bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vivo Assessment of Myocardial Glucose Uptake by Positron Emission Tomography in Adults With the
PRKAG2
Cardiac Syndrome
Authors: Ha Andrew C.T. , Renaud Jennifer M. , deKemp Robert A. , Thorn Stephanie , DaSilva Jean , Garrard Linda , Yoshinaga Keiichiro , Abraham Arun , Green Martin S. , Beanlands Rob S.B. , Gollob Michael H.
Published: September 2009

Background—

The
PRKAG2
cardiac syndrome is an inherited metabolic disease of the heart characterized by excessive myocardial glycogen deposition. The biochemical alterations associated with this condition remain controversial and have not previously been studied in affected humans.

Methods and Results—

Positron emission tomography (PET) imaging was used to quantitatively assess myocardial glucose uptake (MGU) in 6 adult subjects with the
PRKAG2
cardiac syndrome and 6 healthy, matched control subjects using the glucose analogue
18
F-Fluoro-2-deoxyglucose (FDG). Studies were performed under a euglycemic hyperinsulinemic clamp to ensure stable blood glucose levels. Rubidium-82 perfusion scans were performed to ensure that myocardial differences in myocardial glucose uptake were not the result of significant myocardial scar. In adult patients with phenotypic expression of disease, the median myocardial glucose uptake of the left ventricle was 0.18 μmol/min/g (interquartile range, 0.14, 0.24), compared with 0.40 μmol/min/g (interquartile range, 0.30 to 0.45) in the control group (
P
=0.01). The median blood glucose during FDG-PET imaging was 4.72 mmol/L (interquartile range, 4.32 to 4.97) in the
PRKAG2
group and 4.38 mmol/L (interquartile range, 3.90, 4.79) in the control group (
P
=NS). The significant decrease observed in myocardial glucose uptake in affected patients occurred in the absence of significant myocardial scar.

Conclusions—

The
PRKAG2
cardiac syndrome is associated with a reduction of glucose uptake in adult patients affected with this genetic condition. In this pilot study,
18
F-FDG-PET imaging is a useful tool to assess alterations in myocardial glucose transport in this inherited metabolic disease and provide insight into the biochemical pathophysiology of the diseased state.
Aldosterone-Induced Activation of Signaling Pathways Requires Activity of Angiotensin Type 1a Receptors
Authors: Lemarié Catherine A. , Simeone Stefania M.C. , Nikonova Anna , Ebrahimian Talin , Deschênes Marie-Eve , Coffman Thomas M. , Paradis Pierre , Schiffrin Ernesto L.
Published: September 2009

Rationale:Aldosterone has been shown to induce vascular damage, endothelial dysfunction, and myocardial fibrosis, which depend in part on activation of angiotensin II (Ang II)–mediated pathways. However, mechanisms underlying crosstalk between Ang II type 1 receptor (AT1R) and mineralocorticoid receptor (MR) are mostly unknown.

Objectives:We tested whether the lack of Ang II type 1a receptor (AT1aR) or Ang II type 1b receptor (AT1bR) would decrease cellular effects induced by aldosterone.

Methods and Results:We examined the effect of Ang II or aldosterone after transfection of mesenteric vascular smooth muscle cells (VSMCs) from C57Bl/6 mice with small interference RNA for AT1aR, AT1bR, or MR for 48 hours. Ang II and aldosterone separately induced ERK1/2, c-Jun NH2-terminal protein kinase (JNK), and nuclear factor (NF)-κB phosphorylation after a 20-minute stimulation. Small interference RNA for AT1aR downregulated phosphorylation of ERK1/2, JNK, and NF-κB after aldosterone stimulation compared to controls. Downregulation of AT1bR or MR only abolished the activation of NF-κB. In VSMCs from C57Bl/6 mice, aldosterone and Ang II induced the activation of the c-fos promoter from 30 minutes to 1 hour. This effect was blocked when using VSMCs from AT1aR knockout mice.

Conclusion:We show for the first time that nongenomic and genomic effects of aldosterone are differentially dependent on activity of both AT1aR and AT1bR. Our data suggest that aldosterone augments AT1R-dependent activation of ERK1/2, JNK, and NF-κB in VSMCs. We provide mechanistic understanding and experimental in vitro support for the benefit of combination therapy with dual blockade of AT1R and MR to treat hypertension and progression of heart failure as reported in clinical studies and animal models.
Insulin-Like Growth Factor Binding Protein-3 Mediates Vascular Repair by Enhancing Nitric Oxide Generation
Authors: Kielczewski Jennifer L. , Jarajapu Yagna P.R. , McFarland Evan L. , Cai Jun , Afzal Aqeela , Li Calzi Sergio , Chang Kyung Hee , Lydic Todd , Shaw Lynn C. , Busik Julia , Hughes Jeffrey , Cardounel Arturo J. , Wilson Kenneth , Lyons Timothy J. , Boulton Michael E. , Mames Robert N. , Chan-Ling Tailoi , Grant Maria B.
Published: September 2009

Rationale
:

Insulin-like growth factor binding protein (IGFBP)-3 modulates vascular development by regulating endothelial progenitor cell (EPC) behavior, specifically stimulating EPC cell migration. This study was undertaken to investigate the mechanism of IGFBP-3 effects on EPC function and how IGFBP-3 mediates cytoprotection following vascular injury.

Objective
:

To examine the mechanism of IGFBP-3–mediated repair following vascular injury.

