bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute Stroke Management in the Elderly
Authors: Zeevi Neer , Chhabra Jyoti , Silverman Isaac E. , Lee Nora S. , McCullough Louise D.
Published: December 2006

Background and Purpose: Though the proportion of elderly stroke patients is increasing, patients >80 years are often excluded from clinical stroke trials. We reviewed the management of older patients presenting with acute ischemic stroke (AIS) and assessed the safety and efficacy of recombinant tissue plasminogen activator (rtPA) administration in a community-based setting. Methods: A retrospective review of patients >80 years (n = 341) admitted to a community stroke center with AIS were compared to their younger counterparts (n = 690) using the stroke center database from April 2003 to December 2005. Parameters that were measured included admission and discharge NIH Stroke Scale (NIHSS), rate of thrombolytic treatment, the frequency and etiology of thrombolytic exclusion criteria and complications from rtPA for the different aged populations. Additional data were collected for Barthel Index at 12 months. Results: A total of 166 patients underwent thrombolysis. Older patients were not delayed in reaching the hospital within 3 h of stroke onset (182/690, 26%, in the <80 cohort vs. 98/341, 29%, in the ≧80 cohort). Although the overall rates of tPA use were similar in both the young and aged cohort, older patients were less likely to be treated with rtPA because of reasons not listed as exclusion criteria (17% in the <80 cohort vs. 32% in the ≧80 cohort).The older group did not have an excess risk of intracranial hemorrhage following rtPA infusion despite equivalent NIHSS on admission (13.5 in the <80 cohort vs. 12.4 in the ≧80 cohort). Both groups showed improvement in NIHSS following thrombolytic treatment with a drop of 7.7 points in the younger age group and 5.6 points in the older group. Elderly patients treated with rtPA had a comparable 12-month modified Barthel Index score to younger cohorts. Conclusions: Early treatment with rtPA in patients >80 years appears to be both safe and efficacious. Treated patients showed improvements both acutely (a decrease in NIHSS at 72 h) and chronically, as shown by a sustained improvement in the Barthel Index. A large number of elderly patients were excluded from rtPA treatment despite arriving within the time frame of treatment for reasons not considered as traditional exclusion criteria. Older patients with AIS can be treated safely with thrombolytic therapy in a community setting. This therapy should not be withheld on the basis of age.
Randomized Crossover Comparison of Proportional Assist Ventilation and Patient-Triggered Ventilation in Extremely Low Birth Weight Infants with Evolving Chronic Lung Disease
Authors: Schulze Andreas , Rieger-Fackeldey Esther , Gerhardt Tilo , Claure Nelson , Everett Ruth , Bancalari Eduardo
Published: December 2006

Background: Refinement of ventilatory techniques remains a challenge given the persistence of chronic lung disease of preterm infants. Objective: To test the hypothesis that proportional assist ventilation (PAV) will allow to lower the ventilator pressure at equivalent fractions of inspiratory oxygen (FiO2) and arterial hemoglobin oxygen saturation in ventilator-dependent extremely low birth weight infants in comparison with standard patient-triggered ventilation (PTV). Methods:Design: Randomized crossover design. Setting:Two level-3 university perinatal centers. Patients: 22 infants (mean (SD): birth weight, 705 g (215); gestational age, 25.6 weeks (2.0); age at study, 22.9 days (15.6)). Interventions: One 4-hour period of PAV was applied on each of 2 consecutive days and compared with epochs of standard PTV. Results: Mean airway pressure was 5.64 (SD, 0.81) cm H2O during PAV and 6.59 (SD, 1.26) cm H2O during PTV (p < 0.0001), the mean peak inspiratory pressure was 10.3 (SD, 2.48) cm H2O and 15.1 (SD, 3.64) cm H2O (p < 0.001), respectively. The FiO2 (0.34 (0.13) vs. 0.34 (0.14)) and pulse oximetry readings were not significantly different. The incidence of arterial oxygen desaturations was not different (3.48 (3.2) vs. 3.34 (3.0) episodes/h) but desaturations lasted longer during PAV (2.60 (2.8) vs. 1.85 (2.2) min of desaturation/h, p = 0.049). PaCO2 measured transcutaneously in a subgroup of 12 infants was similar. One infant met prespecified PAV failure criteria. No adverse events occurred during the 164 cumulative hours of PAV application. Conclusions: PAV safely maintains gas exchange at lower mean airway pressures compared with PTV without adverse effects in this population. Backup conventional ventilation breaths must be provided to prevent apnea-related desaturations.
How Many Deaths Can Be Prevented by Newborn Screening for Congenital Adrenal Hyperplasia?
Authors: Grosse Scott D. , Van Vliet Guy
Published: December 2006

Background/Aims: Congenital adrenal hyperplasia (CAH) is increasingly being included in newborn screening programs. Screening can prevent neonatal mortality in children with salt-wasting CAH, but the number of deaths prevented is not known. Cost-effectiveness analyses of screening require estimates of the probability of mortality in CAH. Methods: We reviewed the literature to identify cohort studies of children with CAH ascertained clinically in the absence of screening. We abstracted the numbers of infant deaths attributable to CAH. We also addressed sex ratios among children with clinically detected CAH and the contribution of ascertainment bias to unbalanced ratios. Results: The evidence suggests a probability of infant death due to adrenal crises in salt-wasting CAH of 4% or less in contemporary advanced economies without screening for CAH. This is lower than previous estimates, although the rate of mortality could be considerably higher in populations with limited clinical awareness or access. Conclusion: Although screening for CAH is conducted in a number of countries, further research is still needed to provide reliable estimates on the numbers of prevented deaths, along with evidence-based assessments of the potential benefits, harms, and costs of screening.
Chimeric VEGF-E
NZ7
/PlGF Specifically Binding to VEGFR-2 Accelerates Skin Wound Healing via Enhancement of Neovascularization
Authors: Zheng Yujuan , Watanabe Makoto , Kuraishi Takeshi , Hattori Shosaku , Kai Chieko , Shibuya Masabumi
Published: December 2006

Objective—

VEGF-E
NZ7
/PlGF molecules composed of Orf virus-derived VEGF-E
NZ7
and human PlGF1 were previously proven to be potent angiogenic factors stimulating angiogenesis without significant enhancement of vascular leakage and inflammation in vivo. For its future clinical application, there is a pressing need to better understand the beneficial effects of VEGF-E
NZ7
/PlGF during wound healing in adulthood.

