF-2–induced angiogenesis in vivo is not known. We used JAM-A null mice to conclusively determine the role of JAM-A in FGF-2–induced neovascularization.

Methods and Results—

We generated JAM-A null (JAM-A
−/−
) mice using gene trap technology. These mice, although viable and fertile, exhibited distorted Mendelian and sex ratios, suggesting partial embryonic lethality. Retinal fluorescein angiogram did not reveal any significant morphological differences in the vasculature of
JAM-A
−/−
mice compared with wild-type (JAMA-A
+/+
) littermates. To evaluate the role of JAM-A in angiogenesis, we performed an aortic ring assay. FGF-2–induced microvessel growth was evident in aortic rings from
JAM-A
+/+
mice, but FGF-2 failed to induce microvessel sproutings in aortic rings from
JAM-A
−/−
mice. In a Matrigel plug assay, a known in vivo model for angiogenesis, we found that FGF-2 induced a robust vessel growth in
JAM-A
+/+
mice, whereas FGF-2 failed to induce blood vessel formation in plugs from
JAM-A
−/−
mice.

Conclusions—

Our results using
JAM-A
−/−
mice presented here conclusively establish an essential role for JAM-A in FGF-2–induced angiogenesis.
Abdominal Aortic Aneurysm Rupture Is Associated With Increased Medial Neovascularization and Overexpression of Proangiogenic Cytokines
Authors: Choke Edward , Thompson Matthew M. , Dawson Joseph , Wilson W. Richard W. , Sayed Saiqa , Loftus Ian M. , Cockerill Gillian W.
Published: June 2006

Objective—

Matrix metalloproteinase (MMP) activity has been linked to abdominal aortic aneurysm (AAA) rupture. Medial neovascularization (MNV), a histopathologic characteristic of AAAs, involves proteolytic degradation of extracellular matrix by MMPs to facilitate endothelial cell migration. The role of MNV in aneurysm rupture is unknown. This study investigated whether MNV is increased in aneurysm rupture.

Methods and Results—

Biopsy samples from aneurysm rupture edge were compared with control biopsy samples from aneurysm wall at the level of rupture and from anterior sac in 12 ruptured AAAs. Further controls were obtained from anterior sac of 10 nonruptured AAAs. MNV, microvessel diameter, maturity index, and inflammatory infiltrate were quantified using morphometric analyses following immunohistochemistry. Expression of proangiogenic mediators was quantified using quantitative real-time-polymerase chain reaction. Compared with anterior sac and aneurysm wall at level of rupture, MNV was increased (
P
<0.001) in rupture edge biopsy samples and consisted of smaller diameter (
P
<0.001) and more immature microvessels (
P
<0.001). mRNA expression of α
v
-integrin, vascular endothelial growth factor, vascular endothelial-cadherin, monocyte chemoattractant protein-1, and vimentin was increased (
P
<0.05) in rupture edge biopsy samples.

Conclusions—

This study demonstrated increased medial neovascularization and overexpression of proangiogenic cytokines at aneurysm rupture edge. Further investigations into whether this angiogenic response was a causative factor of aneurysm rupture are needed.
CX
3
CR1 Deficiency Confers Protection From Intimal Hyperplasia After Arterial Injury
Authors: Liu Peng , Patil Sarita , Rojas Mauricio , Fong Alan M. , Smyth Susan S. , Patel Dhavalkumar D.
Published: June 2006

Objective—

A functional polymorphism in the chemokine receptor CX
3
CR1 is associated with protection from vascular diseases including coronary artery disease and internal carotid artery occlusive disease. We investigated the mechanisms by which CX
3
CR1 may be involved by evaluating the inflammatory response to arterial injury in CX
3
CR1-deficient animals.

Methods and Results—

Femoral arteries of CX
3
CR1
−/−
and wild-type (WT) mice were injured with an angioplasty guide wire. After 1, 5, 14, and 28 days, arteries were harvested and evaluated by histology, morphometry, and immunohistochemistry. Arterial injury upregulated the CX
3
CR1 ligand CX
3
CL1. In CX
3
CR1
−/−
compared with WT animals, the incidence of neointima formation was 58% lower (
P
=0.0017), accompanied by no difference in the area of platelet accumulation at day 1 (
P
=0.48) but a significant decrease in intimal monocyte infiltration at day 5 (
P
=0.006), vascular smooth muscle cell (VSMC) proliferation at days 5 and 14, and intimal area at day 28 (
P
=0.009).

Conclusions—

In an endothelial denudation injury model, CX
3
CR1 deficiency protects animals from developing intimal hyperplasia as a result of decreased monocyte trafficking to the lesion. CX
3
CR1 deficiency decreases VSMC proliferation and intimal accumulation either directly or indirectly as a result of defective monocyte infiltration.
Adrenomedullin/Cyclic AMP Pathway Induces Notch Activation and Differentiation of Arterial Endothelial Cells From Vascular Progenitors
Authors: Yurugi-Kobayashi Takami , Itoh Hiroshi , Schroeder Timm , Nakano Akiko , Narazaki Genta , Kita Fumiyo , Yanagi Kentoku , Hiraoka-Kanie Mina , Inoue Emi , Ara Toshiaki , Nagasawa Takashi , Just Ursula , Nakao Kazuwa , Nishikawa Shin-Ichi , Yamashita Jun K.
Published: June 2006

Objective—

The acquisition of arterial or venous identity is highlighted in vascular development. Previously, we have reported an embryonic stem (ES) cell differentiation system that exhibits early vascular development using vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2)-positive cells as common vascular progenitors. In this study, we constructively induced differentiation of arterial and venous endothelial cells (ECs) in vitro to elucidate molecular mechanisms of arterial-venous specification.

