bluuebunny/crossref_metadata_2025 huggingface dataset:
Dosing of Erythropoiesis-Stimulating Agents Can Be Reduced by a New Administration Regimen
Authors: Stefánsson Bergur V. , Haraldsson Börje , Nilsson Ulf
Published: August 2011

Background/Aims:At our hemodialysis (HD) unit, we noted a drop in the treatment dose of erythropoietin-stimulating agents (ESAs) when the frequency of dose adjustment was reduced from weekly, where doses were withheld if hemoglobin was >130 g/l, to monthly, where doses were not withheld. The aim of this study was to find an explanation for this reduction in ESA requirement. Methods: This is a retrospective study on 18 stable HD patients. Comparable follow-up periods of 6 months with the two different ESA adjustment regimens were established and data on ESA dose, hemoglobin and known predictors of ESA response were collected. Results: With the new ESA administration regimen, a 22.5% drop in the total ESA dose was noted. The corresponding fall in the erythropoietin resistance index was 20.0%. Simultaneously, the dialysis dose and transferrin saturation increased significantly. However, in a multivariate linear regression model, changes in these factors did not significantly predict changes in ESA requirement. No relevant changes were noted in other erythropoiesis-modulating factors. Conclusion: Frequent dose adjustments and the current ESA administration practice of withholding ESA doses does not seem to reduce ESA demand. On the contrary, such practice is likely to increase ESA requirement over time.
Purinergic P2X7 Receptors Participate in Disturbed Intracellular Calcium Homeostasis in Peripheral Blood Mononuclear Cells of Patients with Chronic Kidney Disease
Authors: Lajdova Ingrid , Oksa Adrian , Chorvat, Jr. Dusan , Topor Peter , Spustova Viera
Published: August 2011

Background: P2X7 receptors intervene with lymphocyte activation and are responsible for multiple processes, including calcium influx. Here, we studied the participation of P2X7 receptors in disturbed intracellular calcium homeostasis regulation in early-stage chronic kidney disease (CKD). Methods: The study involved 20 healthy volunteers and 20 CKD stage 2–3 patients. The free cytosolic calcium concentration ([Ca2+]i) was measured using fluorimetry. The P2X7 pore function was evaluated by the fluorescent dye ethidium bromide. Results: In peripheral blood mononuclear cells (PBMCs) of patients, [Ca2+]i, intracellular calcium stores and the capacitative calcium entry were increased when compared with healthy subjects. The agonist of P2X7 receptor BzATP caused a sustained increase in [Ca2+]i in both groups, but the effect was smaller in patients. The antagonist at the P2X7 receptor KN-62 reduced [Ca2+]i in patients, but had no effect in healthy subjects. In patients, the permeability of ethidium bromide through P2X7 pores, as well as through BzATP-activated and KN-62-inhibited pores, was distinct from permeability in healthy volunteers. Conclusions: These results demonstrate that the calcium signaling pathway in PBMCs of CKD patients is defective already in CKD stage 2–3, and the pore-forming P2X7 receptors are involved in these pathophysiological processes.
Clinical Efficacy of a Specifically Targeted Antimicrobial Peptide Mouth Rinse: Targeted Elimination of Streptococcus mutans and Prevention of Demineralization
Authors: Sullivan R. , Santarpia P. , Lavender S. , Gittins E. , Liu Z. , Anderson M.H. , He J. , Shi W. , Eckert R.
Published: August 2011

Background/Aims:Streptococcus mutans, the major etiological agent of dental caries, has a measurable impact on domestic and global health care costs. Though persistent in the oral cavity despite conventional oral hygiene, S. mutans can be excluded from intact oral biofilms through competitive exclusion by other microorganisms. This suggests that therapies capable of selectively eliminating S. mutans while limiting the damage to the normal oral flora might be effective long-term interventions to fight cariogenesis. To meet this challenge, we designed C16G2, a novel synthetic specifically targeted antimicrobial peptide with specificity for S. mutans. C16G2 consists of a S. mutans-selective ‘targeting region’ comprised of a fragment from S. mutans competence stimulation peptide (CSP) conjoined to a ‘killing region’ consisting of a broad-spectrum antimicrobial peptide (G2). In vitro studies have indicated that C16G2 has robust efficacy and selectivity for S. mutans, and not other oral bacteria, and affects targeted bacteria within seconds of contact. Methods: In the present study, we evaluated C16G2 for clinical utility in vitro, followed by a pilot efficacy study to examine the impact of a 0.04% (w/v) C16G2 rinse in an intra-oral remineralization/demineralization model. Results and Conclusions: C16G2 rinse usage was associated with reductions in plaque and salivary S. mutans, lactic acid production, and enamel demineralization. The impact on total plaque bacteria was minimal. These results suggest that C16G2 is effective against S. mutans in vivo and should be evaluated further in the clinic.
Prevalence and Severity of Clinical Consequences of Untreated Dentine Carious Lesions in Children from a Deprived Area of Brazil
Authors: Figueiredo M.J. , de Amorim R.G. , Leal S.C. , Mulder J. , Frencken J.E.
Published: August 2011