Methods and Results—

In this study, several angiogenic factors were administrated to skin punched wounds of both wild-type and diabetic mice. The treatment with VEGF-E
NZ7
/PlGF accelerated wound closure accompanied with enhanced angiogenesis, the process was occurring slightly faster than that in VEGF-A
164
group. Moreover, the macrophage infiltration and lymphangiogenesis level in healed wounds were strikingly lower in VEGF-E
NZ7
/PlGF group than VEGF-A
164
group, suggesting that the increased inflammation was the key issue preventing speedy wound healing of VEGF-A
164
–treated skin. Considering clinical safety, we further examined the antigenicity of chimeric VEGF-E
NZ7
/PlGF. Compared with the original VEGF-E
NZ7
, the immunogenicity of VEGF-E
NZ7
/PlGF molecules was markedly decreased in mice and squirrel monkeys with the increase of PlGF1 humanized ratio.

Conclusion—

These results indicate that VEGF-E
NZ7
/PlGF molecules are superior to VEGF-A for the acceleration of either normal or delayed skin wound healing and might be regarded as potential drugs in therapeutic angiogenesis.
KLF2 Suppresses TGF-β Signaling in Endothelium Through Induction of Smad7 and Inhibition of AP-1
Authors: Boon Reinier A. , Fledderus Joost O. , Volger Oscar L. , van Wanrooij Eva J.A. , Pardali Evangelia , Weesie Frank , Kuiper Johan , Pannekoek Hans , ten Dijke Peter , Horrevoets Anton J.G.
Published: December 2006

Objective—

The flow-responsive Kruppel-like factor 2 (KLF2) is crucial for maintaining endothelial cell quiescence. Here, we describe its detailed effects on transforming growth factor-β (TGF-β) signaling, which normally has proatherogenic effects on endothelium.

Methods and Results—

In-depth analysis of genome-wide expression data shows that prolonged lentiviral-mediated overexpression of KLF2 in human umbilical vein endothelial cells (HUVECs) diminishes the expression of a large panel of established TGF-β–inducible genes. Both baseline and TGF-β–induced expression levels of plasminogen activator inhibitor 1 (PAI-1) and thrombospondin-1 are greatly diminished by KLF2. Using a combination of ectopic expression, small interfering RNA–mediated knockdown, and promoter activity assays, we show that KLF2 partly inhibits the phosphorylation and subsequent nuclear accumulation of Smad2, thereby suppressing the TGF-β–induced Smad4-mediated transcriptional activity. This is achieved through TGF-β–independent induction of inhibitory Smad7. Additionally, a full inhibition of TGF-β signaling is functionally achieved through a simultaneous suppression of activator protein 1 (AP-1), which is an essential cofactor for TGF-β–dependent transcription of many genes.

Conclusions—

The concerted mechanism by which KLF2 inhibits TGF-β signaling through induction of inhibitory Smad7 and attenuation of AP-1 activity provides a novel mechanism by which KLF2 contributes to sustaining a quiescent, atheroprotective status of vascular endothelium.
Increasing Peripheral Artery Intima Thickness From Childhood to Seniority
Authors: Osika Walter , Dangardt Frida , Grönros Julia , Lundstam Ulf , Myredal Anna , Johansson Mats , Volkmann Reinhard , Gustavsson Tomas , Ming Gan Li , Friberg Peter
Published: December 2006

Background—

Using new, very high-resolution ultrasound biomicroscopy, we examined the thickness of artificial layers of silicone and intima thickness (IT) of radial and anterior tibial arteries in healthy subjects and in patients with vascular disease.

Methods and Results—

Silicone layers of varying thicknesses and mesenteric artery specimens obtained from 18 patients undergoing colectomy were measured by both ultrasound biomicroscopy (55 MHz) and morphometry. There was high correlation (
r
>0.9;
P
<0.0001) between IT and intima area versus ultrasound biomicroscopy. In 90 healthy subjects (aged between 10 and 90 years), radial and anterior tibial arterial IT and intima-media thickness were measured, as was carotid intima-media thickness in 56 of these subjects. Age was strongly related with both media thickness and IT of both peripheral arteries. Correlations were found between carotid intima-media thickness and both radial and anterior tibial IT/intima-media thickness (
r
=0.44 to 0.53;
P
<0.0001). The IT-to-lumen diameter ratio increased with age and was larger at all ages in the anterior tibial artery (0.067±0.034) versus the radial artery (0.036±0.012;
P
<0.0001). A thicker radial intimal layer was found in patients with peripheral artery disease.