Methods and Results
:

We used 2 complementary vascular injury models: laser occlusion of retinal vessels in adult green fluorescent protein (GFP) chimeric mice and oxygen-induced retinopathy in mouse pups. Intravitreal injection of IGFBP-3–expressing plasmid into lasered GFP chimeric mice stimulated homing of EPCs, whereas reversing ischemia induced increases in macrophage infiltration. IGFBP-3 also reduced the retinal ceramide/sphingomyelin ratio that was increased following laser injury. In the OIR model, IGFBP-3 prevented cell death of resident vascular endothelial cells and EPCs, while simultaneously increasing astrocytic ensheathment of vessels. For EPCs to orchestrate repair, these cells must migrate into ischemic tissue. This migratory ability is mediated, in part, by endogenous NO generation. Thus, we asked whether the migratory effects of IGFBP-3 were attributable to stimulation of NO generation. IGFBP-3 increased endothelial NO synthase expression in human EPCs leading to NO generation. IGFBP-3 exposure also led to the redistribution of vasodilator-stimulated phosphoprotein, an NO regulated protein critical for cell migration. IGFBP-3–mediated NO generation required high-density lipoprotein receptor activation and stimulation of phosphatidylinositol 3-kinase/Akt pathway.

Conclusion
:

These studies support consideration of IGFBP-3 as a novel agent to restore the function of injured vasculature and restore NO generation.
Myeloid Differentiation Factor-88/Interleukin-1 Signaling Controls Cardiac Fibrosis and Heart Failure Progression in Inflammatory Dilated Cardiomyopathy
Authors: Blyszczuk Przemyslaw , Kania Gabriela , Dieterle Thomas , Marty Rene R. , Valaperti Alan , Berthonneche Corinne , Pedrazzini Thierry , Berger Christoph T. , Dirnhofer Stephan , Matter Christian M. , Penninger Josef M. , Lüscher Thomas F. , Eriksson Urs
Published: September 2009

Rationale
:

The myeloid differentiation factor (MyD)88/interleukin (IL)-1 axis activates self–antigen-presenting cells and promotes autoreactive CD4
+
T-cell expansion in experimental autoimmune myocarditis, a mouse model of inflammatory heart disease.

Objective
:

The aim of this study was to determine the role of MyD88 and IL-1 in the progression of acute myocarditis to an end-stage heart failure.

Methods and Results
:

Using α-myosin heavy chain peptide (MyHC-α)–loaded, activated dendritic cells, we induced myocarditis in wild-type and MyD88
−/−
mice with similar distributions of heart-infiltrating cell subsets and comparable CD4
+
T-cell responses. Injection of complete Freund’s adjuvant (CFA) or MyHC-α/CFA into diseased mice promoted cardiac fibrosis, induced ventricular dilation, and impaired heart function in wild-type but not in MyD88
−/−
mice. Experiments with chimeric mice confirmed the bone marrow origin of the fibroblasts replacing inflammatory infiltrates and showed that MyD88 and IL-1 receptor type I signaling on bone marrow–derived cells was critical for development of cardiac fibrosis during progression to heart failure.

Conclusions
:

Our findings indicate a critical role of MyD88/IL-1 signaling in the bone marrow compartment in postinflammatory cardiac fibrosis and heart failure and point to novel therapeutic strategies against inflammatory cardiomyopathy.
Shear Stress Regulates Angiotensin Type 1 Receptor Expression in Endothelial Cells
Authors: Ramkhelawon Bhama , Vilar Jose , Rivas Daniel , Mees Barend , de Crom Rini , Tedgui Alain , Lehoux Stéphanie
Published: September 2009

Rationale
:

Shear stress (SS) has an established role in atherosclerotic plaque localization, but how it exerts its protective effect is not fully understood.

Objective
:

To test the hypothesis that SS may downregulate angiotensin type 1 receptors (AT
1
Rs). Angiotensin II has been shown to be proinflammatory and to promote atherosclerosis.

Methods and Results
:

Using immunohistochemistry, we found a pronounced expression of AT
1
R in the inner, atheroprone regions of the aortic arch of C57BL/6 and endothelial NO synthase–deficient (eNOS
−/−
) mice but not eNOS-overexpressing mice. In human umbilical vein endothelial cells (HUVECs), laminar SS (15 dyn/cm
2
) induced a biphasic decrease in AT
1
R protein expression characterized by a first reduction at 1 hour (31±4% of static control,
P
<0.01), partial recovery at 3 hours (65±9%), and a second more prolonged decline at 6, 12, and 24 hours (48±9%, 36±9%, 33±5%, respectively,
P
<0.05). One and 24 hours of SS significantly reduced fluorescent angiotensin binding compared to static HUVECs. Shear-induced downregulation of AT
1
R was abolished by treatment with protein kinase A and G inhibitors or
N
G
-nitro-
l
-arginine methyl ester (L-NAME). Fittingly, stimulating static HUVECs with an NO donor decreased AT
1
R protein levels. RT-PCR revealed a significant (
P
<0.05) decrease of AT
1
R mRNA in HUVECs exposed to SS during 3 (6±2% of static control), 6 (4±1%), 12 (4±1%), and 24 hours (15±4%), suggesting a transcriptional downregulation of AT
1
R at length. Finally, angiotensin-induced vascular cell adhesion molecule was abated in HUVECs exposed to SS and in the outer aortic arch of mice.

Conclusions
:

Our results demonstrate that SS may convey some of its atheroprotective effects through downregulation of AT
1
R in endothelial cells.
Myocardial Salvage Through Coronary Collateral Growth by Granulocyte Colony-Stimulating Factor in Chronic Coronary Artery Disease
Authors: Meier Pascal , Gloekler Steffen , de Marchi Stefano F. , Indermuehle Andreas , Rutz Tobias , Traupe Tobias , Steck Hélène , Vogel Rolf , Seiler Christian
Published: September 2009

Background—

The efficacy of granulocyte colony-stimulating factor (G-CSF) for coronary collateral growth promotion and thus impending myocardial salvage has not been studied so far, to our best knowledge.

