bluuebunny/crossref_metadata_2025 huggingface dataset:
Gastro-Intestinal Exposure to Latex Antigens Induce Allergic Responses in Mice
Authors: Barrios Christy S. , Kurup Viswanath P. , Rickaby David A. , Henderson Jr. James D. , Fink Jordan N. , Kelly Kevin J.
Published: August 2006

Background: Natural rubber latex (NRL) has emerged as a major cause of respiratory allergy among specific exposed groups of individuals. Since latex allergens are dispersed in the environment it is conceivable that latex proteins are both inhaled and ingested. The mechanism of latex allergy and the immune responses following reexposure of latex allergens by the intranasal route was studied in a murine model of latex allergy developed by intragastric sensitization with NRL. Methods:BALB/c mice were sensitized intragastrically (‘ig’), intranasally (‘in’) or ‘ig’ followed by ‘in’ challenge with NRL allergens. The cellular and humoral immune responses, lung function and histological changes were determined. Results: Peripheral blood eosinophilia was observed in the ‘ig’ and ‘ig/in’-NRL-sensitized animals in comparison to normal controls (p < 0.05). The ‘ig’ group showed a marked increase over control mice in serum total IgE, NRL-specific IgG and IgG subclasses (p < 0.05). Increased levels of IL-4, IL-5, IL-10, and IL-13 were detected in ‘ig’-NRL-sensitized mice. Intranasal exposure with NRL after ‘ig’ sensitization further enhanced the cytokine levels. A tendency towards enhanced stimulation was determined in ‘ig’-sensitized mice; a significant difference was shown in the ‘ig/in’-group (p < 0.05). Increased airway hyperreactivity was found in ‘ig’-NRL-sensitized-mice (15.1 ± 2.5 vs. 8.9 ± 1.7 cm H2O·ml–1·s, p < 0.05). Mucus secretion from jejunal epithelium and eosinophilic infiltration into the jejunal lamina propria were observed in the ‘ig’-NRL-sensitized-mice. Conclusions:The results demonstrate that intragastric NRL sensitization did not induce specific tolerance, and additional intranasal exposure with latex allergens resulted in systemic allergic manifestations in the murine model.
Poor Control Increases the Economic Cost of Asthma
Authors: Accordini Simone , Bugiani Massimiliano , Arossa Walter , Gerzeli Simone , Marinoni Alessandra , Olivieri Mario , Pirina Pietro , Carrozzi Laura , Dallari Rossano , De Togni Aldo , de Marco Roberto
Published: August 2006

Background/Aims: Up to now, few cost-of-illness (COI) studies have estimated the cost of adult asthma at an individual level on general population samples. We sought to evaluate the cost of current asthma from the societal perspective in young Italian adults and the determinants of cost variation. Methods: In 2000, a COI study was carried out in the frame of the Italian Study on Asthma in Young Adults on 527 current asthmatics (20–44 years) screened out of 15,591 subjects from the general population in seven centres. Detailed information about direct medical expenditures (DMEs) and indirect costs due to asthma was collected at an individual level over the past 12 months. Results: The mean annual cost per patient was EUR 741 (95% CI: 599–884). DMEs represented 42.8% of the total cost, whereas the remaining 57.2% was indirect costs. The largest component of DMEs was medication costs (47.3%; 23.0% was due to hospitalization). The mean annual cost per patient ranged from EUR 379 (95% CI: 216–541)for well-controlled asthmatics to EUR 1,341 (95% CI: 978–1,706) for poorly controlled cases that accounted for 46.2% of the total cost. Poor control, coexisting chronic cough and phlegm, and low socio-economic status were significantly associated with high DMEs and indirect costs. Conclusions: In Italy, asthma-related costs were substantial even in unselected patients and were largely driven by indirect costs. Since about half of the total cost was due to a limited proportion of poorly controlled asthmatics, interventions aimed at these high-cost patients could reduce the economic burden of the disease.
Beta-Adrenoceptor Blockade Markedly Attenuates Transgene Expression From Cytomegalovirus Promoters Within the Cardiovascular System
Authors: Salem Husein K. , Ranjzad Parisa , Driessen Anita , Appleby Clare E. , Heagerty Anthony M. , Kingston Paul A.
Published: August 2006

Objectives—

The major immediate–early cytomegalovirus enhancer/promoter (MIECMV), widely used in cardiovascular gene therapy, contains several positively regulatory cAMP response elements (CRE). Catecholamine signaling via β-adrenoceptors might increase transgene expression from MIECMV, and if so, β-blockers may have a detrimental effect on the efficacy of clinical cardiovascular gene therapy strategies.