Conclusion—

This study is the first to our knowledge in humans to show the feasibility of measuring IT of the radial and anterior tibial arteries using very high-resolution ultrasound. IT progresses with age, and the IT-to-lumen diameter ratio is largest in the arteries of the foot. Assessment of IT by ultrasound biomicroscopy may aid in detecting early peripheral vascular abnormalities.
Effects of Peroxisome Proliferator-Activated Receptor Ligands, Bezafibrate and Fenofibrate, on Adiponectin Level
Authors: Hiuge Aki , Tenenbaum Alexander , Maeda Norikazu , Benderly Michal , Kumada Masahiro , Fisman Enrique Z. , Tanne David , Matas Zipora , Hibuse Toshiyuki , Fujita Koichi , Nishizawa Hitoshi , Adler Yehuda , Motro Michael , Kihara Shinji , Shimomura Iichiro , Behar Solomon , Funahashi Tohru
Published: December 2006

Objective—

Adiponectin is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule. We previously found peroxisome proliferators response element in adiponectin promoter region, suggesting that peroxisome proliferator-activated receptor (PPAR) ligands elevate adiponectin. Fibrates are known to be PPARα ligands and were shown to reduce risks of diabetes and cardiovascular disease. Effect of fibrates on adiponectin has not been clarified, whereas thiazolidinediones enhance adiponectin. Thus, we explored the possibility and mechanism that fibrates enhance adiponectin in humans, mice, and cells.

Methods and Results—

Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The Bezafibrate Infarction Prevention study. Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes. Fibrates, bezafibrate and fenofibrate, significantly elevated adiponectin levels in wild-type mice and 3T3-L1 adipocytes. Such an effect was not observed in PPARα-deficient mice and adipocytes. Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARα was knocked down by PPARα-RNAi.

Conclusions—

Our results suggest that fibrates enhance adiponectin partly through adipose PPARα and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes.
Heparin Cofactor II Modulates the Response to Vascular Injury
Authors: Tollefsen Douglas M.
Published: December 2006

Heparin cofactor II (HCII) has several biochemical properties that distinguish it from other serpins: (1) it specifically inhibits thrombin; (2) the mechanism of inhibition involves binding of an acidic domain in HCII to thrombin exosite I; and (3) the rate of inhibition increases dramatically in the presence of dermatan sulfate molecules having specific structures. Human studies suggest that high plasma HCII levels are protective against in-stent restenosis and atherosclerosis. Studies with HCII knockout mice directly support the hypothesis that HCII interacts with dermatan sulfate in the arterial wall after endothelial injury and thereby exerts an antithrombotic effect. In addition, HCII deficiency appears to promote neointima formation and atherogenesis in mice. These results suggest that HCII plays a unique and important role in vascular homeostasis.
Hyperuricemia and Incidence of Hypertension Among Men Without Metabolic Syndrome
Authors: Krishnan Eswar , Kwoh C. Kent , Schumacher H. Ralph , Kuller Lewis
Published: December 2006

The aim of this project was to study the risk of developing hypertension over a 6-year follow-up in normotensive men with baseline hyperuricemia (serum uric acid >7.0 mg/dL) but without diabetes/glucose intolerance or metabolic syndrome. We analyzed the data on men without metabolic syndrome or hypertension at baseline from the Multiple Risk Factor Intervention Trial. These men (n=3073; age: 35 to 57 years) were followed for an average of 6 years by annual examinations. Follow-up blood pressure among those with baseline was consistently higher than among those with normal serum uric acid concentration. We used Cox regression models for adjustment for the effects of serum creatinine, body mass index, age, blood pressure, proteinuria, serum cholesterol and triglycerides, alcohol and tobacco use, risk factor interventions, and use of diuretics. In these models, normotensive men with baseline hyperuricemia had an 80% excess risk for incident hypertension (hazard ratio: 1.81; 95% CI: 1.59 to 2.07) compared with those who did not. Each unit increase in serum uric acid was associated with a 9% increase in the risk for incident hypertension (hazard ratio: 1.09; 95% CI: 1.02 to 1.17). We conclude that the hyperuricemia–hypertension risk relationship is present among normotensive middle-aged men without diabetes/glucose intolerance or metabolic syndrome.
Reactive Oxygen Species–Dependent Hypertension in Dopamine D
2
Receptor–Deficient Mice
Authors: Armando Ines , Wang Xiaoyan , Villar Van Anthony M. , Jones John E. , Asico Laureano D. , Escano Crisanto , Jose Pedro A.
Published: December 2006

Dysfunction of D
2
-like receptors has been reported in essential hypertension. Disruption of D
2
R in mice (D
2
−/−
) results in high blood pressure, and several D
2
R polymorphisms are associated with decreased D
2
R expression. Because D
2
R agonists have antioxidant activity, we hypothesized that increased blood pressure in D
2
−/−
is related to increased oxidative stress. D
2
−/−
mice had increased urinary excretion of 8-isoprostane, a parameter of oxidative stress; increased activity of reduced nicotinamide-adenine dinucleotide phosphate oxidase in renal cortex; increased expression of the reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits Nox1, Nox2, and Nox4; and decreased expression of the antioxidant enzyme heme-oxygenase-2 in the kidneys, suggesting that regulation of reactive oxygen species (ROS) production by D
2
R involves both pro-oxidant and antioxidant systems. Apocynin, a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, or hemin, an inducer of heme oxigenase-1, normalized the blood pressure in D
2
−/−
mice. Because D
2
Rs in the adrenal gland are implicated in aldosterone regulation, we evaluated whether alterations in aldosterone secretion contribute to ROS production in this model. Urinary aldosterone was increased in D
2
−/−
mice and its response to a high-sodium diet was impaired. Spirolactone normalized the blood pressure in D
2
−/−
mice and the renal expression of Nox1 and Nox4, indicating that the increased blood pressure and ROS production are, in part, mediated by impaired aldosterone regulation. However, spironolactone did not normalize the excretion of 8-isoprostane and had no effect on expression of Nox2 or heme-oxygenase-2. Our results show that the D
2
R is involved in the regulation of ROS production and that, by direct and indirect mechanisms, altered D
2
R function may result in ROS-dependent hypertension.
Hypothalamic Arcuate Nucleus Mediates the Sympathetic and Arterial Pressure Responses to Leptin
Authors: Rahmouni Kamal , Morgan Donald A.
Published: December 2006