Methods and Results—

In 52 patients with chronic stable coronary artery disease, age 62±11 years, the effect on a marker of myocardial infarct size (ECG ST segment elevation) and on quantitative collateral function during a 1-minute coronary balloon occlusion was tested in a randomized, placebo-controlled, double-blind fashion. The study protocol before coronary intervention consisted of occlusive surface and intracoronary lead ECG recording as well as collateral flow index (CFI, no unit) measurement in a stenotic and a ≥1 normal coronary artery before and after a 2-week period with subcutaneous G-CSF (10 μg/kg; n=26) or placebo (n=26). The CFI was determined by simultaneous measurement of mean aortic, distal coronary occlusive, and central venous pressure. The ECG ST segment elevation >0.1 mV disappeared significantly more often in response to G-CSF (11/53 vessels; 21%) than to placebo (0/55 vessels;
P
=0.0005), and simultaneously, CFI changed from 0.121±0.087 at baseline to 0.166±0.086 at follow-up in the G-CSF group, and from 0.152±0.082 to 0.131±0.071 in the placebo group (
P
<0.0001 for interaction of treatment and time). The absolute change in CFI from baseline to follow-up amounted to +0.049±0.062 in the G-CSF group and to −0.010±0.060 in the placebo group (
P
<0.0001).

Conclusions—

Subcutaneous G-CSF is efficacious during a short-term protocol in improving signs of myocardial salvage by coronary collateral growth promotion.
Pressure-Induced Vascular Oxidative Stress Is Mediated Through Activation of Integrin-Linked Kinase 1/βPIX/Rac-1 Pathway
Authors: Vecchione Carmine , Carnevale Daniela , Di Pardo Alba , Gentile Maria Teresa , Damato Antonio , Cocozza Germana , Antenucci Giovanna , Mascio Giada , Bettarini Umberto , Landolfi Alessandro , Iorio Luca , Maffei Angelo , Lembo Giuseppe
Published: September 2009

High blood pressure induces a mechanical stress on vascular walls and evokes oxidative stress and vascular dysfunction. The aim of this study was to characterize the intracellular signaling causing vascular oxidative stress in response to pressure. In carotid arteries subjected to high pressure levels, we observed not only an impaired vasorelaxation, increased superoxide production, and NADPH oxidase activity, but also a concomitant activation of Rac-1, a small G protein. Selective inhibition of Rac-1, with an adenovirus carrying a dominant-negative Rac-1 mutant, significantly reduced NADPH oxidase activity and oxidative stress and, more importantly, rescued vascular function in carotid arteries at high pressure. The analysis of molecular events associated with mechanotransduction demonstrated at high pressure levels an overexpression of integrin-linked kinase 1 and its recruitment to plasma membrane interacting with paxillin. The inhibition of integrin-linked kinase 1 by small interfering RNA impaired Rac-1 activation and rescued oxidative stress–induced vascular dysfunction in response to high pressure. Finally, we showed that βPIX, a guanine-nucleotide exchange factor, is the intermediate molecule recruited by integrin-linked kinase 1, converging the intracellular signaling toward Rac-1–mediated oxidative vascular dysfunction during pressure overload. Our data demonstrate that biomechanical stress evoked by high blood pressure triggers an integrin-linked kinase 1/βPIX/Rac-1 signaling, thus generating oxidative vascular dysfunction.
HINTS to Diagnose Stroke in the Acute Vestibular Syndrome
Authors: Kattah Jorge C. , Talkad Arun V. , Wang David Z. , Hsieh Yu-Hsiang , Newman-Toker David E.
Published: September 2009

Background and Purpose—

Acute vestibular syndrome (AVS) is often due to vestibular neuritis but can result from vertebrobasilar strokes. Misdiagnosis of posterior fossa infarcts in emergency care settings is frequent. Bedside oculomotor findings may reliably identify stroke in AVS, but prospective studies have been lacking.

Methods—

The authors conducted a prospective, cross-sectional study at an academic hospital. Consecutive patients with AVS (vertigo, nystagmus, nausea/vomiting, head-motion intolerance, unsteady gait) with ≥1 stroke risk factor underwent structured examination, including horizontal head impulse test of vestibulo-ocular reflex function, observation of nystagmus in different gaze positions, and prism cross-cover test of ocular alignment. All underwent neuroimaging and admission (generally <72 hours after symptom onset). Strokes were diagnosed by MRI or CT. Peripheral lesions were diagnosed by normal MRI and clinical follow-up.

Results—

One hundred one high-risk patients with AVS included 25 peripheral and 76 central lesions (69 ischemic strokes, 4 hemorrhages, 3 other). The presence of normal horizontal head impulse test, direction-changing nystagmus in eccentric gaze, or skew deviation (vertical ocular misalignment) was 100% sensitive and 96% specific for stroke. Skew was present in 17% and associated with brainstem lesions (4% peripheral, 4% pure cerebellar, 30% brainstem involvement; χ
2
,
P
=0.003). Skew correctly predicted lateral pontine stroke in 2 of 3 cases in which an abnormal horizontal head impulse test erroneously suggested peripheral localization. Initial MRI diffusion-weighted imaging was falsely negative in 12% (all <48 hours after symptom onset).