Methods and Results—

Cultured smooth muscle cells were exposed to isoprenaline, atenolol, or propranolol, alone and in combination before infection with adenoviruses expressing β-galactosidase. β-galactosidase expression was assayed 72 hours later. Isoprenaline increased transgene expression from MIECMV up to 8-fold (
P
<0.001), but had no effect on a promoter containing no CRE. The effect of isoprenaline was inhibited by β-blockade and by specific CRE-decoy oligonucleotides. β-blockers did not reduce transgene expression below basal levels. After adenovirus-mediated porcine intracoronary gene transfer, however, β-blockade reduced β-galactosidase expression by up to 250-fold compared with non-β-blocked animals (
P
<0.01).

Conclusions—

Enhancement of promoter activity by endogenous catecholamines is essential for high-level transgene expression from MIECMV within the vasculature. β-blocker-mediated suppression of transgene expression from MIECMV in vascular tissues has a significant bearing on clinical studies of cardiovascular gene transfer. This is the first described interaction to our knowledge between widely prescribed pharmaceuticals and a commonly used promoter of clinical transgene expression.
Impaired Development of Atherosclerosis in Hyperlipidemic
Ldlr
−/−
and
ApoE
−/−
Mice Transplanted With
Abcg1
−/−
Bone Marrow
Authors: Baldán Ángel , Pei Liming , Lee Richard , Tarr Paul , Tangirala Rajendra K. , Weinstein Michael M. , Frank Joy , Li Andrew C. , Tontonoz Peter , Edwards Peter A.
Published: August 2006

Objective—

The lungs of
Abcg1
−/−
mice accumulate macrophage foam cells that contain high levels of unesterified and esterified cholesterol, consistent with a role for ABCG1 in facilitating the efflux of cholesterol from macrophages to high-density lipoprotein (HDL) and other exogenous sterol acceptors. Based on these observations, we investigated whether loss of ABCG1 affects foam cell deposition in the artery wall and the development of atherosclerosis.

Methods and Results—

Bone marrow from wild-type or
Abcg1
−/−
mice was transplanted into
Ldlr
−/−
or
ApoE
−/−
mice. After administration of a high-fat/high-cholesterol diet, plasma and tissue lipid levels and atherosclerotic lesion size were quantified and compared. Surprisingly, transplantation of
Abcg1
−/−
bone marrow cells resulted in a significant reduction in lesion size in both mouse models, despite the fact that lipid levels increased in the lung, spleen, and kidney. Lesions of
Ldlr
−/−
mice transplanted with
Abcg1
−/−
cells contained increased numbers of apoptotic cells. Consistent with this observation, in vitro studies demonstrated that
Abcg1
−/−
macrophages were more susceptible to oxidized low-density lipoprotein (ox-LDL)-dependent apoptosis than
Abcg1
+/+
cells.

Conclusions—

Diet-induced atherosclerosis is impaired when atherosclerotic-susceptible mice are transplanted with
Abcg1
−/−
bone marrow. The demonstration that
Abcg1
−/−
macrophages undergo accelerated apoptosis provides a mechanism to explain the decrease in the atherosclerotic lesions.
Regionalized Sequence of Myocardial Cell Growth and Proliferation Characterizes Early Chamber Formation
Authors: Soufan Alexandre T. , van den Berg Gert , Ruijter Jan M. , de Boer Piet A.J. , van den Hoff Maurice J.B. , Moorman Antoon F.M.
Published: August 2006