Leptin is an adipocyte-derived hormone that plays an important role in the regulation of energy homeostasis through its action in the central nervous system. Leptin decreases body weight by promoting satiety and increasing thermogenesis via increasing sympathetic nerve activity (SNA) to brown adipose tissue. Leptin also increases renal SNA and arterial pressure. The arcuate nucleus is considered as a major nucleus for leptin action on energy homeostasis. We tested whether leptin action in the arcuate nucleus simultaneously activates SNA to brown adipose tissue and the kidney. The sympathetic and cardiovascular responses to intra-arcuate injection of leptin were compared with those evoked by intracerebroventricular administration of leptin in rat. Intracerebroventricular administration of leptin (10 μg) caused a significant increase in SNA to brown adipose tissue and the kidney. Intracerebroventricular leptin also increased mean arterial pressure. Direct injection of leptin (500 ng) into the arcuate nucleus increased both brown adipose tissue (254±49%;
P
<0.001 versus vehicle) and renal SNA (111±31%;
P
<0.001 versus vehicle). Microinjection of leptin into the arcuate nucleus also produced a substantial increase in mean arterial pressure (from 82±3 to 100±7 mm Hg;
P
=0.02). These data demonstrate that leptin action in the arcuate nucleus of the hypothalamus is important for the control of sympathetic outflow to both brown adipose tissue and the kidney. These results also suggest that the cardiovascular effects of leptin might be evoked by the action of this hormone in the arcuate nucleus of the hypothalamus.
Neurons of the Rostral Ventrolateral Medulla Contribute to Obesity-Induced Hypertension in Rats
Authors: Stocker Sean D. , Meador Rachel , Adams Julye M.
Published: December 2006

Activation of the sympathetic nervous system contributes to the pathogenesis of obesity-induced hypertension. The present study sought to determine whether sympathetic regulatory neurons of the rostral ventrolateral medulla contribute to the elevated blood pressure in obese rats. Male Sprague–Dawley rats (350 to 425 g) were placed on a moderately high-fat diet (32% kcal as fat) or a low-fat (LF) diet (10.6% kcal as fat). After 13 weeks, rats fed the moderately high-fat diet segregated into obesity-prone (OP) and obesity-resistant (OR) groups based on their body weight (OP: 839±22 g; OR: 668±15 g; LF: 680±18 g; n=15 for all groups;
P
<0.01). Under isoflurane anesthesia, baseline mean arterial blood pressure was significantly elevated in the OP rats versus the OR and LF rats (OP: 108±2 mm Hg; OR: 100±2 mm Hg; LF: 97±3 mm Hg; n=7;
P
<0.05). Inhibition of the rostral ventrolateral medulla with bilateral microinjection of the GABA
A
receptor agonist muscimol (200 pmol/100 nL) decreased mean arterial blood pressure to similar levels across the groups (OP: 49±1 mm Hg; OR: 50±2 mm Hg; LF: 49±1 mm Hg), but the magnitude of this decrease was significantly greater in the OP versus the OR and LF rats (OP: −58±2 mm Hg; OR: −49±1 mm Hg; LF: −48±3 mm Hg;
P
<0.01). These differences in mean arterial blood pressure cannot be explained by changes in vascular reactivity as the ED
50
in response to phenylephrine and norepinephrine was similar across the groups. The present findings suggest that the elevated sympathetic nerve activity and arterial blood pressure in obese rats depends on the tonic activity of rostral ventrolateral medulla sympathetic neurons.
Intrarenal Aminopeptidase N Inhibition Augments Natriuretic Responses to Angiotensin III in Angiotensin Type 1 Receptor–Blocked Rats
Authors: Padia Shetal H. , Kemp Brandon A. , Howell Nancy L. , Siragy Helmy M. , Fournie-Zaluski Marie-Claude , Roques Bernard P. , Carey Robert M.
Published: December 2006

The renal angiotensin angiotensin type 2 receptor has been shown to mediate natriuresis, and angiotensin III, not angiotensin II, may be the preferential angiotensin type 2 receptor activator of this response. Angiotensin III is metabolized to angiotensin IV by aminopeptidase N. The present study hypothesizes that inhibition of aminopeptidase N will augment natriuretic responses to intrarenal angiotensin III in angiotension type 1 receptor–blocked rats. Rats received systemic candesartan for 24 hours before the experiment. After a 1-hour control, cumulative renal interstitial infusion of angiotensin III at 3.5, 7, 14, and 28 nmol/kg per minute (each dose for 30 minutes) or angiotensin III combined with aminopeptidase N inhibitor PC-18 was administered into 1 kidney. The contralateral control kidney received renal interstitial infusion of vehicle. In kidneys infused with angiotensin III alone, renal sodium excretion rate increased from 0.05±0.01 μmol/min in stepwise fashion to 0.11±0.01 μmol/min at 28 nmol/kg per minute of angiotensin III (overall ANOVA F=3.68;
P
<0.01). In angiotensin III combined with PC-18, the renal sodium excretion rate increased from 0.05±0.01 to 0.32±0.08 μmol/min at 28 nmol/kg per minute of angiotensin III (overall ANOVA F=6.2;
P
<0.001). The addition of intrarenal PD-123319, an angiotensin type 2 receptor antagonist, to renal interstitial angiotensin III plus PC-18 inhibited the natriuretic response. Mean arterial blood pressure and renal sodium excretion rate from control kidneys were unchanged by angiotensin III ± PC-18 + PD-123319. Angiotensin III plus PC-18 induced a greater natriuretic response than Ang III alone (overall ANOVA F=16.9;
P
=0.0001). Aminopeptidase N inhibition augmented the natriuretic response to angiotensin III, suggesting that angiotensin III is a major agonist of angiotensin type 2 receptor–induced natriuresis.
Multiple System Utilization and Mortality for Veterans With Stroke
Authors: Jia Huanguang , Zheng Yu , Reker Dean M. , Cowper Diane C. , Wu Samuel S. , Vogel W. Bruce , Young Gail C. , Duncan Pamela W.
Published: December 2006