Conclusions—

Skew predicts brainstem involvement in AVS and can identify stroke when an abnormal horizontal head impulse test falsely suggests a peripheral lesion. A 3-step bedside oculomotor examination (HINTS: Head-Impulse—Nystagmus—Test-of-Skew) appears more sensitive for stroke than early MRI in AVS.
Noninvasive Detection of Vertebral Artery Stenosis
Authors: Khan Sofia , Rich Philip , Clifton Andrew , Markus Hugh S.
Published: September 2009

Background and Purpose—

Vertebral stenosis is associated with a high risk of recurrent stroke, but noninvasive imaging techniques to identify it have lacked sensitivity. Contrast-enhanced MR angiography and CT angiography have been recently developed and appear to have better sensitivity. However, no prospective studies have compared both of these techniques with ultrasound against the gold standard of intra-arterial angiography in the same group of patients.

Methods—

Forty-six patients were prospectively recruited in whom intra-arterial angiography was being performed. Contrast-enhanced MR angiography, CT angiography, and duplex ultrasound were also performed. Angiographic images were analyzed blinded to patient identity by 2 experienced neuroradiologists.

Results—

Contrast-enhanced MR angiography had the highest sensitivity and specificity (Radiologist 1, 0.83 and 0.91, respectively; Radiologist 2, 0.89 and 0.87) for detecting ≥50% stenosis. CT angiography had good sensitivity (Radiologist 1, 0.68; Radiologist 2, 0.58) and excellent specificity (Radiologist 1, 0.92; Radiologist 2, 0.93), whereas duplex had low sensitivity (0.44) but excellent specificity (0.95). For vertebral origin stenosis ≥50%, sensitivities were similar for contrast-enhanced MR angiography (Radiologist 1, 0.91; Radiologist 2, 0.82) but relatively higher for CT angiography (Radiologist 1, 0.82; Radiologist 2, 0.82) and duplex (0.67).

Conclusions—

Contrast-enhanced MR angiography is the most sensitive noninvasive technique to detect vertebral artery stenosis and also has high specificity. CT angiography has good sensitivity and high specificity. In contrast, ultrasound has low sensitivity and will miss many vertebral stenoses.
Prophylactic, Endovascularly Based, Long-Term Normothermia in ICU Patients With Severe Cerebrovascular Disease
Authors: Broessner Gregor , Beer Ronny , Lackner Peter , Helbok Raimund , Fischer Marlene , Pfausler Bettina , Rhorer Janelle , Küppers-Tiedt Lea , Schneider Dietmar , Schmutzhard Erich
Published: September 2009

Background and Purpose—We sought to study the effectiveness and safety of endovascular cooling to maintain prophylactic normothermia in comparison with standardized, stepwise, escalating fever management to reduce fever burden in patients with severe cerebrovascular disease.

Methods—This study was a prospective, randomized, controlled trial with a blinded neurologic outcome evaluation comparison between prophylactic, catheter-based normothermia (CoolGard; ie, body core temperature 36.5°C) and conventional, stepwise fever management with anti-inflammatory drugs and surface cooling. Patients admitted to 1 of the 2 neurointensive care units were eligible for study inclusion when they had a (1) spontaneous subarachnoid hemorrhage with Hunt & Hess grade between 3 and 5, (2) spontaneous intracerebral hemorrhage with a Glasgow Coma Scale score ≤10, or (3) complicated cerebral infarction requiring intensive care unit treatment with a National Institutes of Health Stroke Scale score ≥15.

Results—A total of 102 patients (56 female) were enrolled during a 3.5-year period. Fifty percent had a spontaneous subarachnoid hemorrhage, 40% had a spontaneous intracerebral hemorrhage, and 10% had a complicated cerebral infarction. Overall median total fever burden during the course of treatment was 0.0°C hour and 4.3°C hours in the catheter and conventional groups, respectively (P<0.0001). Prophylactic normothermia did not lead to an increase in the number of patients who experienced a major adverse event. No significant difference was found in mortality and neurologic long-term follow-up.

Conclusions—Long-term, catheter-based, prophylactic normothermia significantly reduces fever burden in neurointensive care unit patients with severe cerebrovascular disease and is not associated with increased major adverse events.
Overground Physical Therapy Gait Training for Chronic Stroke Patients With Mobility Deficits
Authors: States Rebecca A. , Pappas Evangelos , Salem Yasser
Published: September 2009

Background and Purpose—

Overground gait training can be defined as a physical therapists’ observation and cueing of the patient’s walking pattern along with related exercises, but does not include high-technology aids such as functional electric stimulation or body weight support. This systematic review investigated the effects of overground physical therapy gait training on walking ability for chronic stroke patients with mobility deficits.

Methods—

A comprehensive literature search was performed as per the Cochrane group guidelines. Only randomized controlled trials that compared overground physical therapy gait training to a placebo intervention or no treatment for chronic stroke patients with mobility deficits were included.

Results—

Nine studies involving 499 participants matched the inclusion criteria and had moderate methodological quality. Results were mixed with no significant effect on the primary variable, gait function. Small effects for several performance variables were found: gait speed increased by 0.07 meters per second (95% confidence interval [CI]=0.05 to 0.10) based on 7 studies with 396 participants, timed up-and-go (TUG) test improved by 1.81 seconds (95% CI=−2.29 to −1.33) based on 3 studies and 118 participants, and 6-minute-walk test (6MWT) increased by 26.06 meters (95% CI=7.14 to 44.97) based on 4 studies with 181 participants. No significant differences in adverse events were found.