Disadvantaged children suffer because tooth cavities are not being treated and their clinical consequences not being surveyed. The present study aimed to assess the prevalence and severity of clinical consequences of untreated dentine carious lesions in schoolchildren from a deprived area of Brazil and to investigate the determinants of the pufa index. A sample of 835 children aged 6–7 years, from six public schools, was examined by 3 calibrated examiners. Clinical consequences of untreated dentine carious lesions in primary teeth were diagnosed using the four codes of the pufa index: ‘p’ (pulpal involvement), ‘u’ (ulceration), ‘f’ (fistulae), ‘a’ (abscess). Effects of gender, age, school, history of extraction, and toothache on the prevalence of pufa codes were tested. The prevalence of pufa codes was 23.7%. The mean pufa score was 0.4 ± 0.9. Code ‘p’ was the most prevalent (19.5%), whereas code ‘u’ was least prevalent (0.1%). Children with a history of extracted primary teeth due to caries had a 2.7 times higher chance to have a pufa code than children with no previous extraction. Children with toothache had a 5.6 times higher chance to have a pufa code than children without toothache. The prevalence of clinical consequences of untreated dentine carious lesions was moderate and the severity was low. The pufa index is an epidemiological tool complementary to existing caries indices aimed to assess dental caries. However, there appears to be no need to include code ‘u’ nor to score codes ‘f’ and ‘a’ separately.
Inhibition of In-Stent Stenosis by Oral Administration of Bindarit in Porcine Coronary Arteries
Authors: Ialenti Armando , Grassia Gianluca , Gordon Peter , Maddaluno Marcella , Di Lauro Maria Vittoria , Baker Andrew H. , Guglielmotti Angelo , Colombo Antonio , Biondi Giuseppe , Kennedy Simon , Maffia Pasquale
Published: August 2011

Objective—

We have previously demonstrated that bindarit, a selective inhibitor of monocyte chemotactic proteins (MCPs), is effective in reducing neointimal formation in rodent models of vascular injury by reducing smooth muscle cell proliferation and migration and neointimal macrophage content, effects associated with the inhibition of MCP-1/CCL2 production. The aim of the current study was to evaluate the efficacy of bindarit on in-stent stenosis in the preclinical porcine coronary stent model.

Methods and Results—

One or 2 bare metal stents (Multi-Link Vision, 3.5 mm) were deployed (1:1.2 oversize ratio) in the coronary arteries of 42 pigs (20 bindarit versus 22 controls). Bindarit (50 mg/kg per day) was administered orally from 2 days before stenting until the time of euthanasia at 7 and 28 days. Bindarit caused a significant reduction in neointimal area (39.4%,
P
<0.001, n=9 group), neointimal thickness (51%,
P
<0.001), stenosis area (37%,
P
<0.001), and inflammatory score (40%,
P
<0.001) compared with control animals, whereas there was no significant difference in the injury score between the 2 groups. Moreover, treatment with bindarit significantly reduced the number of proliferating cells (by 45%,
P
<0.05; n=6 group) and monocyte/macrophage content (by 55%,
P
<0.01; n=5–6 group) in stented arteries at day 7 and 28, respectively. These effects were associated with a significant (
P
<0.05) reduction of MCP-1 plasma levels at day 28. In vitro data showed that bindarit (10–300 μmol/L) reduced tumor necrosis factor-α (50 ng/mL)–induced pig coronary artery smooth muscle cell proliferation and inhibited MCP-1 production.

Conclusion—

Our results show the efficacy of bindarit in the prevention of porcine in-stent stenosis and support further investigation for clinical application of this compound.
Directed Differentiation of Skin-Derived Precursors Into Functional Vascular Smooth Muscle Cells
Authors: Steinbach Sarah K. , El-Mounayri Omar , DaCosta Ralph S. , Frontini Matthew J. , Nong Zengxuan , Maeda Azusa , Pickering J. Geoffrey , Miller Freda D. , Husain Mansoor
Published: August 2011

Objective—

The goal of this study was to characterize the factors and conditions required for smooth muscle cell (SMC)–directed differentiation of Sox2
+
multipotent rat and human skin-derived precursors (SKPs) and to define whether they represent a source of fully functional vascular SMCs for applications in vivo.

Methods and Results—

We found that rat SKPs can differentiate almost exclusively into SMCs by reducing serum concentrations to 0.5% to 2% and plating them at low density. Human SKPs derived from foreskin required the addition of transforming growth factor-β1 or -β3 to differentiate into SMCs, but they did so even in the absence of serum. SMC formation was confirmed by quantitative reverse transcription–polymerase chain reaction, immunocytochemistry, and fluorescence-activated cell sorting, with increased expression of smoothelin-B and little to no expression of telokin or smooth muscle γ-actin, together indicating that SKPs differentiated into vascular rather than visceral SMCs. Rat and human SKP-derived SMCs were able to contract in vitro and also wrap around and support new capillary and larger blood vessel formation in angiogenesis assays in vivo.

Conclusion—

SKPs are Sox2
+
progenitors that represent an attainable autologous source of stem cells that can be easily differentiated into functional vascular SMCs in defined serum-free conditions without reprogramming. SKPs represent a clinically viable cell source for potential therapeutic applications in neovascularization.
Left Atrial Blood Stasis and Von Willebrand Factor–ADAMTS13 Homeostasis in Atrial Fibrillation
Authors: Ammash Naser , Konik Ewa A. , McBane Robert D. , Chen Dong , Tange Julie I. , Grill Diane E. , Herges Regina M. , McLeod Thomas G. , Friedman Paul A. , Wysokinski Waldemar E.
Published: August 2011

Objective—

Left atrial blood stasis is associated with increased risk for left atrial appendage thrombus (LAAT) and stroke in atrial fibrillation (AF). Von Willebrand factor (VWF) is associated with thromboembolism in AF. VWF thrombogenic activity is proportional to multimer size, which is regulated by VWF-cleaving protease (ADAMTS13).

Methods and Results—

To assess the association between left atrial blood stasis and VWF-ADAMTS13 system, plasma VWF antigen (VWF:Ag), VWF activity (VWF:Act), and ADAMTS13 activity were measured in 414 consecutive patients with nonvalvular AF (age 63±13 years; 25% women) and in 100 patients (age 64±14 years; 39% women) with normal sinus rhythm. Spontaneous echocardiographic contrast (SEC), left atrial appendage emptying velocity, and LAAT were assessed by transesophageal echocardiography. Presence and intensity of SEC varied directly with VWF:Ag and VWF:Act but not with ADAMTS13 activity. AF patients with LAAT had higher VWF:Ag (200±61 versus 155±52,
P
=0.0006) and VWF:Act (179±57 versus 141±51
P
=0.0026) compared with those without LAAT. VWF:Ag and VWF:Act were independent predictors of LAAT after adjustment for CHADS
2
score (
P
=0.0179 and
P
=0.0497, respectively).