Increase in cell size and proliferation of myocytes are key processes in cardiac morphogenesis, yet their regionalization during development of the heart has been described only anecdotally. We have made quantitative reconstructions of embryonic chicken hearts ranging in stage from the fusion of the heart-forming fields to early formation of the chambers. These reconstructions reveal that the early heart tube is recruited from a pool of rapidly proliferating cardiac precursor cells. The proliferation of these small precursor cells ceases as they differentiate into overt cardiomyocytes, producing a slowly proliferating straight heart tube composed of cells increasing in size. The largest cells were found at the ventral side of the heart tube, which corresponds to the site of the forming ventricle, as well as the site where proliferation is reinitiated. The significance of these observations is 2-fold. First, they support a model of early cardiac morphogenesis in 2 stages. Second, they demonstrate that regional increase in size of myocytes contributes significantly to chamber formation.
FHL2/SLIM3 Decreases Cardiomyocyte Survival by Inhibitory Interaction With Sphingosine Kinase-1
Authors: Sun Jianxin , Yan Guijun , Ren Aixia , You Bei , Liao James K.
Published: August 2006

Sphingosine kinase-1 (SK1) is a key enzyme catalyzing the phosphorylation of sphingosine to sphingosine-1–phosphate (S1P). Recent studies suggest that SK1, and its product S1P, regulate diverse biological functions, including cell growth, differentiation, proliferation, and apoptosis. S1P may also play an important role in cardiac development and ischemic preconditioning, but the mechanism underlying these effects is not known. Using a yeast 2-hybrid screen with SK1 as bait and a cardiac cDNA library to identify novel proteins involved in regulating SK1 activity in cardiomyocytes, we identified the LIM-only factor FHL2 (SLIM3) as a SK1-interacting protein in both yeast and mammalian cells. FHL2, but not FHL1 or FHL3, interacted with SK1, and FHL2 colocalized with SK1 in the cytoplasm. The interaction sites with SK1 consisted of at least 4 LIM domains in FHL2, whereas the C-terminal portion of SK1 mediates the binding of FHL2 in SK1. Overexpression of FHL2 attenuated the activity and antiapoptotic effects of SK1. Indeed, endothelin-1, which is a potent survival factor in cardiomyocytes, inhibited FHL2-SK1 association and increased SK1 activity. These findings indicate that FHL2 is a novel inhibitor of SK1 activity in cardiomyocytes and suggest that targeting FHL2 for inhibition may prevent myocardial apoptosis through activation of SK1.
Incidence of New Brain Lesions After Carotid Stenting With and Without Cerebral Protection
Authors: Kastrup Andreas , Nägele Thomas , Gröschel Klaus , Schmidt Friederike , Vogler Eva , Schulz Jörg , Ernemann Ulrike
Published: August 2006

Background and Purpose—

Diffusion-weighted imaging (DWI) may be a useful tool to evaluate the efficacy of cerebral protection devices in preventing thromboembolic complications during carotid angioplasty and stenting (CAS). The goals of this study were (1) to compare the frequency, number, and size of new DWI lesions after unprotected and protected CAS; and (2) to determine the clinical significance of these lesions.

Methods—

DWI was performed immediately before and within 48 hours after unprotected or protected CAS. Clinical outcome measures were stroke and death within 30 days.

Results—

The proportion of patients with any new ipsilateral DWI lesion (49% versus 67%;
P
<0.05) as well as the number of new ipsilateral DWI lesions (median=0; interquartile range [IQR]=0 to 3 versus median=1; IQR=0 to 4;
P
<0.05) were significantly lower after protected (n=139) than unprotected (n=67) CAS. The great majority of these lesions were asymptomatic and less than 10 mm in diameter. Although there were no significant differences in clinical outcome between patients treated and not treated with protection devices (7.5% versus 4.3%, not significant), the number of new DWI lesions was significantly higher in patients who developed a stroke (median=7.5; IQR=1.5 to 17) than in patients who did not (median=0; IQR=1 to 3.25;
P
<0.01).