Conclusions—

There is insufficient evidence to determine whether overground gait training directly benefits broad measures of gait function. Results from recent studies, however, suggest that specific training protocols may provide limited benefits for more uni-dimensional performance variables like gait speed, TUG test, and 6MWT.
Severity of Hypoperfusion in Distinct Brain Regions Predicts Severity of Hemispatial Neglect in Different Reference Frames
Authors: Shirani Peyman , Thorn Julia , Davis Cameron , Heidler-Gary Jennifer , Newhart Melissa , Gottesman Rebecca F. , Hillis Argye E.
Published: September 2009

Background and Purpose—

Hemispatial neglect is among the most common and disabling consequences of right hemisphere stroke. A variety of variables have been associated with the presence or severity of neglect but have not evaluated the independent effects of location, severity, and volume of ischemia. Few have determined areas involved in different types of neglect. We identified the contributions of these variables to severity of viewer-centered versus stimulus-centered neglect in acute ischemic right hemisphere stroke.

Methods—

We studied 137 patients within 24 hours of stroke onset with MR diffusion- and perfusion-weighted imaging and a test of hemispatial neglect that distinguishes between viewer-centered and stimulus-centered neglect. Using multivariable linear regression, we identified the independent contributions of severity of ischemia in specific locations, volume of ischemia, and age in accounting for severity of each neglect type.

Results—

Severity of hypoperfusion in angular gyrus was the only variable that significantly and independently contributed to severity of viewer-centered neglect. Volume of dysfunctional tissue and hypoperfusion in posterior frontal cortex also accounted for some variability in severity of viewer-centered neglect. Severity of hypoperfusion of superior temporal cortex was the only variable that independently and significantly contributed to severity of stimulus-centered neglect.

Conclusions—

Location, severity, and volume of ischemia together determine the type and severity of neglect after right hemisphere stroke. Results also show that perfusion-weighted MRI can be used as a semiquantitative measure of tissue dysfunction in acute stroke and can account for a substantial proportion of the variability in functional deficits in the acute stage.
Multi-Modal Reperfusion Therapy for Patients With Acute Anterior Circulation Stroke in Israel
Authors: Leker Ronen R. , Eichel Roni , Arkadir David , Gomori John M. , Raphaeli Guy , Ben-Hur Tamir , Cohen Jose E.
Published: September 2009

Background and Purpose—

We aimed to delineate prognostic variables in Israeli patients with anterior circulation strokes treated with endovascular multi-modal reperfusion therapy (MMRT).

Methods—

Clinical and radiological data from consecutive tpa-ineligible stroke patients with large anterior circulation infarcts involving either the entire internal carotid artery or the proximal middle cerebral artery territory were analyzed. Stroke subtypes were categorized according to TOAST criteria. Neurological deficits were assessed with the NIH stroke scale (NIHSS), and vessel recanalization was determined using the thrombolysis in myocardial infarction (TIMI) scale at the end of MRRT. Good outcome was defined as a modified Rankin score (mRS) ≤2.

Results—

Fifty patients were included with a median age of 68. Thirteen patients died and 17 patients achieved an mRS ≤2 at 90 days. Variables associated with survival on multivariate analysis were admission NIHSS <20 (OR 15 95% CI 1 to 230) and postprocedure TIMI score 2 to 3 (OR 35.5 95% CI 2.3 to 603.9). Variables associated with good outcome included admission NIHSS <20 (OR 9.4 95% CI 1.3 to 71.3), day 1 NIHSS <15 (OR 6.4 95% CI 1.1 to 38.4), and postprocedure TIMI 3 (OR 7.4 95% CI 1.1 to 50.3).

Conclusions—

MMRT resulted in high survival and good outcome rates in these critically ill patients. Lower baseline impairment and vessel recanalization increase the chances for good outcome. Our results suggest that the benefits of MMRT may merit further study and could be generalized to centers outside the United States and Europe.
Pharmacogenetics and Stroke
Authors: Meschia James F.
Published: September 2009

Genetic variations have been shown to influence drug metabolism, risk of adverse drug events, and pharmacodynamic responses for many drugs routinely used to treat patients with stroke or at risk for stroke. Examples include clopidogrel, statins, antihypertensive medications, and coumadin. Further validation studies are needed to assess the clinical utility of selecting drugs and doses based on genetic tests. Physicians, pharmaceutical companies, regulatory agencies, and health insurers continue to grapple with how best to translate this burgeoning field into effective individualized medicine.
Cerebral Microbleeds Are Frequent in Infective Endocarditis
Authors: Klein Isabelle , Iung Bernard , Labreuche Julien , Hess Agathe , Wolff Michel , Messika-Zeitoun David , Lavallée Philippa , Laissy Jean-Pierre , Leport Catherine , Duval Xavier ,   the IMAGE Study Group
Published: September 2009

Background and Purpose—

Cerebral microbleeds (CMBs) have been described using MRI in patients with cardiovascular risk factors or prior stroke and could be an indicator of small vessel disease. CMBs have been reported in isolated cases of infective endocarditis (IE), but their frequency and the association of CMBs with IE have not yet been studied.

Methods—

A case-control imaging study in a referral institutional tertiary care center was conducted. Systematic brain MRIs, including T2*-weighted sequences, were performed in 60 patients with IE within 7 days of hospital admission and in 120 age- and gender-matched control subjects without IE. Two neuroradiologists, who were blinded to patient characteristics, independently assessed the presence, location, and size of CMBs using a standardized form.

Results—

The interobserver agreement level on the presence of CMBs was high with a κ coefficient range (95% CI) of 0.70 (0.42 to 0.98) for subcortical regions to 0.91 (0.82 to 0.99) for cortical areas. CMBs were more prevalent in patients with IE (57% [n=34]) than in control subjects (15% [n=18]; matched OR, 10.06; 95% CI, 3.88 to 26.07). Moreover, the OR of IE increased gradually with CMBs number with an OR of 6.12 (95% CI, 2.09 to 17.94) for one to 3 CMBs and of 20.12 (95% CI, 5.20 to 77.80) for >3 CMBs.