Conclusion—

The association between VWF and SEC may explain the thrombotic propensity in AF. Elevated VWF:Ag may help identify AF patients at risk for LAAT.
CCL20 Is Increased in Hypercholesterolemic Subjects and Is Upregulated By LDL in Vascular Smooth Muscle Cells
Authors: Calvayrac Olivier , Rodríguez-Calvo Ricardo , Alonso Judith , Orbe Josune , Martín-Ventura Jose Luis , Guadall Anna , Gentile Maurizio , Juan-Babot Oriol , Egido Jesus , Beloqui Oscar , Paramo José A. , Rodríguez Cristina , Martínez-González José
Published: August 2011

Objective—

Our aim was to analyze the regulation of CC Chemokine ligand 20 (CCL20) by LDL in human vascular smooth muscle cells (VSMC).

Methods and Results—

In asymptomatic subjects, circulating CCL20 levels were higher in patients with hypercholesterolemia (18.5±3.2 versus 9.1±1.3 pg/mL;
P
<0.01). LDL induced the expression of CCL20 in VSMC in a dose- and time-dependent manner. Increased levels of CCL20 secreted by LDL-treated VSMC significantly induced human lymphocyte migration, an effect reduced by CCL20 silencing. The upregulation of CCL20 by LDL was dependent on the activation of kinase signaling pathways and NF-κB. By site-directed mutagenesis, electrophoretic mobility shift assay, and chromatin immunoprecipitation, we identified a NF-κB site (−80/−71) in CCL20 promoter critical for LDL responsiveness. Lysophosphatidic acid mimicked the upregulation of CCL20 induced by LDL, and minimal oxidation of LDL increased the ability of LDL to induce CCL20 through a mechanism that involves lysophosphatidic acid receptors. CCL20 was overexpressed in atherosclerotic lesions from coronary artery patients, colocalizing with VSMC. CCL20 was detected in conditioned media from healthy human aorta and its levels were significantly higher in secretomes from carotid endarterectomy specimens.

Conclusion—

This study identifies CCL20 in atherosclerotic lesions and recognizes this chemokine as a mediator highly sensitive to the inflammatory response elicited by LDL.
MicroRNA-133 Controls Vascular Smooth Muscle Cell Phenotypic Switch In Vitro and Vascular Remodeling In Vivo
Authors: Torella Daniele , Iaconetti Claudio , Catalucci Daniele , Ellison Georgina M. , Leone Angelo , Waring Cheryl D. , Bochicchio Angela , Vicinanza Carla , Aquila Iolanda , Curcio Antonio , Condorelli Gianluigi , Indolfi Ciro
Published: August 2011

Rationale:

MicroRNA (miR)-1 and -133 play a crucial role in skeletal and cardiac muscle biology and pathophysiology. However, their expression and regulation in vascular cell physiology and disease is currently unknown.

Objective:

The aim of the present study was to evaluate the role, if any, of miR-1 and miR-133 in vascular smooth muscle cell (VSMC) phenotypic switch in vitro and in vivo.

Methods and Results:

We demonstrate here that miR-133 is robustly expressed in vascular smooth muscle cells (VSMCs) in vitro and in vivo, whereas miR-1 vascular levels are negligible. miR-133 has a potent inhibitory role on VSMC phenotypic switch in vitro and in vivo, whereas miR-1 does not have any relevant effect per se. miR-133 expression is regulated by extracellular signal–regulated kinase 1/2 activation and is inversely correlated with VSMC growth. Indeed, miR-133 decreases when VSMCs are primed to proliferate in vitro and following vascular injury in vivo, whereas it increases when VSMCs are coaxed back to quiescence in vitro and in vivo. miR-133 loss- and gain-of-function experiments show that miR-133 plays a mechanistic role in VSMC growth. Accordingly, adeno-miR-133 reduces but anti-miR-133 exacerbates VSMC proliferation and migration in vitro and in vivo. miR-133 specifically suppresses the transcription factor Sp-1 expression in vitro and in vivo and through Sp-1 repression regulates smooth muscle gene expression.

Conclusions:

Our data show that miR-133 is a key regulator of vascular smooth muscle cell phenotypic switch in vitro and in vivo, suggesting its potential therapeutic application for vascular diseases.
Distribution and Functional Role of Inositol 1,4,5-
tris
phosphate Receptors in Mouse Sinoatrial Node
Authors: Ju Yue-Kun , Liu Jie , Lee Bon Hyang , Lai Donna , Woodcock Elizabeth A. , Lei Ming , Cannell Mark B. , Allen David G.
Published: August 2011

Rationale:

Inositol 1,4,5-
tris
phosphate receptors (IP
3
Rs) have been implicated in the generation of arrhythmias and cardiac muscle nuclear signaling. However, in the mammalian sinoatrial node (SAN), where the heart beat originates, the expression and functional activity of IP
3
Rs have not been investigated.

Objectives:

To determine whether SAN express IP
3
Rs and which isoforms are present. To examine the response of the SAN to IP
3
R agonists and antagonist, and the potential role played by IP
3
Rs in cardiac pacemaking.

Methods and Results:

The expression and distribution of IP
3
Rs were studied by reverse-transcription polymerase chain reaction, Western blotting, and immunolabeling. Ca
2+
signaling and electric activity in intact mouse SAN were measured with Ca
2+
-sensitive fluorescent dyes. We found that although the entire SAN expressed three IP
3
R mRNA isoforms, the type II IP
3
R (IP
3
R2) was the predominant protein isoform detected by Western blot using protein extracts from the SAN, atrioventricular node, and atrial tissue. Immunohistochemistry studies also showed that IP
3
R2 was expressed in the central SAN region. Studies using isolated single pacemaker cells revealed that IP
3
R2 (but not IP
3
R1) was located with a similar distribution to the sarcoplasmic reticulum marker protein SERCA2a with some labeling adjacent to the surface membrane. The application of membrane-permeable IP
3
(IP
3
-butyryloxymethyl ester) increased Ca
2+
spark frequency and the pacemaker firing rate in single isolated pacemaker cells. In intact SAN preparations, IP
3
R agonists, endothelin-1 and IP
3
-butyryloxymethyl ester both increased intracellular Ca
2+
and the pacemaker firing rate, whereas the IP
3
R antagonist, 2-aminoethoxydiphenyl borate decreased Ca
2+
and the firing rate. Both of these effects were absent in the SAN from transgenic IP
3
R2 knockout mice.