Conclusions—

The use of cerebral protection devices significantly reduces the incidence of new DWI lesions after CAS of which the majority are asymptomatic and less than 10 mm in diameter. The frequent occurrence of these lesions and their close correlation with the clinical outcome indicates that DWI could become a sensitive surrogate end point in future randomized trials of unprotected versus protected CAS.
Dental and Periodontal Status and Risk for Progression of Carotid Atherosclerosis
Authors: Schillinger Thomas , Kluger Wolf , Exner Markus , Mlekusch Wolfgang , Sabeti Schila , Amighi Jasmin , Wagner Oswald , Minar Erich , Schillinger Martin
Published: August 2006

Background and Purpose—

Dental and periodontal disease are potentially involved in the pathogenesis of atherosclerosis. We investigated whether dental and periodontal status is associated with the presence and future progression of carotid stenosis.

Methods—

We randomly selected 411 of 1268 participants from the prospective Inflammation and Carotid Artery Risk for Atherosclerosis Study and evaluated dental and periodontal status and oral hygiene at baseline measuring three World Health Organization-validated indices: DMFT (decayed, missing, filled teeth), SLI (Silness-Löe Index), and CPITN (community periodontal index for treatment needs), respectively. The degree of carotid stenosis was measured by duplex ultrasound at baseline and after median 7.5 months (range=6 to 9 months) to identify patients with progressive carotid stenosis.

Results—

DMFT (
P
<0.01), SLI (
P
=0.048), CPITN (
P
=0.007), and edentulousness (
P
=0.007) were associated with the baseline degree of carotid stenosis. Atherosclerosis progression was observed in 48 of 411 patients (11.7%). DMFT (adjusted odds ratio [OR]=1.11, 95% CI=1.01 to 1.22,
P
=0.032) and SLI (adjusted OR=1.77, 95% CI=1.09 to 2.79,
P
=0.021), but not CPITN (adjusted OR=1.51, 95% CI=0.89 to 2.45,
P
=0.16) were significant predictors of disease progression, irrespective of traditional cardiovascular risk factors and the baseline degree of stenosis. Edentulous patients had a significantly increased risk for disease progression as compared with patients with teeth (adjusted OR=2.10, 95% CI=1.06 to 4.16,
P
=0.33).

Conclusion—

Dental status, oral hygiene, and particularly tooth loss are associated with the degree of carotid stenosis and predict future progression of the disease.
Thyroid Autoimmunity and Spontaneous Cervical Artery Dissection
Authors: Pezzini Alessandro , Del Zotto Elisabetta , Mazziotti Gherardo , Ruggeri Giuseppina , Franco Fabio , Giossi Alessia , Giustina Andrea , Padovani Alessandro
Published: August 2006

Background and Purpose—

The possibility that a disorder of immunity might have a role in the mechanism of local inflammatory alterations leading to spontaneous cervical artery dissection (sCAD) has been recently advocated.

Methods—

We explored this hypothesis in a case-control study, including patients with sCAD (n=29) and patients with non-CAD ischemic stroke (non-CAD; n=29). Serum levels of antithyroperoxidase, antithyroglobulin, and antithyroid-stimulating hormone receptor antibodies, antinuclear antibodies, antineutrophil cytoplasmic antibodies, antidouble-stranded deoxyribonucleic acid antibodies, antiextractable nuclear antigen antibodies, rheumatoid factor, C3 and C4 complement fraction, and cryoglobulins were measured in all subjects.

Results—

Antithyroid autoimmunity was found in 31.0% (9 of 29) of patients with sCAD and 6.9% (2 of 29) of patients with non-CAD ischemic stroke (
P
=0.041).