Conclusion—

CMBs are highly frequent in patients with IE. The strong association found between IE and CMBs supports the need for further evaluation of CMBs as additional diagnostic criteria of IE.
Routine Use of Intravenous Low-Dose Recombinant Tissue Plasminogen Activator in Japanese Patients
Authors: Toyoda Kazunori , Koga Masatoshi , Naganuma Masaki , Shiokawa Yoshiaki , Nakagawara Jyoji , Furui Eisuke , Kimura Kazumi , Yamagami Hiroshi , Okada Yasushi , Hasegawa Yasuhiro , Kario Kazuomi , Okuda Satoshi , Nishiyama Kazutoshi , Minematsu Kazuo
Published: September 2009

Background and Purpose—

A retrospective, multicenter, observational study was conducted to document clinical outcomes and to identify outcome predictors in patients treated with low-dose intravenous recombinant tissue plasminogen activator (0.6 mg/kg alteplase), which was approved in Japan in 2005, within 3 hours of stroke onset.

Methods—

Consecutive patients with stroke treated with recombinant tissue plasminogen activator in 10 Japanese stroke centers were included.

Results—

A total of 600 patients (377 men, 72±12 years old) were studied. Median National Institutes of Health Stroke Scale scores decreased from 13 before recombinant tissue plasminogen activator to 8 at 24 hours later. Symptomatic intracerebral hemorrhage within 36 hours with a ≥1-point increase from the baseline National Institutes of Health Stroke Scale score developed in 23 patients (3.8%; 95% CI, 2.6% to 5.7%). At 3 months, 43 patients had died (7.2%; 5.4% to 9.5%), and 199 patients (33.2%; 29.5% to 37.0%) had a modified Rankin Scale score ≤1. Analysis of 399 patients with a premorbid modified Rankin Scale score ≤1 who met the criteria of the European license (≤80 years old, an initial National Institutes of Health Stroke Scale score ≤24, etc) showed that 40.6% (35.9% to 45.5%) had a 3-month modified Rankin Scale score ≤1. After multivariate adjustment, younger age, lower initial National Institutes of Health Stroke Scale score, absence of internal carotid artery occlusion, higher Alberta Stroke Program Early CT Score on CT, and absence of intravenous antihypertensives just before recombinant tissue plasminogen activator were independently related to a 3-month modified Rankin Scale score ≤1. Congestive heart failure and hyperglycemia were independently related to mortality.

Conclusions—

Three-month outcomes of patients receiving low-dose intravenous recombinant tissue plasminogen activator therapy in the present study were similar to those from postmarketing surveys using 0.9 mg/kg alteplase.
Hypoplasia or Occlusion of the Ipsilateral Cranial Venous Drainage Is Associated With Early Fatal Edema of Middle Cerebral Artery Infarction
Authors: Yu Wengui , Rives Joanna , Welch Babu , White Jonathan , Stehel Edward , Samson Duke
Published: September 2009

Background and Purpose—

Thrombosis of the cerebral venous sinus may cause venous congestion, cerebral edema, and infarction. The role of cerebrovenous disorders in arterial ischemic stroke is unknown. The objective of this study was to examine the contribution of ipsilateral cranial venous abnormalities to the development of cerebral edema in middle cerebral artery infarction.

Methods—

This is a retrospective study of consecutive patients with large middle cerebral artery infarction admitted to our neurocritical care unit from January 2007 to October 2008. Medical records, laboratory data, and imaging of cerebral edema and cranial venous sinuses were analyzed.

Results—

Of the 14 patients identified to have large middle cerebral artery infarction and images of cranial venous drainages, 5 (35.7%) had fatal edema with clinical signs of transtentorial herniation. Four of the 5 patients developed fatal edema within 48 hours of ictus and were found to have abnormal ipsilateral cranial venous drainage, including atresia of the transverse sinus (one), occlusion of the internal jugular vein (one), and hypoplasia of the transverse sinus and internal jugular vein (2). The fifth patient had symmetrical bilateral cranial venous drainages and fatal edema at Day 5. Of the 9 patients with nonmalignant middle cerebral artery infarction, all had ipsilateral dominant or symmetrical bilateral venous drainages.

Conclusions—

In this small case series, we demonstrated that only the patients with hypoplasia or occlusion of the ipsilateral cranial venous drainage developed early fatal edema after large middle cerebral artery infarction. Our results suggest a role of cranial venous outflow abnormalities in the development of brain edema after arterial ischemic stroke.
Electrical Stimulation of the Cerebral Cortex Exerts Antiapoptotic, Angiogenic, and Anti-Inflammatory Effects in Ischemic Stroke Rats Through Phosphoinositide 3-Kinase/Akt Signaling Pathway
Authors: Baba Tanefumi , Kameda Masahiro , Yasuhara Takao , Morimoto Takamasa , Kondo Akihiko , Shingo Tetsuro , Tajiri Naoki , Wang Feifei , Miyoshi Yasuyuki , Borlongan Cesario V. , Matsumae Mitsunori , Date Isao
Published: September 2009

Background and Purpose—

Neuroprotective effects of electric stimulation have been recently shown in ischemic stroke, but the underlying mechanisms remain poorly understood.

Methods—

Adult Wistar rats weighing 200 to 250 g received occlusion of the right middle cerebral artery for 90 minutes. At 1 hour after reperfusion, electrodes were implanted to rats on the right frontal epidural space. Electric stimulation, at preset current (0 to 200 μA) and frequency (0 to 50 Hz), was performed for 1 week. Stroke animals were subjected to behavioral tests at 3 days and 1 week postmiddle cerebral artery and then immediately euthanized for protein and immunohistochemical assays. After demonstration of behavioral and histological benefits, subsequent experiments pursued the mechanistic hypothesis that electric stimulation exerted antiapoptotic effects through the phosphoinositide 3-kinase-dependent pathway; thus, cortical stimulation was performed in the presence or absence of specific inhibitors of phosphoinositide 3-kinase (LY294002) in stroke rats.