Conclusions:

This study provides new evidence that functional IP
3
R2s are expressed in the mouse SAN and could serve as an additional Ca
2+
-dependent mechanism in modulating cardiac pacemaker activity as well as other Ca
2+
-dependent processes.
Safety of Tirofiban in Acute Ischemic Stroke
Authors: Siebler Mario , Hennerici Michael G. , Schneider Dietmar , von Reutern Gerhard M. , Seitz Rüdiger J. , Röther Joachim , Witte Otto W. , Hamann Gerhard , Junghans Ulrich , Villringer Arno , Fiebach Jochen B.
Published: August 2011

Background and Purpose—

Tirofiban is a highly selective, fast-acting nonpeptide glycoprotein IIb/IIIa platelet receptor antagonist with a short half-life time. Glycoprotein IIb/IIIa antagonists are effective for the treatment of acute coronary syndromes proven in large clinical trials. Safety and efficacy in patients with ischemic stroke are uncertain. This was addressed in the Safety of Tirofiban in acute Ischemic Stroke (SaTIS) trial.

Methods—

Two hundred sixty patients with acute ischemic stroke were randomized in a placebo-controlled, prospective, open-label treatment, blinded outcome reading multicenter trial. Subjects with a National Institutes of Health Stroke Scale between 4 and 18 received intravenously either tirofiban or placebo within 3 to 22 hours after symptom onset for 48 hours. The primary end point was the rate of cerebral bleeding as measured in follow-up CT scans 2 to 7 days after inclusion. The secondary end point was clinical efficacy within 1 week (National Institutes of Health Stroke Scale, modified Rankin Scale) and after 5 months (Barthel Index, modified Rankin Scale).

Results—

The rate of cerebral hemorrhagic transformation (I/II) and parenchymal hemorrhage (I/II) did not differ between both groups (tirofiban 36 of 120; placebo 33 of 124: OR, 1.18; 95% CI, 0.66 to 2.06). Mortality after 5 months was significantly lower in patients treated with tirofiban (3 of 130 [2.3%] versus 11 of 126 [8.7%]; OR, 4.05; 95% CI, 1.1 to 14.9). No difference in neurological/functional outcome was found after 1 week and after 5 months.

Conclusions—

We conclude that tirofiban might be safe in acute moderate ischemic stroke even when administered within a large time window after symptom onset and might save lives in the late outcome.

Clinical Trial Registration—

URL:
www.strokecenter.org/trials/
. Trial name: SaTIS. Enrollment began before July 1, 2005.
Chronic Kidney Disease and Drinking Status in Relation to Risks of Stroke and Its Subtypes
Authors: Shimizu Yuji , Maeda Kenji , Imano Hironori , Ohira Tetsuya , Kitamura Akihiko , Kiyama Masahiko , Okada Takeo , Ishikawa Yoshinori , Shimamoto Takashi , Yamagishi Kazumasa , Tanigawa Takeshi , Iso Hiroyasu
Published: August 2011

Background and Purpose—

Several epidemiological studies have established an association between chronic kidney disease (CKD), based on estimated glomerular filtration rate (GFR), and risk of stroke. However, sex-specific evidence for the relationship between CKD and risk of stroke and its subtypes is still limited.

Methods—

We conducted a prospective cohort study of 12 222 Japanese men and women age 40 to 69 years living in 4 communities under systematic surveillance of stroke incidence to determine the relationship between CKD and risk of stroke and its subtypes.

Results—

During the 17-year follow-up, there were 566 strokes (327 ischemic and 186 hemorrhagic strokes). GFR was inversely associated with age- and community-adjusted risk of total stroke for both men and women. Compared with the reference group without CKD (GFR ≥60 mL/min per 1.73m
2
), the adjusted risks of total stroke for subjects with CKD (GFR <60 mL/min per 1.73m
2
) were 1.63 (1.22–2.17) for men and 1.51 (1.13–2.02) for women. Excess risk of stroke associated with CKD was identified primarily for hemorrhagic stroke among men and for ischemic stroke among women. After adjustment for traditional cardiovascular risk factors, associations remained statistically significant. When stratified by drinking status, excess risk of hemorrhagic stroke with CKD was confined to drinkers; adjusted risks were 4.18 (2.31–7.57) for men and 7.00 (1.92–25.56) for women.

Conclusions—

CKD was associated with increased risk of hemorrhagic stroke for men, and of ischemic stroke for women. This sex difference may partly be explained by the difference in prevalence of drinkers between men and women.
Cerebral Oxygen Transport Failure?: Decreasing Hemoglobin and Hematocrit Levels After Ischemic Stroke Predict Poor Outcome and Mortality
Authors: Kellert Lars , Martin Evgenia , Sykora Marek , Bauer Harald , Gussmann Philipp , Diedler Jennifer , Herweh Christian , Ringleb Peter A. , Hacke Werner , Steiner Thorsten , Bösel Julian
Published: August 2011

Background and Purpose—

Although conceivably relevant for penumbra oxygenation, the optimal levels of hemoglobin (Hb) and hematocrit (Hct) in patients with acute ischemic stroke are unknown.

Methods—

We identified patients from our prospective local stroke database who received intravenous thrombolysis based on multimodal magnet resonance imaging during the years 1998 to 2009. A favorable outcome at 3 months was defined as a modified Rankin Scale score ≤2 and a poor outcome as a modified Rankin Scale score ≥3. The dynamics of Hemoglobin (Hb), Hematocrit (Hct), and other relevant laboratory parameters as well as cardiovascular risk factors were retrospectively assessed and analyzed between these 2 groups.