Methods and Results—

ECs were induced from VEGFR2
+
progenitor cells with various conditions. VEGF was essential to induce ECs. Addition of 8bromo-cAMP or adrenomedullin (AM), an endogenous ligand-elevating cAMP, enhanced VEGF-induced EC differentiation. Whereas VEGF alone mainly induced venous ECs, 8bromo-cAMP (or AM) with VEGF supported substantial induction of arterial ECs. Stimulation of cAMP pathway induced Notch signal activation in ECs. The arterializing effect of VEGF and cAMP was abolished in recombination recognition sequence binding protein at the Jκ site deficient ES cells lacking Notch signal activation or in ES cells treated with γ-secretase inhibitor. Nevertheless, forced Notch activation by the constitutively active Notch1 alone did not induce arterial ECs.

Conclusions—

Adrenomedullin/cAMP is a novel signaling pathway to activate Notch signaling in differentiating ECs. Coordinated signaling of VEGF, Notch, and cAMP is required to induce arterial ECs from vascular progenitors.
PICOT Inhibits Cardiac Hypertrophy and Enhances Ventricular Function and Cardiomyocyte Contractility
Authors: Jeong Dongtak , Cha Hyeseon , Kim Eunyoung , Kang Misuk , Yang Dong Kwon , Kim Ji Myoung , Yoon Pyoung Oh , Oh Jae Gyun , Bernecker Oliver Y. , Sakata Susumu , Thu Le Thi , Cui Lei , Lee Young-Hoon , Kim Do Han , Woo Sun-Hee , Liao Ronglih , Hajjar Roger J. , Park Woo Jin
Published: June 2006

Multiple signaling pathways involving protein kinase C (PKC) have been implicated in the development of cardiac hypertrophy. We observed that a putative PKC inhibitor, PICOT (
P
KC-
I
nteracting
C
ousin
O
f
T
hioredoxin) was upregulated in response to hypertrophic stimuli both in vitro and in vivo. This suggested that PICOT may act as an endogenous negative feedback regulator of cardiac hypertrophy through its ability to inhibit PKC activity, which is elevated during cardiac hypertrophy. Adenovirus-mediated gene transfer of PICOT completely blocked the hypertrophic response of neonatal rat cardiomyocytes to enthothelin-1 and phenylephrine, as demonstrated by cell size, sarcomere rearrangement, atrial natriuretic factor expression, and rates of protein synthesis. Transgenic mice with cardiac-specific overexpression of PICOT showed that PICOT is a potent inhibitor of cardiac hypertrophy induced by pressure overload. In addition, PICOT overexpression dramatically increased the ventricular function and cardiomyocyte contractility as measured by ejection fraction and end-systolic pressure of transgenic hearts and peak shortening of isolated cardiomyocytes, respectively. Intracellular Ca
2+
handing analysis revealed that increases in myofilament Ca
2+
responsiveness, together with increased rate of sarcoplasmic reticulum Ca
2+
reuptake, are associated with the enhanced contractility in PICOT-overexpressing cardiomyocytes. The inhibition of cardiac remodeling by of PICOT with a concomitant increase in ventricular function and cardiomyocyte contractility suggests that PICOT may provide an efficient modality for treatment of cardiac hypertrophy and heart failure.
Cardiac Myosin Light Chain-2
Authors: Rottbauer Wolfgang , Wessels Georgia , Dahme Tillman , Just Steffen , Trano Nicole , Hassel David , Burns Charles Geoffrey , Katus Hugo A. , Fishman Mark C.
Published: June 2006

Although it is well known that mutations in the cardiac regulatory myosin light chain-2 (
mlc-2
) gene cause hypertrophic cardiomyopathy, the precise in vivo structural and functional roles of MLC-2 in the heart are only poorly understood. We have isolated a mutation in zebrafish, tell tale heart (
tel
m225
), which selectively perturbs contractility of the embryonic heart. By positional cloning, we identified
tel
to encode the zebrafish
mlc-2
gene. In contrast to mammals, zebrafish have only 1 cardiac-specific
mlc-2
gene, which we find to be expressed in atrial and ventricular cardiomyocytes during early embryonic development, but also in the adult heart. Accordingly, loss of zMLC-2 function cannot be compensated for by upregulation of another
mlc-2
gene. Surprisingly, ultrastructural analysis of
tel
cardiomyocytes reveals complete absence of organized thick myofilaments. Thus, our findings provide the first in vivo evidence that cardiac MLC-2 is required for thick-filament stabilization and contractility in the vertebrate heart.
Potential New Risk Factors for Ischemic Stroke
Authors: Hankey Graeme J.
Published: June 2006

Background and Purpose—

About 60% to 80% of all ischemic strokes can be attributed to increasing blood pressure, blood cholesterol, cigarette smoking, carotid stenosis, and diabetes mellitus (atherosclerotic ischemic stroke), and atrial fibrillation and valvular heart disease (cardiogenic ischemic stroke). The aim of this review was to examine the potential role of other risk factors in the etiology of ischemic stroke.