Results—

Cortical stimulation abrogated the ischemia-associated increase in apoptotic cells in the injured cortex by activating antiapoptotic cascades, which was reversed by the phosphoinositide 3-kinase inhibitor LY294002 as reflected behaviorally and immunohistochemically. Furthermore, brain levels of neurotrophic factors (glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor) were upregulated, which coincided with enhanced angiogenesis and suppressed proliferation of inflammatory cells in the ischemic cortex.

Conclusions—

These results suggest that electric stimulation prevents apoptosis through the phosphoinositide 3-kinase pathway. Consequently, the ischemic brain might have been rendered as a nurturing microenvironment characterized by robust angiogenesis and diminished microglial/astrocytic proliferation, resulting in the reduction of infarct volumes and behavioral recovery. Electric stimulation is a novel and potent therapeutic tool for cerebral ischemia.
Pre–Tissue Plasminogen Activator Blood Pressure Levels and Risk of Symptomatic Intracerebral Hemorrhage
Authors: Tsivgoulis Georgios , Frey James L. , Flaster Murray , Sharma Vijay K. , Lao Annabelle Y. , Hoover Steven L. , Liu Wei , Stamboulis Elefterios , Alexandrov Anne W. , Malkoff Marc D. , Alexandrov Andrei V.
Published: September 2009

Background and Purpose—

From small pilot studies, uncontrolled pretreatment systolic blood pressure >185 mm Hg and diastolic blood pressure >110 mm Hg in patients with acute ischemic stroke were introduced in the National Institute of Neurological Diseases and Stroke rtPA Stroke Study as a contraindication for thrombolysis. We sought to determine if pretreatment blood pressure protocol violations in patients with acute ischemic stroke receiving intravenous tissue plasminogen activator are related to the subsequent risk of symptomatic intracranial hemorrhage (sICH).

Methods—

We reviewed medical records of consecutive ischemic stroke admissions treated with intravenous thrombolysis over a 10-year period at our tertiary care hospital. The National Institutes of Health Stroke Scale score on admission was used to determine baseline stroke severity. The closest documented blood pressure values to the time of tissue plasminogen activator bolus (range, 0 to 10 minutes) were considered as pretreatment blood pressure. Pretreatment blood pressure protocol violations were identified as systolic blood pressure >185 or diastolic blood pressure >110 mm Hg prebolus. sICH was defined as brain imaging evidence of intracranial hemorrhage with clinical worsening by the National Institutes of Health Stroke Scale score increase of ≥4 points.

Results—

Among 510 patients with ischemic stroke treated with intravenous tissue plasminogen activator (282 men; mean age, 65±15 years), sICH occurred in 31 patients (6.1%). Blood pressure protocol violations were present in 63 patients (12.4%) and they were more frequent in patients with sICH (26% versus 12%;
P
=0.019). After adjusting for demographic characteristics, onset-to-treatment time, baseline National Institutes of Health Stroke Scale, stroke risk factors and medications, pretreatment blood pressure protocol violations were independently associated with a higher likelihood of sICH (OR, 2.59; 95% CI, 1.07 to 6.25;
P
=0.034).

Conclusions—

These data support current guidelines advising not to use intravenous tissue plasminogen activator when pretreatment blood pressure exceeds the prespecified thresholds by showing that blood pressure protocol violations are independently associated with a higher likelihood of sICH.
Anxiety After Cardiac Arrest/Cardiopulmonary Resuscitation
Authors: Neigh Gretchen N. , Karelina Kate , Glasper Erica R. , Bowers Stephanie L.K. , Zhang Ning , Popovich Phillip G. , DeVries A. Courtney
Published: September 2009

Background and Purpose—

Stress is an important risk factor for cardiovascular disease; however, most of the research on this topic has focused on incidence rather than outcome. The goal of this study was to determine the effects of prior exposure to chronic stress on ischemia-induced neuronal death, microglial activation, and anxiety-like behavior.

Methods—

In Experiment 1, mice were exposed to 3 weeks of daily restraint (3 hours) and then subjected to either 8 minutes of cardiac arrest/cardiopulmonary resuscitation (CA/CPR) or sham surgery. Anxiety-like behavior, microglial activation, and neuronal damage were assessed on postischemic Day 4. In Experiment 2, mice were infused intracerebroventricularly with minocycline (10 μg/day) to determine the effect of inhibiting post-CA/CPR microglial activation on the development of anxiety-like behavior and neuronal death.

Results—

CA/CPR precipitated anxiety-like behavior and increased microglial activation and neuronal damage within the hippocampus relative to sham surgery. Prior exposure to stress exacerbated these measures among CA/CPR mice, but had no significant effect on sham-operated mice. Treatment with minocycline reduced both neuronal damage and anxiety-like behavior among CA/CPR animals. Anxiety-like behavior was significantly correlated with measures of microglial activation but not neuronal damage.