Results—

Of 217 patients, 114 had a favorable and 103 a poor outcome. In a multivariable regression model, anemia until day 5 after admission (odds ratio [OR]=2.61; 95% CI, 1.33 to 5.11;
P
=0.005), Hb nadir (OR=0.81; 95% CI, 0.67 to 0.99;
P
=0.038), and Hct nadir (OR=0.93; 95% CI, 0.87 to 0.99;
P
=0.038) remained independent predictors for poor outcome at 3 months. Mortality after 3 months was independently associated with Hb nadir (OR=0.80; 95% CI, 0.65 to 0.98;
P
=0.028) and Hb decrease (OR=1.34; 95% CI, 1.01 to 1.76;
P
=0.04) as well as Hct decrease (OR=1.12; 95% CI, 1.01 to 1.23;
P
=0.027).

Conclusions—

Poor outcome and mortality after ischemic stroke are strongly associated with low and further decreasing Hb and Hct levels. This decrease of Hb and Hct levels after admission might be more relevant and accessible to treatment than are baseline levels.
Value of Carotid Intima-Media Thickness and Significant Carotid Stenosis as Markers of Stroke Recurrence
Authors: Roquer Jaume , Segura Tomás , Serena Joaquín , Cuadrado-Godia Elisa , Blanco Miguel , García-García Jorge , Castillo José
Published: August 2011

Background and Purpose—

Data on the predictive value of carotid intima-media thickness (IMT) for stroke recurrence are scarce. We sought to analyze outcome differences in stroke patients with high IMT values compared with patients with significant carotid stenosis (SCS).

Methods—

The multicenter observational ARTICO study included 620 independent patients older than 60 years with a first-ever noncardioembolic stroke. Patients were followed-up for 1 year. The primary end point was a composite of cardiovascular events and death. The IMT-ARTICO substudy analyzed ultrasonographic data from 599 patients. After Doppler carotid echography, patients were classified into the SCS group (carotid stenosis ≥50%; 117 cases), high IMT group (patients with the common carotid IMT in the highest quartile ≥1.11 mm and without SCS; 110 cases), and control group (stroke patients with an IMT <1.11 mm and without SCS; 372 cases). We analyzed the impact of both conditions on the primary end point.

Results—

During follow-up, 88 patients (14.7%) had an end point event. Univariate analysis showed that male gender, diabetes, symptomatic peripheral arterial disease, ankle brachial index ≤0.9, SCS, and high IMT were related to the primary end point. Cox regression showed that peripheral arterial disease (hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.18–3.59;
P
=0.011), SCS (HR, 3.02; 95% CI, 1.78–5.13;
P
=0.0001), and high IMT (HR, 1.86; 95% CI, 1.05–3.29;
P
=0.032) were related to the primary end point. If patients with scheduled revascularization procedures were excluded from the Cox regression, then ultrasonographic markers were SCS (HR, 1.84; 95% CI, 1.03–3.28;
P
<0.039) and high IMT (HR, 1.86; 95% CI, 1.06–3.27;
P
=0.030).

Conclusions—

Both SCS and high IMT have an independent impact as markers of major cardiovascular events or death after a first-ever noncardioembolic stroke.
Prevalence and Prognosis of Asymptomatic Vertebral Artery Origin Stenosis in Patients With Clinically Manifest Arterial Disease
Authors: Compter Annette , van der Worp H. Bart , Algra Ale , Kappelle L. Jaap
Published: August 2011

Background and Purpose—

The risk of ischemic stroke in patients with asymptomatic vertebral artery stenosis is unknown. We examined the incidence of posterior circulation ischemic stroke in patients with asymptomatic stenosis of the vertebral artery origin (VAo).

Methods—

We studied a hospital-based cohort of 3717 patients (median age, 60 years; interquartile range, 52 to 68 years) with atherosclerotic arterial disease enrolled in the Second Manifestations of ARTerial disease (SMART) study. We included patients in whom duplex ultrasound of the carotid artery and vertebral artery had been performed. Patients with symptomatic VAo stenosis or planned revascularization of the carotid artery or vertebral artery were excluded. Data were analyzed with Cox regression; hazard ratios were adjusted for age and vascular risk factors.

Results—

In 282 patients (7.6%), asymptomatic VAo stenosis >50% was diagnosed with duplex ultrasound. During a mean follow-up of 4.6 years (SD, 3.0), posterior circulation ischemic stroke occurred in 5 of the 282 patients with asymptomatic VAo stenosis at baseline (annual stroke rate, 0.4%) and in 12 of the 3435 patients without VAo stenosis (annual stroke rate, <0.1%). The risk of posterior circulation ischemic stroke was higher in patients with VAo stenosis than in patients without VAo stenosis (hazard ratio, 4.2; 95% CI, 1.4 to 13.1) and was further increased in patients with both VAo and carotid artery stenosis (hazard ratio, 10.5; 95% CI, 3.0 to 37.3). In multivariable analysis, this risk remained essentially the same.

Conclusions—

Patients with atherosclerotic arterial disease and asymptomatic VAo stenosis have a higher risk of posterior circulation ischemic stroke than patients without such a stenosis, but the absolute risk remains low.
Activation of Transient Receptor Potential Vanilloid 1 by Dietary Capsaicin Delays the Onset of Stroke in Stroke-Prone Spontaneously Hypertensive Rats
Authors: Xu Xingsen , Wang Peijian , Zhao Zhigang , Cao Tingbing , He Hongbo , Luo Zhidan , Zhong Jian , Gao Feng , Zhu Zhenyu , Li Li , Yan Zhencheng , Chen Jing , Ni Yinxing , Liu Daoyan , Zhu Zhiming
Published: August 2011

Background and Purpose—

Previous studies show that endothelial nitric oxide synthase (eNOS) plays a prominent role in maintaining cerebral blood flow and preventing stroke. Capsaicin in hot pepper can increase the phosphorylation of eNOS in endothelial cells. We test the hypothesis that chronic dietary capsaicin can prevent stroke through activation of cerebrovascular transient receptor potential vanilloid 1 (TRPV1) channels in stroke-prone spontaneously hypertensive rats (SHRsp).