Summary of Review—

About 10% to 20% of atherosclerotic ischemic strokes can probably be attributed to recently established, causal risk factors for ischemic heart disease: raised apoB/apoA 1 ratio, obesity, physical inactivity, pyschosocial stress and low fruit and vegetable intake. However, their causal role remains to be proven. The direct genetic contribution of any single gene towards ischemic stroke is likely to be modest and apply in selected patients only and in combination with environmental factors or via other epistatic (gene-gene or gene-environmental) effects.

Conclusions—

Research resources should not be allocated disproportionately to emerging novel risk factors that may account for up to only 20% of all strokes at the expense of researching the determinants of the relatively few established causal factors that account for up to 80% of all strokes.
Atrial Fibrillation and Stroke in the General Medicare Population
Authors: Lakshminarayan Kamakshi , Solid Craig A. , Collins Allan J. , Anderson David C. , Herzog Charles A.
Published: June 2006

Background and Purpose—

Clinical trials have illustrated warfarin’s protective effect on stroke risk in patients with atrial fibrillation (AF). The current study investigated temporal trends in AF prevalence, warfarin use, and its relation to stroke risk in Medicare patients with AF from 1992 to 2002.

Methods—

The Medicare 5% sample for 1992 to 2002 was used to create 1-year cohorts of patients with Medicare as primary payer throughout the year.
International Classification of Diseases, Ninth Revision, Clinical Modification
codes were used to identify AF, ischemic and hemorrhagic stroke, and comorbid conditions. A previously validated surrogate measure, prothrombin/international normalized ratio claims, was used to identify warfarin use. Cox proportional hazards regression was used to examine time to stroke with warfarin use as a time-dependent variable.

Results—

Among Medicare patients aged ≥65 years, AF prevalence increased from 3.2% in 1992 to 6.0% in 2002 with higher prevalence in older subsets of the study population. Among patients with AF, warfarin use increased significantly (
P
≤0.001) for each year examined, from 24.5% in 1992 to 56.3% in 2002. Stroke rates per 1000 patient-years declined from 46.7 in 1992 to 19.5 in 2002 for ischemic stroke but remained fairly steady for hemorrhagic stroke (range, 1.6 to 2.9). Time-to-event modeling confirmed a protective association of warfarin against ischemic stroke among Medicare patients with AF.

Conclusions—

This analysis represents an observational validation of stroke prevention in AF trials. The significant increase in warfarin use among patients with AF illustrates diffusion of trial evidence into clinical practice.
The ALIAS Pilot Trial
Authors: Ginsberg Myron D. , Hill Michael D. , Palesch Yuko Y. , Ryckborst Karla J. , Tamariz Diego
Published: June 2006

Background and Purpose—

In preclinical stroke models, high-dose human albumin confers robust neuroprotection. We investigated the safety and tolerability of this therapy in patients with acute ischemic stroke.

Methods—

The ALIAS (
Al
bumin
i
n
A
cute
S
troke) Pilot Clinical Trial used a multiple-tier, open-label, dose-escalation design. Subjects with acute ischemic stroke (NIH Stroke Scale [NIHSS] of 6 or above) received a 2-hour infusion of 25% human albumin (ALB) beginning within 16 hours of stroke onset. Six successive ALB dose tiers were assessed ranging from 0.34 to 2.05 g/kg. Neurologic and cardiac function was sequentially monitored. At 3 months, the NIHSS, modified Rankin Scale, and Barthel Index were measured.

Results—

Eighty-two subjects (mean age, 65 years) received ALB at 7.8±3.4 hours after stroke onset (mean±standard deviation). Forty-two patients also received standard-of-care intravenous tissue plasminogen activator (tPA). Vital signs were unaltered by ALB treatment. Dose-related increases in plasma albumin and mild hemodilution were maximal at 4 to 12 hours. Age-related plasma brain natriuretic peptide levels increased at 24 hours after ALB but did not predict cardiac adverse events. The sole ALB-related adverse event was mild or moderate pulmonary edema in 13.4% of subjects, which was readily managed with diuretics. In the tPA-treated subgroup, symptomatic intracranial hemorrhage occurred in only one of 42 subjects.

Conclusions—

Twenty-five percent human albumin in doses ranging up to 2.05 g/kg was tolerated by patients with acute ischemic stroke without major dose-limiting complications. tPA therapy did not affect the safety profile of ALB. The companion article presents neurologic outcome data and efficacy analysis in these subjects.
The ALIAS Pilot Trial
Authors: Palesch Yuko Y. , Hill Michael D. , Ryckborst Karla J. , Tamariz Diego , Ginsberg Myron D.
Published: June 2006

Background and Purpose—

High-dose human albumin (ALB) is robustly neuroprotective in rodent stroke models. A phase I dose-escalation study was conducted to assess the safety of ALB therapy in ischemic stroke. We analyzed the data for preliminary evidence of treatment efficacy.