Background and Purpose—

Many Veteran Health Administration (VHA) enrollees receive health services outside the VHA system. However, limited information is available about poststroke utilization and mortality by veterans who used multiple sources of health care. This study assessed the likelihood of 12-month poststroke rehospitalization and mortality of veterans who used VHA only versus those who used multiple sources of care.

Methods—

Our retrospective observational study examined veterans living in Florida and diagnosed with acute stroke. We categorized users into 4 groups: VHA-only, VHA-Medicare, VHA-Medicaid, and VHA-Medicare-Medicaid based on their use of each health care program. Logistic regression models were fitted for 12-month poststroke general rehospitalization, recurrent stroke readmission, and mortality, adjusting for sociodemographic and clinical factors.

Results—

The sample consisted of 29% VHA-only users, 61% VHA-Medicare users, 3% VHA-Medicaid users, and 7% VHA-Medicare-Medicaid triple users. Compared with the VHA-only users, multiple system users were significantly more likely to be rehospitalized for any cause and for recurrent stroke 12-months postindex. Mortality outcomes depended on when the outcome was measured; at the index admission date, we found no significant difference in mortality across the user groups; at the index discharge date, the VHA-only users was less likely to die within the first 12 months than the users of the 2 dual groups (VHA-Medicare and VHA-Medicaid).

Conclusions—

Multiple health care source use was common among VHA enrollees with acute stroke in Florida. Multiple system users were more likely to be rehospitalized and the mortality outcomes were dependent on when the outcome was measured.
Efficient Tracking of Non-Iron-Labeled Mesenchymal Stem Cells With Serial MRI in Chronic Stroke Rats
Authors: Shyu Woei-Cherng , Chen Chie-Pein , Lin Shinn-Zong , Lee Yih-Jing , Li Hung
Published: December 2006

Background and Purpose—

Although stem cell-based treatments for neurodegenerative diseases have advanced rapidly, there is currently no clinically available method to monitor the fate of transplanted cells in the brain.

Methods—

To use magnetic resonance imaging for tracking transplanted stem cells in the ischemic rat brain, we used the cellular labeling substance Effectene to transfect a standard contrast agent (Gd-DTPA) into immortalized human bone marrow stromal cells.

Results—

The transfection efficiency of this method was up to 90%, which is substantially better than pure spontaneous endocytosis or other transfection agents. In addition, cellular uptake of Gd-DTPA in vitro was maintained for >28 days. Therefore, we could follow transplanted stem cell migration and homing into the penumbric area. Using double immunofluorescence, the transplanted cells were seen to differentiate into glial cells, neurons and vascular endothelial cells. Cortical neurochemical activity as evaluated by proton magnetic resonance spectroscopy (
1
H-MRS) also increased considerably after immortalized human bone marrow stromal cell transplantation.

Conclusion—

This method of tracking immortalized human bone marrow stromal cells is highly efficient and allows for nontoxic labeling of cells.
Effects of Triflusal and Aspirin in a Rat Model of Cerebral Ischemia
Authors: Whitehead Shawn N. , Bayona Nestor A. , Cheng Guanliang , Allen Gary V. , Hachinski Vladimir C. , Cechetto David F.
Published: December 2006

Background and Purpose—

Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. Triflusal, a selective cyclooxygenase-2, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and aspirin treatment on infarct volume, and inflammation after cerebral ischemia in the rat.

Methods—

Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or aspirin. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured.

Results—

Both triflusal and aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. Triflusal (30 mg/kg) or aspirin treatment (30 mg/kg) did not reduce the levels of GFAP or Hsp27 immunostaining. Triflusal (30 mg/kg) also significantly decreased the protein levels of IL-Iβ but not nuclear factor kappa B or tumor necrosis factor-α in the cortex ipsilateral to the middle cerebral artery occlusion.

Conclusions—

The results suggest that triflusal and aspirin appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury.
Mode of Onset Predicts Etiological Diagnosis of Arterial Ischemic Stroke in Children
Authors: Braun Kees P.J. , Rafay Mubeen F. , Uiterwaal Cuno S.P. M. , Pontigon Anne-Marie , DeVeber Gabrielle
Published: December 2006

Background and Purpose—

In children, early differentiation among various etiologies of arterial ischemic stroke (AIS) is important. Cerebral arteriopathy is a frequently identified cause of childhood stroke. Children with arteriopathies require a different therapeutic approach from children with AIS of nonarteriopathic origin. We aimed to investigate the association between temporal features of the onset of neurological symptoms and stroke etiology in children with AIS.