Methods—

SHRsp were fed dietary capsaicin, and their onset of stroke was examined. TRPV1 knockout and transgenic mice were used for determining the function of TRPV1 channels. Expression of eNOS and cerebrovascular reactivity were examined.

Results—

Immunofluorescence showed TRPV1 channels and eNOS coexpression in cerebral arterioles. Administration of capsaicin significantly increased phosphorylated eNOS in carotid arteries from wild-type mice but not in TRPV1 knockout mice. Inhibition of eNOS using
N
G
-nitro-
l
-arginine methyl ester, removal of endothelium, or mutant TRPV1 significantly reduced capsaicin-induced endothelium-dependent relaxation of basilar arteries in mice. Chronic dietary capsaicin also remarkably increased eNOS expression in carotid arteries from SHRsp. Compared with Wistar-Kyoto rats, SHRsp had impaired endothelium-dependent relaxation of basilar arteries. Administration of capsaicin or
l
-arginine significantly improved the endothelium-dependent relaxation of basilar arteries in SHRsp. SHRsp had hypertrophy of cerebral arterioles, which was reversed by dietary capsaicin. Importantly, long-term administration of capsaicin significantly delayed the onset of stroke and increased the survival time in SHRsp.

Conclusions—

Activation of TRPV1 channels by dietary capsaicin mediated increases in phosphorylation of eNOS and could represent a novel target for dietary intervention of stroke.
Technological Advances in the Management of Unruptured Intracranial Aneurysms Fail to Improve Outcome in New York State
Authors: Zacharia Brad E. , Ducruet Andrew F. , Hickman Zachary L. , Grobelny Bartosz T. , Badjatia Neeraj , Mayer Stephan A. , Berman Mitchell F. , Solomon Robert A. , Connolly E. Sander
Published: August 2011

Background and Purpose—

Unruptured intracranial aneurysms (UIAs) are being identified more frequently and endovascular coil embolization has become an increasingly popular treatment modality.

Our study evaluates patient outcomes with changing patterns of treatment of UIA.

Methods—

We conducted a retrospective, longitudinal cohort study of 3132 hospital discharges for UIA identified from the New York Statewide Database (SPARCS) in 2005 to 2007 and 2200 discharges from 1995 to 2000. The rates of endovascular coiling and surgical clipping were examined along with hospital variables and discharge outcome. Anatomic specifics of UIA were unavailable for analysis.

Results—

The case rate for treatment of UIA doubled from 1.59 (1995 to 2000) to 3.45 per 100 000 (2005 to 2007,
P
<0.0001) and increased in the case treatment rate for coiling of UIA (0.36 versus 1.98 per 100 000,
P
<0.0001). Compared with the old epoch, there were more UIAs clipped at high-volume centers (55.8% versus 78.8%,
P
<0.0001) but fewer coiled at high-volume centers (94.8% versus 84.5%,
P
<0.0001) in the new epoch. Coiling and increasing hospital UIA treatment volume were associated with good discharge outcome. However, there was no significant improvement in overall good outcome when comparing 1995 to 2000 versus 2005 to 2007 (79% versus 81%,
P
=0.168) and a worsening of good outcomes for clipping (76.3% versus 71.7%,
P
=0.0132).

Conclusions—

Despite coiling being associated with an increased incidence of good outcome relative to clipping of UIA, the increase in coiling has failed to improve overall patient outcome. The shift in coiling venue from high-volume centers to low-volume centers and decreasing microsurgical volume accompanied by a worsening in microsurgical results contribute to this. This argues for greater centralization of care.
Accumulation of Dietary Docosahexaenoic Acid in the Brain Attenuates Acute Immune Response and Development of Postischemic Neuronal Damage
Authors: Lalancette-Hébert Mélanie , Julien Carl , Cordeau Pierre , Bohacek Ivan , Weng Yuan-Cheng , Calon Frédéric , Kriz Jasna
Published: August 2011

Background and Purpose—

Consumption of fish has been shown to reduce risk of coronary heart disease and, possibly, of ischemic stroke. Because docosahexaenoic acid (DHA) is the most likely neuroactive component within fish oil, we hypothesized that exposing mice to a DHA-enriched diet may reduce inflammation and protect neurons against ischemic injury.

Methods—

To visualize the effects of DHA on neuroinflammation after stroke, TLR2-fluc-GFP transgenic mice were exposed to either a control diet, a diet depleted in n-3 polyunsaturated fatty acid, or a diet enriched in DHA during 3 months. Real-time biophotonic/bioluminescence imaging of the TLR2 response was performed before and after middle cerebral artery occlusion, whereas cytokines concentrations and stroke area analyses were performed at 3 and 7 days after middle cerebral artery occlusion, respectively.

Results—

We show that a 3-month DHA treatment prevented microglial activation after ischemic injury, reduced the ischemic lesion size, and increased levels of the antiapoptotic molecule Bcl-2 in the brain. Additional analysis revealed a significant decrease in the levels of COX2 and IL-1β, but not in other proinflammatory cytokines. Importantly, long-term DHA supplementation significantly changed the n-3:n-6 polyunsaturated fatty acid ratio in the brain.