Conclusions—

A history of stress exposure increases the pathophysiological response to ischemia and anxiety-like behavior, whereas inhibiting microglial activation reduces neuronal damage and mitigates the development of anxiety-like behavior after CA/CPR. Thus, modulating inflammatory signaling after cerebral ischemia may be beneficial in protecting the brain and preventing the development of affective disorders.
Visuotactile Representation of Peripersonal Space: A Neural Network Study
Authors: Magosso Elisa , Zavaglia Melissa , Serino Andrea , di Pellegrino Giuseppe , Ursino Mauro
Published: September 2009

Neurophysiological and behavioral studies suggest that the peripersonal space is represented in a multisensory fashion by integrating stimuli of different modalities. We developed a neural network to simulate the visual-tactile representation of the peripersonal space around the right and left hands. The model is composed of two networks (one per hemisphere), each with three areas of neurons: two are unimodal (visual and tactile) and communicate by synaptic connections with a third downstream multimodal (visual-tactile) area. The hemispheres are interconnected by inhibitory synapses. We applied a combination of analytic and computer simulation techniques. The analytic approach requires some simplifying assumptions and approximations (linearization and a reduced number of neurons) and is used to investigate network stability as a function of parameter values, providing some emergent properties. These are then tested and extended by computer simulations of a more complex nonlinear network that does not rely on the previous simplifications. With basal parameter values, the extended network reproduces several in vivo phenomena: multisensory coding of peripersonal space, reinforcement of unisensory perception by multimodal stimulation, and coexistence of simultaneous right- and left-hand representations in bilateral stimulation. By reducing the strength of the synapses from the right tactile neurons, the network is able to mimic the responses characteristic of right-brain-damaged patients with left tactile extinction: perception of unilateral left tactile stimulation, cross-modal extinction and cross-modal facilitation in bilateral stimulation. Finally, a variety of sensitivity analyses on some key parameters was performed to shed light on the contribution of single-model components in network behaviour. The model may help us understand the neural circuitry underlying peripersonal space representation and identify its alterations explaining neurological deficits. In perspective, it could help in interpreting results of psychophysical and behavioral trials and clarifying the neural correlates of multisensory-based rehabilitation procedures.
Estimation of Sparse Nonnegative Sources from Noisy Overcomplete Mixtures Using MAP
Authors: Caiafa Cesar F. , Cichocki Andrzej
Published: September 2009

In this letter, we propose a new algorithm for estimating sparse nonnegative sources from a set of noisy linear mixtures. In particular, we consider difficult situations with high noise levels and more sources than sensors (underdetermined case). We show that when sources are very sparse in time and overlapped at some locations, they can be recovered even with very low signal-to-noise ratio, and by using many fewer sensors than sources. A theoretical analysis based on Bayesian estimation tools is included showing strong connections with algorithms in related areas of research such as ICA, NMF, FOCUSS, and sparse representation of data with overcomplete dictionaries. Our algorithm uses a Bayesian approach by modeling sparse signals through mixed-state random variables. This new model for priors imposes ℓ0 norm-based sparsity. We start our analysis for the case of nonoverlapped sources (1-sparse), which allows us to simplify the search of the posterior maximum avoiding a combinatorial search. General algorithms for overlapped cases, such as 2-sparse and k-sparse sources, are derived by using the algorithm for 1-sparse signals recursively. Additionally, a combination of our MAP algorithm with the NN-KSVD algorithm is proposed for estimating the mixing matrix and the sources simultaneously in a real blind fashion. A complete set of simulation results is included showing the performance of our algorithm.
The Computational Structure of Spike Trains
Authors: Haslinger Robert , Klinkner Kristina Lisa , Shalizi Cosma Rohilla
Published: September 2009

Neurons perform computations, and convey the results of those computations through the statistical structure of their output spike trains. Here we present a practical method, grounded in the information-theoretic analysis of prediction, for inferring a minimal representation of that structure and for characterizing its complexity. Starting from spike trains, our approach finds their causal state models (CSMs), the minimal hidden Markov models or stochastic automata capable of generating statistically identical time series. We then use these CSMs to objectively quantify both the generalizable structure and the idiosyncratic randomness of the spike train. Specifically, we show that the expected algorithmic information content (the information needed to describe the spike train exactly) can be split into three parts describing (1) the time-invariant structure (complexity) of the minimal spike-generating process, which describes the spike train statistically; (2) the randomness (internal entropy rate) of the minimal spike-generating process; and (3) a residual pure noise term not described by the minimal spike-generating process. We use CSMs to approximate each of these quantities. The CSMs are inferred nonparametrically from the data, making only mild regularity assumptions, via the causal state splitting reconstruction algorithm. The methods presented here complement more traditional spike train analyses by describing not only spiking probability and spike train entropy, but also the complexity of a spike train's structure. We demonstrate our approach using both simulated spike trains and experimental data recorded in rat barrel cortex during vibrissa stimulation.
Assessment and Comparison of Culturally Based Explanations for Mental Disorder Among Singaporean Chinese Youth
Authors: Mathews Mathew
Published: September 2009

Background: Culture is important to how populations understand the cause of mental disorder, a variable that has implications for treatment-seeking behaviour. Asian populations underutilize professional mental health treatment partly because of their endorsement of supernatural causation models to explain mental disorders, beliefs that stem from their religious backgrounds.

Aims: This study sought to understand the dimensions of explanatory models used by three groups of Singaporean Chinese youth ( n = 842) — Christian, Chinese religionist, no religion — and examined their responses to an instrument that combined explanations from psychological and organic perspectives on mental disorder with approaches from Asian and Western religious traditions.

Results: Factor analysis revealed five factors. Two were psychological corresponding to the humanistic and cognitive-behavioural perspectives respectively. Another two, which were supernatural in nature, dealt with karmaic beliefs popular among Asian religionists and more classical religious explanations common in monotheistic religions. The remaining factor was deemed a physiological model although it incorporated an item that made it consistent with an Asian organic model. Conclusion: While groups differed in their endorsement of supernatural explanations, psychological perspectives had the strongest endorsement among this population. Regression analysis showed that individuals who endorsed supernatural explanations more strongly tended to have no exposure to psychology courses and heightened religiosity.