Methods—

From a consecutive cohort of children (6 months to 18 years) with a confirmed diagnosis of AIS at one center, we selected all patients with transient cerebral arteriopathy (n=10), postvaricella angiopathy (n=20), dissection (n=8), cardio-embolic (n=8), and cryptogenic stroke (n=10). We retrospectively reviewed medical charts for mode of onset and classified the onset as either abrupt, reaching maximum severity of symptoms within 30 minutes, or nonabrupt, including a progressing, stuttering, or recurring course. We compared the mode of onset in patients with known cerebral arteriopathy to those with nonarteriopathic stroke using multivariate logistic regression modeling.

Results—

There were no significant differences for age, gender, location of infarction, seizures, and headache between the arteriopathic and nonarteriopathic group. Most children with nonarteriopathic AIS had an abrupt onset (72%), compared with 32% in children with arteriopathic stroke. With nonabrupt onset, the odds of having an arteriopathic etiology was 6.1 (95% CI, 1.6 to 22.8;
P
=0.007) after correction for possible confounders.

Conclusions—

Mode of onset predicts etiological diagnosis of childhood AIS and may guide prioritization of ancillary investigations and choice of treatment. A nonabrupt onset of symptoms is associated with arteriopathic stroke, particularly with presumed inflammatory arteriopathies.
Insular Cortex Hypoperfusion and Acute Phase Blood Glucose After Stroke
Authors: Moreton Fiona C. , McCormick Michael , Muir Keith W
Published: December 2006

Background and Purpose—

Insular cortex ischemia is proposed to mediate a sympathetic stimulus that leads to acute hyperglycemia after stroke.

Methods—

We retrospectively analyzed insular perfusion on perfusion CT (median 180 minutes after onset) in 35 patients.

Results—

We found no association of hypoperfusion (relative cerebral blood flow <0.51) with early (<6 hours) or delayed (<72 hours) hyperglycemia, or hemispheric lateralization.

Conclusions—

Insular cortex hypoperfusion <6 hours after stroke onset was not associated with hyperglycemia.
Quantitative Perihematomal Blood Flow in Spontaneous Intracerebral Hemorrhage Predicts In-Hospital Functional Outcome
Authors: Tayal Ashis H. , Gupta Rishi , Yonas Howard , Jovin Tudor , Uchino Ken , Hammer Maxim , Wechsler Lawrence , Gebel James M.
Published: December 2006

Background and Purpose—

Few data on xenon computed tomography-based quantitative cerebral blood flow (CBF) in spontaneous intracerebral hemorrhage have been reported. We correlated perihematomal CBF in a retrospective series of 42 subacute spontaneous intracerebral hemorrhage patients undergoing xenon computed tomography with in-hospital discharge status and mortality.

Methods—

We calculated 3 area-weighted mean CBF values: (1) within the computed tomography-visible rim of perihematomal edema, (2) within a 1-cm marginal radius around the hematoma, and (3) all cortical regions of interest immediately adjacent to the hematoma. Primary outcomes were in-hospital mortality and discharge status (ordinally as 0=home, 1=acute rehabilitation, 2=nursing home, 3=death). Discharge status was used as a surrogate for in-hospital functional outcome.

Results—

Median hematoma volume was 14.4 cm
3
(range, 2 to 70). Median perihematomal (low-attenuation rim) CBF was 21.9 cm
3
·100 g
−1
·min
−1
(range, 6.1 to 81.1), and the median 1-cm marginal radius CBF was 26.8 cm
3
·100 g
−1
·min
−1
(range, 10.8 to 72.8). The median regional cortical CBF was 26.7 cm
3
·100 g
−1
·min
−1
(range, 6.9 to 72.6). Eight patients had 1-cm marginal radius or regional cortical CBF values <20 cm
3
·100 g
−1
·min
−1
. Hematoma volume (odds ratio [OR], 1.68 per 10-cm
3
volume;
P
=0.036) and intraventricular hemorrhage (OR, 1.88 per grade of intraventricular hemorrhage;
P
=0.036) predicted mortality. Two CBF measures, hydrocephalus, and IVH predicted poor in-hospital functional outcome in bivariate analysis. Each CBF measure (OR, 0.34 to 0.43;
P
<0.001 to 0.003) and intraventricular hemorrhage (OR, 3.42;
P
<0.001) predicted in-hospital functional outcome in multivariable analyses.

Conclusions—

Most spontaneous intracerebral hemorrhage patients lack perihematomal penumbra. Perihematomal CBF independently predicts in-hospital discharge status but not in-hospital mortality. Further studies are warranted to determine whether perihematomal CBF predicts long-term functional outcomes.
Spontaneous and Endothelial-Independent Vasodilation Are Impaired in Patients With Spontaneous Carotid Dissection
Authors: Baumgartner Ralf W. , Lienhardt Barbara , Mosso Maria , Gandjour Joubin , Michael Nicolaus , Georgiadis Dimitrios
Published: December 2006

Background and Purpose—

We undertook this case-control study in patients with unilateral spontaneous dissection of the cervical internal carotid artery to investigate spontaneous and endothelium-independent dilation of the nondissected, contralateral carotid arteries and the ipsilateral brachial artery using high-resolution ultrasound.

Methods—

Spontaneous and endothelial-independent (nitroglycerin-mediated) absolute and relative dilation were assessed in the internal and common carotid and brachial arteries of 27 patients with unilateral spontaneous dissection of the cervical internal carotid artery and 27 age- and sex-matched healthy controls.

Results—

Absolute and relative spontaneous and endothelial-independent dilation of the carotid, but not brachial arteries, were significantly lower in patients as compared with controls.