Conclusions—

Collectively, these data indicate that diet-induced accumulation of DHA in the brain protects against postischemic inflammation and injury. Because DHA is widely available at low cost and has an excellent safety profile, our data suggest that increased DHA intake may provide protection against acute immune response/brain damage in ischemic stroke.
Diabetes and Poor Outcomes Within 6 Months After Acute Ischemic Stroke
Authors: Jia Qian , Zhao Xingquan , Wang Chunxue , Wang Yilong , Yan Yu , Li Hao , Zhong Liyong , Liu Liping , Zheng Huaguang , Zhou Yong , Wang Yongjun
Published: August 2011

Background and Purpose—

Diabetes mellitus (DM) is an independent risk factor for ischemic stroke. However, controversy exists with regard to the impact of DM on prognosis after ischemic stroke in the Chinese population. We investigated the associations between DM and death, dependency, and stroke recurrence in patients after ischemic stroke onset in a nationwide, prospective registry, the China National Stroke Registry.

Methods—

The China National Stroke Registry consecutively recruited patients hospitalized for acute ischemic stroke in 2007 to 2008 and who were prospectively followed up for clinical and functional outcomes (death, dependency, and stroke recurrence) at 3 and 6 months after disease onset. Multivariable logistic regression was performed to analyze the association between DM and stroke outcomes after adjusting for potential confounding including age, sex, National Institutes of Health Stroke Scale score, glucose level at admission, hypertension, coronary heart disease, smoking, urinary tract infection, and other factors.

Results—

DM was identified in 3483 (27.0%) of stroke patients. Compared with stroke patients without DM, patients with DM had a significantly higher incidence of death or dependency and of recurrent stroke at 3 and 6 months after stroke onset. DM was an independent risk factor for death or dependency (adjusted odds ratio=1.23; 95% confidence interval, 1.10 to 1.37) in patients with ischemic stroke at 6 months after onset.

Conclusions—

DM independently predicted poor outcomes in Chinese patients after acute ischemic stroke.
Optimizing Protocols for Risk Prediction in Asymptomatic Carotid Stenosis Using Embolic Signal Detection
Authors: King Alice , Shipley Martin , Markus Hugh
Published: August 2011

Background and Purpose—

Improved methods are required to identify patients with asymptomatic carotid stenosis at high risk for stroke. The Asymptomatic Carotid Emboli Study recently showed embolic signals (ES) detected by transcranial Doppler on 2 recordings that lasted 1-hour independently predict 2-year stroke risk. ES detection is time-consuming, and whether similar predictive information could be obtained from simpler recording protocols is unknown.

Methods—

In a predefined secondary analysis of Asymptomatic Carotid Emboli Study, we looked at the temporal variation of ES. We determined the predictive yield associated with different recording protocols and with the use of a higher threshold to indicate increased risk (≥2 ES). To compare the different recording protocols, sensitivity and specificity analyses were performed using analysis of receiver-operator characteristic curves.

Results—

Of 477 patients, 467 had baseline recordings adequate for analysis; 77 of these had ES on 1 or both of the 2 recordings. ES status on the 2 recordings was significantly associated (
P
<0.0001), but there was poor agreement between ES positivity on the 2 recordings (κ=0.266). For the primary outcome of ipsilateral stroke or transient ischemic attack, the use of 2 baseline recordings lasting 1 hour had greater predictive accuracy than either the first baseline recording alone (
P
=0.0005), a single 30-minute (
P
<0.0001) recording, or 2 recordings lasting 30 minutes (
P
<0.0001). For the outcome of ipsilateral stroke alone, two recordings lasting 1 hour had greater predictive accuracy when compared to all other recording protocols (all
P
<0.0001).

Conclusions—

Our analysis demonstrates the relative predictive yield of different recording protocols that can be used in application of the technique in clinical practice. Two baseline recordings lasting 1 hour as used in Asymptomatic Carotid Emboli Study gave the best risk prediction.
Multimodality Monitoring for Cerebral Perfusion Pressure Optimization in Comatose Patients With Intracerebral Hemorrhage
Authors: Ko Sang-Bae , Choi H. Alex , Parikh Gunjan , Helbok Raimund , Schmidt J. Michael , Lee Kiwon , Badjatia Neeraj , Claassen Jan , Connolly E. Sander , Mayer Stephan A.
Published: August 2011

Background and Purpose—

Limited data exist to recommend specific cerebral perfusion pressure (CPP) targets in patients with intracerebral hemorrhage. We sought to determine the feasibility of brain multimodality monitoring for optimizing CPP and potentially reducing secondary brain injury after intracerebral hemorrhage.

Methods—

We retrospectively analyzed brain multimodality monitoring data targeted at perihematomal brain tissue in 18 comatose intracerebral hemorrhage patients (median monitoring, 164 hours). Physiological measures were averaged over 1-hour intervals corresponding to each microdialysis sample. Metabolic crisis was defined as a lactate/pyruvate ratio >40 with a brain glucose concentration <0.7 mmol/L. Brain tissue hypoxia (BTH) was defined as P
bt
O
2
<15 mm Hg. Pressure reactivity index and oxygen reactivity index were calculated.

Results—

Median age was 59 years, median Glasgow Coma Scale score was 6, and median intracerebral hemorrhage volume was 37.5 mL. The risk of BTH, and to a lesser extent metabolic crisis, increased with lower CPP values. Multivariable analyses showed that CPP <80 mm Hg was associated with a greater risk of BTH (odds ratio, 1.5; 95% confidence interval, 1.1–2.1;
P
=0.01) compared to CPP >100 mm Hg as a reference range. Six patients died (33%). Survivors had significantly higher CPP and P
bt
O
2
and lower ICP values starting on postbleed day 4, whereas lactate/pyruvate ratio and pressure reactivity index values were persistently lower, indicating preservation of aerobic metabolism and pressure autoregulation.

Conclusions—

P
bt
O
2
monitoring can be used to identify CPP targets for optimal brain tissue oxygenation. In patients who do not undergo multimodality monitoring, maintaining CPP >80 mm Hg may reduce the risk of BTH.
Inhibition of Protein Kinase Cβ Reverses Increased Blood–Brain Barrier Permeability During Hyperglycemic Stroke and Prevents Edema Formation In Vivo
Authors: Cipolla Marilyn J. , Huang Quillan , Sweet Julie G.
Published: August 2011

Background and Purpose—

We investigated the effect of circulating factors and protein kinase Cβ on blood–brain barrier permeability and edema during hyperglycemic stroke.