Methods—

Eighty-two subjects with acute ischemic stroke (NIH Stroke Scale [NIHSS] of 6 or above) received 25% ALB beginning within 16 hours of stroke onset. Six successive ALB dose tiers were assessed (range, 0.34 to 2.05 g/kg). Forty-two patients also received standard-of-care intravenous tissue plasminogen activator (tPA). Efficacy outcomes were determined at 3 months. We compared the highest three, putatively therapeutic ALB dose tiers (1.37 to 2.05 g/kg) with the lowest three, presumed subtherapeutic doses (0.34 to 1.03 g/kg) and with historical cohort data derived from the NINDS rt-PA Stroke Study.

Results—

After adjusting for the tPA effect, the probability of good outcome (defined as modified Rankin Scale 0 to 1 or NIH Stroke Scale 0 to 1 at 3 months) at the highest three ALB doses was 81% greater than in the lower dose-tiers (relative risk [RR], 1.81; 95% confidence interval [CI], 1.11 to 2.94) and was 95% greater than in the comparable NINDS rt-PA Stroke Study cohort (RR, 1.95; 95% CI, 1.47 to 2.57). The tPA-treated subjects who received higher-dose ALB were three times more likely to achieve a good outcome than subjects receiving lower-dose ALB, suggesting a positive synergistic effect between ALB and tPA.

Conclusions—

Our data suggest that high-dose ALB therapy may be neuroprotective after ischemic stroke. These results have led to a multicenter, randomized, placebo-controlled efficacy trial of ALB in acute ischemic stroke—the ALIAS Phase III Trial.
ADMA Increases Arterial Stiffness and Decreases Cerebral Blood Flow in Humans
Authors: Kielstein Jan T. , Donnerstag Frank , Gasper Sandra , Menne Jan , Kielstein Anousheh , Martens-Lobenhoffer Jens , Scalera Fortunato , Cooke John P. , Fliser Danilo , Bode-Böger Stefanie M.
Published: June 2006

Background and Purpose—

Preclinical studies have revealed that the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA), increases vascular tone in cerebral blood vessels. Marked elevations of ADMA blood levels were found in patients with diseases characterized by decreased cerebral perfusion, such as ischemic stroke. Arterial stiffness is an independent predictor of stroke and other adverse cardiovascular events. The aim of this study was to investigate the influence of a systemic subpressor dose of ADMA on arterial stiffness and cerebral perfusion in humans.

Methods—

Using a double-blind, vehicle-controlled study design, we allocated 20 healthy men in random order to infusion of either ADMA (0.10 mg ADMA/kg per min) or vehicle over a period of 40 minutes. Arterial stiffness was assessed noninvasively by pulse wave analysis. All volunteers underwent measurement of cerebral perfusion by dynamic contrast-enhanced perfusion magnetic resonance imaging of the brain.

Results—

Infusion of ADMA significantly decreased total cerebral perfusion by 15.1±4.5% (
P
=0.007), whereas blood flow in the vehicle group increased by 7.7±2.8% (
P
=0.02). ADMA also increased arterial stiffness as assessed by measurement of the augmentation index (−12.6±1.9 to −9.6±1.5,
P
=0.007).

Conclusions—

Our results document for the first time that subpressor doses of ADMA increase vascular stiffness and decrease cerebral perfusion in healthy subjects. Thus, ADMA is an important endogenous modulator of cerebral vascular tone and may be involved in the pathogenesis of cerebrovascular disease.
Recurrent Extracranial Carotid Artery Vasospasms
Authors: Janzarik Wibke G. , Ringleb Peter A. , Reinhard Matthias , Rauer Sebastian
Published: June 2006

Background and Purpose—

Spontaneous vasospasms of the submandibular internal carotid arteries are rarely observed. They are a highly dynamic process, recur frequently, and can be detected by serial ultrasound examinations.

Summary of Cases—

We present 2 cases of recurrent extracranial vasospasms of the internal carotid artery as a cause of stroke. In both cases, arterial dissection was initially suspected, but no intramural hematoma was detected on magnetic resonance imaging. Duplex sonography demonstrated recurrent high-grade stenoses of both internal carotid arteries that resolved spontaneously within hours to days. The vasospasms were treated with calcium antagonists and in 1 patient with oral corticoids.

Conclusions—

Extracranial vasospasms as a cause of stroke might be underestimated. Vasospasms of the internal carotid arteries should be considered in patients with recurring ischemic events in the absence of any other explanation. Antiphlogistic treatment in combination with calcium antagonists might be effective to reduce the frequency of vasospasms.
Complement C3 and C-Reactive Protein Are Elevated in South Asians Independent of a Family History of Stroke
Authors: Somani Riyaz , Grant Peter J. , Kain Kirti , Catto Andrew J. , Carter Angela M.
Published: June 2006

Background and Purpose—

Complement components are emerging risk factors for cardiovascular disease. In this study, we examined the relation among C3, C-reactive protein (CRP), factor B, and features of the insulin resistance (IR) syndrome in 143 first-degree relatives of South Asian subjects with ischemic stroke, 141 South Asian controls, and 121 white controls.