Conclusions—

Vasodilation abnormalities may be a predisposing factor for spontaneous dissection of the cervical internal carotid artery.
Hemorrhage Rate in Patients With Spetzler-Martin Grades IV and V Arteriovenous Malformations
Authors: Jayaraman Mahesh V. , Marcellus Mary L. , Do Huy M. , Chang Steven D. , Rosenberg Jarrett K. , Steinberg Gary K. , Marks Michael P.
Published: December 2006

Background and Purpose—

We sought to examine the prospective annual risk of hemorrhage in patients harboring Spetzler-Martin grades IV and V arteriovenous malformations (AVMs) before and after initiation of treatment.

Methods—

Medical records of 61 consecutive patients presenting with Spetzler-Martin grades IV and V AVMs were retrospectively reviewed for demographics, angiographic features, presenting symptom(s), and time of all hemorrhage events, before or after treatment initiation. Pretreatment hemorrhage rates (excluding hemorrhages at presentation) and posttreatment rates were subsequently calculated. Modified Rankin Scale (mRS) scores before and after treatment were recorded.

Results—

The annual pretreatment hemorrhage rate for all patients was 10.4% per year (95% CI, 2.2 to 15.4%), 13.9% (95% CI, 3.5 to 22.1%) in patients with hemorrhagic presentation and 7.3% (2.6 to 14.3%) in patients with nonhemorrhagic presentation. Posttreatment hemorrhage rates were 6.1% per year (95% CI, 2.5 to 13.2%) for all patients, 5.6% (95% CI, 2.1 to 11.8%) for patients presenting with hemorrhage and 6.4% (95% CI, 1.6 to 10.1%) in patients with nonhemorrhagic presentation. A noninferiority test showed that the posttreatment hemorrhage rate was less than or equal to the pretreatment hemorrhage rate (
P
<0.0001), with some indication that the reduction was greatest in patients with hemorrhagic presentation. Of the 62 patients, 51 (82%) had an mRS score of 0 to 2 before treatment, and 47 (76%) had an mRS score of 0 to 2 at the last follow-up after treatment.

Conclusions—

The annual rate of hemorrhage in grades IV and V AVMs is higher in this series than reported for all AVMs, which may reflect some referral bias in this single-center study. Nevertheless, initiation of treatment does not appear to increase the rate of subsequent hemorrhage. Treatment for these lesions may be warranted, given their poor natural history.
Is it Time for a Cardiovascular Primary Prevention Trial in the Elderly?
Authors: Robinson Jennifer G. , Bakris George , Torner James , Stone Neil J. , Wallace Robert
Published: December 2006

Background and Purpose—

Statins have been shown conclusively to reduce the risk of cardiovascular events in subjects with clinical cardiovascular disease or diabetes aged 65 to 80 years of age. However, few data are available for primary prevention of cardiovascular disease in those aged ≥70 years.

Summary of Review—

A moderate-dose statin was of little benefit in a population aged 70 to 82 years when given for 3 years in the setting of suboptimally treated blood pressure. More evidence supports the use of blood pressure–lowering medications, but few data are available regarding the appropriate blood pressure target and most effective agents in the elderly. Some evidence also suggests that the elderly could experience higher mortality with antihypertensive treatment. These findings, along with greater safety concerns and an increasing number of competing risks and medical conditions with advancing age, make it imperative to carefully evaluate the risk/benefit balance from treating hypercholesterolemia and hypertension in persons aged ≥70 years.

Conclusions—

We propose a 5-year 2×2 factorial trial of primary prevention in the elderly that will (1) evaluate whether statin therapy will reduce the risk of cardiovascular events when added to the treatment of hypertension to achieve a blood pressure <140/90 mm Hg in most patients and (2) determine the most appropriate blood pressure regimen for the prevention of cardiovascular and renal events.
Reduced Poststroke Mortality in Patients With Stroke and Atrial Fibrillation Treated With Anticoagulants
Authors: Andersen Klaus Kaae , Olsen Tom Skyhøj
Published: December 2006

Background and Purpose—

The preventive effect of anticoagulation in patients with stroke and atrial fibrillation (AF) is documented only in trials of minor stroke. Although anticoagulation reduced stroke recurrence, those trials did not demonstrate an influence of anticoagulation on survival.

Methods—

A nationwide registry that was started in 2001 with the aim of registering all hospitalized stroke patients in Denmark now includes 24 791 patients. We studied the survival of patients with ischemic stroke and AF with respect to anticoagulation treatment. All underwent an evaluation for stroke severity (according to the Scandinavian Stroke Scale), computed tomography scan, and an evaluation for cardiovascular risk factors. Follow-up duration was 4 years (mean, 1.2 years).

Results—

Of all patients, 22 179 (89.4%) experienced an ischemic stroke. In total, 3670 (16.5%) had AF, and 1909 had no contraindication to anticoagulation treatment. Anticoagulation treatment was initiated in 1149 of these patients (60.2%) but omitted in 760 (39.8%) despite no contraindication to such treatment. Of the patients so treated, 18.9% died during follow-up versus 45.2% without treatment. Patients who received treatment were younger (76.7±9.5 versus 80.7±9.0 years,
P
<0.0001) and had less severe strokes (Scandinavian Stroke Scale score, 42.0±15.0 versus 33.6±18.2,
P
<0.0001). A Cox proportional-hazards model was built to study the effect of anticoagulation on survival in patients without contraindications to treatment while controlling for stroke severity, sex, and cardiovascular risk factors. Patients without anticoagulation treatment were at greater risk of dying (hazard ratio=1.91, 95% CI=1.44 to 2.52) compared with patients who received anticoagulation treatment.