Methods—

Male Wistar rats that were hyperglycemic by streptozotocin (50 mg/kg) for 5 to 6 days underwent middle cerebral artery occlusion (MCAO) for 2 hours with 2 hours of reperfusion. Blood–brain barrier permeability was measured in middle cerebral arteries that were ischemic (MCAO) or nonischemic (CTL) and perfused with plasma (20% in buffer) from MCAO or CTL animals. A separate set of MCAO vessels was perfused with the protein kinase Cβ inhibitor CGP53353 (0.5 μmol/L) and permeability measured. Lastly, hyperglycemic rats were treated intravenously with CGP53353 (10 or 100 μg/kg or vehicle 15 minutes before reperfusion and edema formation measured by wet:dry weights (n=6/group).

Results—

MCAO vessels had increased permeability compared with controls regardless of the plasma perfusate. Permeability (water flux, μm
3
×10
8
) of CTL vessel/CTL plasma (n=8), CTL vessel/MCAO plasma (n=7), MCAO vessel/CTL plasma (n=6), and MCAO vessel/MCAO plasma (n=6) was 0.98±0.11, 1.13±0.07, 1.36±0.02, and 1.34±0.06;
P
<0.01). Inhibition of protein kinase Cβ in MCAO vessels (n=6) reversed the increase in permeability (0.92±0.1;
P
<0.01). In vivo, hyperglycemia increased edema versus normoglycemia after MCAO (water content=78.84%±0.11% versus 81.38%±0.21%;
P
<0.01). Inhibition of protein kinase Cβ with 10 or 100 μg/kg CGP53353 during reperfusion prevented the increased edema in hyperglycemic animals (water content=79.54%±0.56% and 79.99%±0.43%;
P
<0.01 versus vehicle).

Conclusions—

These results suggest that the pronounced vasogenic edema that occurs during hyperglycemic stroke is mediated in large part by activation of protein kinase Cβ.
Guaranteed Cost Synchronization of Chaotic Cellular Neural Networks with Time-Varying Delay
Authors: Tu Jianjun , He Hanlin
Published: August 2011

Synchronization of cellular neural networks with time-varying delay is discussed in this letter. Based on Razumikhin theorem, a guaranteed cost synchronous controller is given. Unlike Lyapunov-Krasovskii analysis process, there is no constraint on the change rate of time delay. The saturated terms emerging in the Razumikhin analysis are amplified by zoned discussion and maximax synthesis rather than by Lipschitz condition and vector inequality, which will bring more conservatism. Then the controller criterion is transformed from quadratic matrix inequality form into linear matrix inequality form, with the help of a sufficient and necessary transformation condition. The minimization of the guaranteed cost is studied, and a further criterion for getting the controller is presented. Finally, the guaranteed cost synchronous control and its corresponding minimization problem are illustrated with examples of chaotic time-varying delay cellular neural networks.
A Model of Motion Transparency Processing with Local Center-Surround Interactions and Feedback
Authors: Raudies Florian , Mingolla Ennio , Neumann Heiko
Published: August 2011

Motion transparency occurs when multiple coherent motions are perceived in one spatial location. Imagine, for instance, looking out of the window of a bus on a bright day, where the world outside the window is passing by and movements of passengers inside the bus are reflected in the window. The overlay of both motions at the window leads to motion transparency, which is challenging to process.

Noisy and ambiguous motion signals can be reduced using a competition mechanism for all encoded motions in one spatial location. Such a competition, however, leads to the suppression of multiple peak responses that encode different motions, as only the strongest response tends to survive. As a solution, we suggest a local center-surround competition for population-encoded motion directions and speeds. Similar motions are supported, and dissimilar ones are separated, by representing them as multiple activations, which occurs in the case of motion transparency. Psychophysical findings, such as motion attraction and repulsion for motion transparency displays, can be explained by this local competition.

Besides this local competition mechanism, we show that feedback signals improve the processing of motion transparency. A discrimination task for transparent versus opaque motion is simulated, where motion transparency is generated by superimposing large field motion patterns of either varying size or varying coherence of motion. The model’s perceptual thresholds with and without feedback are calculated. We demonstrate that initially weak peak responses can be enhanced and stabilized through modulatory feedback signals from higher stages of processing.
Estimating Parameters of Generalized Integrate-and-Fire Neurons from the Maximum Likelihood of Spike Trains
Authors: Dong Yi , Mihalas Stefan , Russell Alexander , Etienne-Cummings Ralph , Niebur Ernst
Published: August 2011

When a neuronal spike train is observed, what can we deduce from it about the properties of the neuron that generated it? A natural way to answer this question is to make an assumption about the type of neuron, select an appropriate model for this type, and then choose the model parameters as those that are most likely to generate the observed spike train. This is the maximum likelihood method. If the neuron obeys simple integrate-and-fire dynamics, Paninski, Pillow, and Simoncelli ( 2004 ) showed that its negative log-likelihood function is convex and that, at least in principle, its unique global minimum can thus be found by gradient descent techniques. Many biological neurons are, however, known to generate a richer repertoire of spiking behaviors than can be explained in a simple integrate-and-fire model. For instance, such a model retains only an implicit (through spike-induced currents), not an explicit, memory of its input; an example of a physiological situation that cannot be explained is the absence of firing if the input current is increased very slowly. Therefore, we use an expanded model (Mihalas & Niebur, 2009 ), which is capable of generating a large number of complex firing patterns while still being linear. Linearity is important because it maintains the distribution of the random variables and still allows maximum likelihood methods to be used. In this study, we show that although convexity of the negative log-likelihood function is not guaranteed for this model, the minimum of this function yields a good estimate for the model parameters, in particular if the noise level is treated as a free parameter. Furthermore, we show that a nonlinear function minimization method (r-algorithm with space dilation) usually reaches the global minimum.