Methods—

C3, CRP (high-sensitivity assay), and factor B levels were measured by ELISAs, and their relation to features of the IR syndrome were assessed. Data are presented as geometric mean (95% CI).

Results—

There was no significant difference in the levels of C3 between South Asian relatives (1.25 [1.21, 1.29] g/L) and South Asian controls (1.20 [1.15, 1.24] g/L,
P
=0.2). Levels in both South Asian groups were significantly higher than in white controls (0.95 [0.92, 0.98] g/L;
P
<0.001 for both comparisons). These differences remained significant after adjustment for covariates. Similarly, levels of CRP were not different between the 2 South Asian groups, but levels in both South Asian groups, after adjustment for covariates, were significantly higher than in white controls. There was no difference in the levels of factor B among the 3 groups. South Asian subjects with elevated C3 levels clustered risk factors associated with IR to a greater extent than those with high CRP.

Conclusions—

These results suggest that South Asians have a greater level of chronic subclinical inflammation than do whites, independent of a family history of stroke. In addition, C3 is more likely to cluster with features of the IR syndrome compared with CRP in South Asians.
Diffusion-Weighted Imaging in Stroke Attributable to Patent Foramen Ovale
Authors: Bonati Leo H. , Kessel-Schaefer Arnheid , Linka André Z. , Buser Peter , Wetzel Stephan G. , Radue Ernst-Wilhelm , Lyrer Philippe A. , Engelter Stefan T.
Published: June 2006

Background and Purpose—

Patent foramen ovale (PFO) is an established cause of stroke in young patients without other determined etiologies (ie, cryptogenic stroke). The additional presence of atrial septum aneurysm (ASA) possibly increases stroke risk, but it remains undetermined which factors best predict thromboembolism in patients with PFO. Diffusion-weighted imaging (DWI) may help to distinguish the characteristics of cerebral embolism associated with different features of the interatrial septum in PFO stroke.

Methods—

In a stroke databank-based cohort study, DWI and transthoracic/transesophageal echocardiography findings were assessed in 48 consecutive patients with cryptogenic ischemic stroke associated with PFO. The number, size, and distribution of acute ischemic lesions on DWI were correlated with PFO size, degree of interatrial right-to-left shunt (RLS), and the presence of ASA.

Results—

Patients with PFO plus ASA combined more often had multiple acute DWI lesions (16 of 30, 53%) than those with PFO alone (3 of 18, 17%;
P
=0.01). This association remained significant after correction for PFO size, degree of RLS, and vascular risk factors in a logistic-regression analysis (
P
=0.04). No significant associations between DWI lesion characteristics and PFO size or degree of RLS were found.

Conclusions—

The presence of concomitant ASA is independently associated with multiple cerebral ischemic lesions in PFO stroke, which may indicate an increased embolic risk.
Statin Treatment Is Not Associated With Consistent Alterations in Inflammatory Status of Carotid Atherosclerotic Plaques
Authors: Verhoeven Bart A.N. , Moll Frans L. , Koekkoek Johan A.F. , van der Wal Allard C. , de Kleijn Dominique P.V. , de Vries Jean Paul P.M. , Verheijen Jan H. , Velema Evelyn , Busser Els , Schoneveld Arjan , Virmani Renu , Pasterkamp Gerard
Published: June 2006

Background and Purpose—

Anti-inflammatory qualities are held partially responsible for the reduction of cardiovascular events after statin treatment. We examined the phenotype of carotid atherosclerotic plaques harvested during carotid endarterectomy in relation to the previous use of different statins prescribed in clinical practice.

Methods—

Three hundred and seventy-eight patients were included. Atherosclerotic plaques were harvested, immunohistochemically stained and semiquantitively examined for the presence of macrophages (CD68), smooth muscle cells, collagen and fat. Adjacent atherosclerotic plaques were used to study protease activity and interleukin levels. Patients’ demographics were recorded and blood samples were stored.

Results—

Serum cholesterol, low-density lipoprotein, apolipoprotein B, and C-reactive protein levels were lower in patients treated with statins compared with patients without statin treatment. Atheromatous plaques were less prevalent in patients receiving statins compared with patients without statin therapy (29% versus 42%,
P
=0.04). An increase of CD68 positive cells was observed in patients receiving statins compared with nonstatin treatment (
P
=0.05). This effect was specifically related to atorvastatin treatment. In patients treated with atorvastatin, the increased amount of CD68 positive cells were not associated with increased protease activity. In contrast, a dose-dependent decrease in protease activity was shown in the atorvastatin group. Interleukin 6 expression was lower in plaques obtained from patients treated with statins (
P
=0.04).

Conclusions—

Statin use may exert pleiotropic effects on plaque phenotype. However, not the presence of macrophages but activation with subsequent protease and cytokine release may be attenuated by statin use.
Temporal Profiles of Axon Terminals, Synapses and Spines in the Ischemic Penumbra of the Cerebral Cortex
Authors: Ito Umeo , Kuroiwa Toshihiko , Nagasao Jun , Kawakami Emiko , Oyanagi Kiyomitsu
Published: June 2006

Background and Purpose—

Because the recovery process of axon terminals, synapses, and spine-dendrites in the ischemic penumbra of the cerebral cortex is obscure, we studied the temporal profile of these structures up to 12 weeks after the ischemic insult, using a gerbil model.