Conclusions—

Our data suggest that anticoagulation treatment reduces poststroke mortality in patients with ischemic stroke and AF.
Inducible Cardiac-Restricted Expression of Enteroviral Protease 2A Is Sufficient to Induce Dilated Cardiomyopathy
Authors: Xiong Dingding , Yajima Toshitaka , Lim Byung-Kwan , Stenbit Antine , Dublin Andrew , Dalton Nancy D. , Summers-Torres Daphne , Molkentin Jeffery D. , Duplain Herve , Wessely Rainer , Chen Ju , Knowlton Kirk U.
Published: December 2006

Background—

Enterovirus infection is a cause of cardiomyopathy. We previously demonstrated that enteroviral protease 2A directly cleaves the cytoskeletal protein dystrophin. However, the direct effect of protease 2A in enteroviral cardiomyopathy is less clear because other viral proteins are also expressed with viral infection.

Methods and Results—

A transgenic mouse with inducible cardiac-restricted expression of enteroviral protease 2A was generated. In the transgenic mouse, a tamoxifen-regulated Cre-loxP system, MerCreMer (MCM), was used to induce genetic recombination in cardiac myocytes, which led to protease 2A expression. Protease 2A and MCM double transgenic (2AxMCM) mice were treated with tamoxifen; the controls included 2AxMCM mice treated with diluents for tamoxifen and tamoxifen-treated MCM littermates. Protease 2A activity was significantly induced after tamoxifen in the 2AxMCM mice compared with controls. Echocardiographic analysis demonstrated an increase in left ventricular end-diastolic and end-systolic chamber size, with decreased fractional shortening in tamoxifen-treated 2AxMCM mice. There was an increase in heart weight-to-body weight ratio in 2AxMCM mice treated with tamoxifen. Only a small increase in interstitial fibrosis and inflammation was found in tamoxifen-treated 2AxMCM mice; however, ultrastructural analysis demonstrated myofibrillar collapse with abnormalities of intercalated discs and sarcolemmal membranes. Evans blue dye–positive myocytes with disruption of dystrophin were present in 2AxMCM mice treated with tamoxifen. Disruption of dystrophin was also found in cultured myocytes isolated from 2AxMCM mice with Cre in the nucleus.

Conclusions—

Protease 2A has a significant role in enteroviral cardiomyopathy and alone is sufficient to induce dilated cardiomyopathy, which is associated with disruption of the sarcolemmal membrane and cleavage of dystrophin with protease 2A expression.
Hemodynamic Modulation of Endocardial Thromboresistance
Authors: Kapur Navin K. , Deming Clayton B. , Kapur Sunil , Bian Ce , Champion Hunter C. , Donahue J. Kevin , Kass David A. , Rade Jeffrey J.
Published: December 2006

Background—

Patients with heart failure are at increased risk for thromboembolic events, including stroke. Historically attributed to blood stasis, little is known about the adverse effects of elevated chamber filling pressure on endocardial function, which could predispose to intracardiac thrombus formation.

Methods and Results—

We investigated changes in the expression of thrombomodulin, a key component of the anticoagulant protein C pathway, in rats subjected to acute atrial pressure overload caused by aortic banding. Acute elevation of left atrial filling pressure, without an associated decline in ventricular systolic function, caused a 70% inhibition of atrial endocardial thrombomodulin expression and resulted in increased local thrombin generation. Targeted restoration of atrial thrombomodulin expression with adenovirus-mediated gene transfer successfully reduced thrombin generation to baseline levels. In vitro co-culture studies revealed that thrombomodulin downregulation is caused by the paracrine release of transforming growth factor-β from cardiac connective tissue in response to mechanical stretch. This was confirmed in vivo by administration of a neutralizing transforming growth factor-β antibody, which effectively prevented thrombomodulin downregulation during acute pressure overload.

Conclusions—

These findings suggest that increased hemodynamic load adversely affects endocardial function and is a potentially important contributor to thromboembolus formation in heart failure.
Association of Cystatin C With Mortality, Cardiovascular Events, and Incident Heart Failure Among Persons With Coronary Heart Disease
Authors: Ix Joachim H. , Shlipak Michael G. , Chertow Glenn M. , Whooley Mary A.
Published: December 2006

Background—

Serum creatinine and related estimating equations predict cardiovascular events and mortality among persons with coronary heart disease (CHD). Cystatin C is a novel and sensitive endogenous marker of kidney function. Whether cystatin C concentrations are associated with adverse events among ambulatory persons with CHD is unknown.

Methods and Results—

Nine hundred ninety ambulatory persons with CHD were categorized into quartiles of serum cystatin C at inception, with ≤0.91 mg/L constituting the lowest quartile (I) and ≥1.30 mg/L constituting the highest (IV). Cox proportional hazards models evaluated time to all-cause mortality, cardiovascular events (composite of CHD death, myocardial infarction, and stroke), and incident heart failure. After a median follow-up of 37 months, 132 participants (13%) died, 101 (10%) had cardiovascular events, and 57 (7%) had incident heart failure. Compared with participants in the lowest cystatin C quartile, those in the highest quartile were at increased risk of all-cause mortality (hazard ratio, 3.6; 95% CI, 1.8 to 7.0), cardiovascular events (hazard ratio, 2.0; 95% CI, 1.0 to 3.8), and incident heart failure (hazard ratio, 2.6; 95% CI, 1.0 to 6.9) in analyses adjusted for traditional cardiovascular risk factors. Cystatin C in the highest quartile predicted similar risk for these outcomes among participants with lower (≤60 mL/min per 1.73 m
2
) or higher estimated glomerular filtration rate and among participants with or without microalbuminuria.

Conclusions—

High cystatin C concentrations predict substantial increased risks of all-cause mortality, cardiovascular events, and incident heart failure among ambulatory persons with CHD. This risk is not completely captured by measures of kidney function routinely used in clinical practice.