Methods—

Stroke-positive animals were selected according to their stroke index score during the first 10-minute left carotid occlusion done twice with 5-hour interval. The animals were euthanized at various times after the second ischemic insult. Ultra-thin sections including the 2nd to 4th cortical layers were obtained from the neocortex coronally sectioned at the infundibular level, in which the penumbra appeared. We counted the number of synapses, spines and multiple synapse boutons, measured neurite thickness, and determined the percent volume of the axon terminals and spines by Weibel point counting method.

Results—

The number of synapses, synaptic vesicles and spines and the total percent volume of the axon terminals and spines decreased until the 4th day. From 1 to 12 weeks after the ischemic insult, these values increased to or exceeded the control ones, and neuritic thickening and increase in number of multiple synapse boutons occurred.

Conclusions—

In the ischemic penumbra, the above structures degenerated, with a reduction in their number and size, until 4 days and then recovered from 1 to 12 weeks after the ischemic insult.
Youth as a Bridge Between Home and School
Authors: Mitra Dana L.
Published: June 2006

This article analyzes efforts to increase parent involvement and student voice among Mexican American families who are low income at a large comprehensive high school. Although the parent-involvement effort ultimately failed, the students developed their own initiatives to help support Latino youth and their families, including the development of a bilingual tutoring program and a translation program for families needing to communicate with the school. The experiences in this article suggest that, rather than focusing solely on parent-involvement strategies, schools also increase student voice as a way to bridge the gap between families and the school and to improve student outcomes.
At the Edge of Danger
Authors: Bisland Beverly Milner (Lee)
Published: June 2006

Teachers were among the public servants at work in New York City on September 11, 2001. This study focuses on the feelings and actions of a representative group of elementary teachers in Queens, New York. As they became aware of the unfolding tragedy of the World Trade Center attacks, they demonstrated the essential qualities of public service, which include selflessness and placing others’ needs above their own. On that day, teachers, and other public servants, such as police and firefighters, became for ordinary citizens the voice and face of the democratic state in a time of crisis.
An Analysis of the Academic Performance of Voucher Students in the Opportunity Scholarship Program
Authors: Abella Rodolfo
Published: June 2006

In accordance with the Florida Opportunity Scholarship Program (OSP), students attending public schools that receive failing grades are eligible to receive vouchers to attend a higher performing public or private school. An analysis of standardized test performance across a 2-year period compared students attending “F” schools to students who participated in the OSP. Students attending “F” schools were more likely to improve their Florida Comprehensive Assessment Test (FCAT) level standing in math during the 2-year period than OSP-Private school students. Also, the percentage of students achieving math and reading proficiency (Level 3 or greater) in the FCAT decreased significantly among the OSP-Private group. Overall, students participating in the OSP academically performed about the same as students attending “F” schools across a 2-year period with the exception that OSP-Private school students underperformed in math when compared to students attending “F” schools.
New Teachers' Experiences of Hiring: Late, Rushed, and Information-Poor
Authors: Liu Edward , Johnson Susan Moore
Published: June 2006

Purpose: Teacher hiring decisions have far-reaching consequences for a school, its students, and faculty. This article examines how new teachers in four states are hired and explores whether the process leads to good matches between these individuals and their schools. The authors conceive of hiring as a two-way process and examine the extent to which the hiring process provides opportunities for prospective teachers and schools to collect rich information about, and form accurate impressions of, one another.

Research Methods: This study surveyed a representative random sample of 486 first-year and second-year teachers in California, Florida, Massachusetts, and Michigan. Participants were chosen using two-stage stratified cluster sampling, and the study achieved a response rate of 65%. Statistical methods used in the analysis include principal components analysis, chi-square analysis, and t tests.

Findings: The data reveal that the majority of new teachers in these states are hired through a decentralized, school-based process. Despite the opportunity this provides schools and prospective teachers to explore the potential match between them, most new teachers actually have limited interactions with school-based personnel during the hiring process, and the process is relatively information-poor. Many new teachers are also hired quite late—more than one third of new teachers in California and Florida are hired after the school year has already started.

Implications: The results of our analysis suggest that shifting hiring decisions to the school level is not sufficient to guarantee information-rich hiring. They also suggest that schools may need help removing barriers to conducting more information-rich hiring.
Accessing Internal Leadership Positions at School: Testing the Similarity-Attraction Approach Regarding Gender in Three Educational Systems in Israel
Authors: Addi-Raccah Audrey
Published: June 2006

Background: Women school leaders may act as social agents who promote gender equality, but evidence is inconclusive regarding the effect of women's leadership on gender stratification in the workplace.

Purpose: Based on the similarity-attraction perspective, this study examined male and female school leaders' relations to similar others in three educational systems: Jewish secular public schools, Jewish religious public schools, and Arab schools. As these school systems represent distinct sociocultural contexts regarding women's status, the study tested for differences among them in women's sponsorship of other women.

Data Collection and Analysis: The study was based on a survey conducted by the Israel Central Bureau of Statistics in 2000 that included ( N = 63, 886) teachers and school administrators. The data were analyzed by conducting several multinomial logistic regression analyses in which the dependent variable was holding an internal leadership position within the school.

Findings: The findings indicated that female school leaders have more diversified behavior to other women than male school leaders show in regard to men. The extent to which women promoted other women depended on their relative social power within each educational system.

Conclusions: The study supports the claim that sponsoring similar others tends to be context bound, as gender inequality in holding internal administrative positions differed according to school principals'gender and to educational system. The implications of the study are discussed.
Going Beyond Role Expectations: Toward an Understanding of the Determinants and Components of Teacher Organizational Citizenship Behavior
Authors: Oplatka Izhar
Published: June 2006

Purpose: To fill the gap in theoretical and empirical knowledge on the patterns of organizational citizenship behavior (OCB) in school, the aim of this study was to explore the components of teacher OCB as well as its personal and contextual determinants.

Research Design: Semistructured interviews were conductedwith 50 schoolteachers, 10 principals, and 10 supervisors, all from the elementary and secondary educational systems of Israel. The analysis followed the principles of qualitative research.

Findings: The article presents an initial conceptualization of the components of teacher OCB. Among these components are supportive behaviors toward students and colleagues, initiation of changes and innovations in teaching, strong orientation toward the organization, and strong loyalty to the teaching profession. In addition, the study identified a variety of determinants of teacher OCB, such as the school principal, the teacher's character, and the school's climate.

Conclusions: Empirical and practical implications for the educational system and the educational research are suggested. Principals are strongly encouraged to establish a school environment that promotes OCB-oriented teachers and to create workshops to help him or her in this task. Researchers of educationalsystems are provided with new directions for research on the teacher's role and behavior.
Pharmacology of Acetylcholinesterase Inhibitors andN‐methyl‐d‐aspartate Receptors for Combination Therapy in the Treatment of Alzheimer's Disease
Authors: Geerts Hugo , Grossberg George T.
Published: June 2006

The search for effective treatments of Alzheimer's disease (AD) is one of the major challenges facing modern medicine. Acetylcholinesterase (AChE) inhibitors (AChEIs) are effective for the treatment of mild to moderate AD, and memantine, anN‐methyl‐d‐aspartate ((NMDA) inhibitor, has been approved for moderate to severe AD. Galantamine is of particular interest because it has a dual mechanism of action: it is postulated to be both an AChEI and an allosteric modulator of nicotinic receptors. Modulation of NMDA and nicotinic receptors by memantine and galantamine may provide an optimal combination therapy for AD. The cholinergic and glutamatergic neurotransmitter systems, which share a close functional relationship, may play a role in the pathogenesis of AD. Close examination of the pharmacology of the 2 compounds suggests that galantamine can augment memantine's glutamatergic noise suppression while simultaneously enhancing the physiologic glutamatergic signal. The link between these systems suggests that AD therapies, which capitalize on this relationship, may be more effective in improving cognition than approaches focusing on a single system.
Rationale for Combination Therapy With Galantamine and Memantine in Alzheimer's Disease
Authors: Grossberg George T. , Edwards Keith R. , Zhao Qinying
Published: June 2006

A combination of cholinergic and glutamatergic dysfunction appears to underlie the symptomatology of Alzheimer's disease. Therefore, one hypothesis is that treatment strategies should address impairments in both systems. Galantamine is an acetylcholinesterase inhibitor that, unlike other acetylcholinesterase inhibitors, has a postulated dual mode of action as a nicotinic receptor modulator. Galantamine has demonstrated long‐term efficacy in improving or maintaining cognition, functionality, and behavior in patients with mild to moderate Alzheimer's disease. Memantine, a noncompetitive N‐methyl‐d‐aspartate‐receptor antagonist, reduces deterioration in cognition and function in patients with moderate to severe Alzheimer's disease. Pharmacokinetic and pharmacodynamic as well as ongoing observation studies support the concept of adjunctive therapy with memantine in patients with advanced moderate Alzheimer's disease currently treated with an established galantamine regimen. The potential to modulate both acetylcholine and glutamate pathways in Alzheimer's disease presents a novel treatment strategy for the management of mild to moderately severe Alzheimer's disease.
Pharmacokinetics and Urinary Excretion of Vincristine Sulfate Liposomes Injection in Metastatic Melanoma Patients
Authors: Bedikian Agop Y. , Vardeleon Anna , Smith Teresa , Campbell Susan , Namdari Rostam
Published: June 2006

Vincristine sulfate liposomes injection (VSLI) is a liposomal formulation of vincristine encapsulated in sphingosomes composed of sphinogomyelin and cholesterol (58/42; mol/mol). The pharmacokinetics and urinary excretion of VSLI were evaluated in 12 patients with metastatic melanoma after single‐dose (2.0 mg/m2every 2 weeks = 1 cycle) and multiple‐dose (cycle 3, pharmacokinetics only) administrations (intravenous infusion over 1 hour). After VSLI infusion, total (released and encapsulated) vincristine concentrations in plasma remained relatively constant for 3 to 12 hours and thereafter declined, with interpatient variability seen in the rate of decline resulting in monoexponential or biexponential profiles. The area under the plasma concentration‐time curve from time zero to infinity of total vincristine in plasma ranged from 4933 to 40495 h·ng/mL and total clearance ranged from 131 to 445 mL/h. The volume of distribution at steady state was 2650 ± 731 mL, indicating VSLI was mainly confined within the plasma. The released vincristine concentrations in plasma were below the level of quantitation in 95% of samples. The pharmacokinetic parameters were similar between cycles 1 and 3, and trough plasma levels of total vincristine were below the level of quantitation of 1 ng/mL. Approximately 8% of the injected dose was excreted in the urine as unchanged vincristine (7%) or N‐desformylvincristine (0.8%). Overall, VSLI exhibited a longer circulation half‐life and higher area under the plasma concentration‐time curve compared to conventional vincristine, whereas its route of elimination remained unchanged.
Discordance Between N‐acetyltransferase 2 Phenotype and Genotype in a Population of Hmong Subjects
Authors: Straka Robert J. , Burkhardt R. Todd , Lang Nicholas P. , Hadsall Kelly Z. , Tsai Michael Y.
Published: June 2006

Polymorphisms of N‐acetyltransferase 2 (NAT2) acetylation may influence drug toxicities and efficacy and are associated with a differential susceptibility to select cancers. Acetylation phenotype may have clinical implications. The purposes of this study were to determine the genetic basis of an apparent predominance of slow acetylation phenotype and to assess concordance with genotype in a population of Hmong residing in Minnesota. Urine and DNA obtained from unrelated Hmong 18 to 65 years of age were used to determine phenotype from caffeine metabolites, whereas direct nucleotide sequencing of the NAT2 coding region, followed by cloning, identified all known allelic variants. From 61 subjects (27 men, 30 ± 11 years), analysis of 50 urine‐DNA pairs identified 46 (92%) slow acetylators and 4 (8%) rapid acetylators by phenotype. Genotypic analysis inferred 5 (10%) slow acetylators and 45 (90%) rapid acetylators. There is 86% discordance between phenotype and genotype. A predominance of NAT2 slow acetylation phenotype in the Hmong is confirmed, and a significant discordance between NAT2 phenotype and genotype is identified. In this population, slow acetylation phenotype determined by a metabolic probe would not have been predicted by genotype alone. Environmental, genetic, or phenotypic anomalies that may contribute to this discordance should be considered and evaluated in future studies within this unique population.
Predictive Power of an In Vitro System to Assess Drug Interactions of an Antimuscarinic Medication: A Comparison of In Vitro and In Vivo Drug‐Drug Interaction Studies of Trospium Chloride With Digoxin
Authors: Sandage B. , Sabounjian L. , Shipley J. , Profy A. , Lasseter K. , Fox L. , Harnett M.
Published: June 2006

The authors studied a potential drug‐drug interaction via findings from in vitro and in vivo studies, to assess whether the in vitro system was predictive of in vivo clinical pharmacokinetic outcomes. An in vitro experiment and a clinical study were performed to assess the potential for interaction. The effect of trospium chloride on human P‐glycoprotein‐mediated transport of [3H]‐digoxin was determined in vitro. A randomized, crossover clinical trial in 40 subjects was performed to evaluate the effect of trospium on the pharmacokinetics of digoxin in vivo. The findings from the studies were then compared. The in vitro findings in this study were corroborated by the clinical study via assessment of inhibition and impact on pharmacokinetic parameters. The in vitro system for assessment of a potential interaction of 2 drugs excreted primarily through the kidney was predictive of the pharmacokinetic outcomes obtained from a clinical setting.
Absolute Bioavailability and Disposition of Lanthanum in Healthy Human Subjects Administered Lanthanum Carbonate
Authors: Pennick Michael , Dennis Kerry , Damment Stephen J. P.
Published: June 2006

Lanthanum carbonate [La2(CO3)3] is a noncalcium, nonaluminum phosphate binder indicated for hyperphosphatemia treatment in end‐stage renal disease. A randomized, open‐label, parallel‐group, phase I study was conducted to determine absolute bioavailability and investigate excretory routes for systemic lanthanum in healthy subjects. Twenty‐four male subjects were randomized to a single lanthanum chloride (LaCl3) intravenous infusion (120 μg elemental lanthanum over a 4‐hour period), a single 1‐g oral dose [chewable La2(CO3)3 tablets; 4 × 250 mg elemental lanthanum], or no treatment (control). Serial blood, urine, and fecal samples were collected for 7 days postdosing. The absolute bioavailability of lanthanum [administered as La2(CO3)3] was extremely low (0.00127% ± 0.00080%), with individual values in the range of 0.00015% to 0.00224%. Renal clearance was negligible following oral administration (1.36 ± 1.43 mL/min). Intravenous administration confirmed low renal clearance (0.95 ± 0.60 mL/min), just 1.7% of total plasma clearance. Fecal lanthanum excretion was not quantifiable after intravenous administration owing to high and variable background fecal lanthanum and constraints on the size of the intravenous dose. These findings demonstrate that lanthanum absorption from the intestinal tract into the systemic circulation is extremely low and that absorbed drug is cleared predominantly by nonrenal mechanisms.