Conclusions—

Autoimmunity may be involved in the process of local inflammation related to sCAD occurrence. The hypothesis that the arterial disease might be one phenotypic expression of a generalized activation of immunity warrants further investigations.
Severe Sleep Apnea and Risk of Ischemic Stroke in the Elderly
Authors: Munoz Roberto , Duran-Cantolla Joaquín , Martínez-Vila Eduardo , Gallego Jaime , Rubio Ramón , Aizpuru Felipe , De La Torre Germán
Published: August 2006

Background and Purpose—

Convincing evidence of a causal relationship between sleep apnea and stroke has been shown recently in several prospective, well-designed studies. However, these studies have focused on middle-aged people, excluding the elderly population from analysis. To investigate whether sleep apnea represents an independent risk factor in this population, we performed a prospective longitudinal study in a population-based cohort of subjects from 70 to 100 years old.

Methods—

Within the context of the Vitoria Sleep Project, a population-based study designed to investigate the prevalence of sleep apnea in the population of Vitoria, Spain, we performed a 6-year longitudinal study in a subsample cohort of 394 noninstitutionalized, initially event-free subjects (70 to 100 years old, median 77.28 years, 57.1% males). Demographic and polysomnographic data and known confounding factors (age, sex, smoking and alcohol consumption status, body mass index, systolic and diastolic blood pressure, total serum cholesterol levels, and the presence or absence of diabetes mellitus, atrial fibrillation, and hypertension) were assessed at baseline. Hazard ratio for developing an ischemic stroke in relation to the apnea-hypopnea index at baseline was calculated.

Results—

Over the 6-year follow-up period, 20 ischemic strokes were registered. After adjustment for confounding factors, subjects with severe obstructive sleep apnea hypopnea (defined as apnea-hypopnea index ≥30) at baseline had an increased risk of developing a stroke (hazard ratio=2.52, 95% CI=1.04 to 6.01,
P
=0.04).

Conclusions—

This study shows that severe obstructive sleep apnea hypopnea (defined as apnea-hypopnea index ≥30) increases the risk of ischemic stroke in the elderly population, independent of known confounding factors.
Candesartan- and Atenolol-Based Treatments Induce Different Patterns of Carotid Artery and Left Ventricular Remodeling in Hypertension
Authors: Ariff Ben , Zambanini Andrew , Vamadeva Sarita , Barratt Dean , Xu Yun , Sever Peter , Stanton Alice , Hughes Alun , Thom Simon
Published: August 2006

Background and Purpose—

Angiotensin receptor blocker (ARB)–based treatment reduces cardiovascular events and stroke more than does β-blocker-based treatment despite similar blood pressure (BP) reduction. We investigated whether these treatments have different effects on cardiac and large-artery remodelling and evaluated the relation of arterial remodelling to hemodynamic changes in subjects with hypertension.

Methods—

We compared the treatment effects of an ARB (candesartan cilexetil)-based regimen and a β-blocker (atenolol)–based regimen for 52 weeks on common carotid artery (CCA) and left ventricular structure in hypertensive patients in a randomized, double-blind study. Clinic brachial BP and 24-hour ambulatory BP, carotid BP, left ventricular mass index, CCA intima-media thickness, lumen diameter, intima-media area, and carotid blood flow were measured. Distensibility, circumferential tensile stress, Young’s elastic modulus (E
m
), and shear stress (τ) in the CCA were also calculated.

Results—

Both candesartan and atenolol reduced intima-media thickness and intima-media area and increased distensibility to similar extents after 52 weeks of treatment. Despite similar reductions in BP, treatment with atenolol resulted in a lesser reduction in left ventricular mass index, a decrease in lumen diameter, and a reduction in carotid blood flow compared with candesartan.

Conclusions—

BP-independent effects of ARB on cardiac and arterial structure may contribute to the beneficial effects of these agents on cardiovascular disease.
Randomized Controlled Trial of Acetylsalicylic Acid in Aneurysmal Subarachnoid Hemorrhage
Authors: van den Bergh Walter M.
Published: August 2006

Background and Purpose—

A previous systematic review of randomized trials suggested a positive effect of antiplatelet therapy in patients with aneurysmal subarachnoid hemorrhage (SAH). We performed a randomized controlled trial to assess whether acetylsalicylic acid (ASA) reduces the risk of delayed ischemic neurological deficit (DIND) in patients with SAH.

Methods—

Criteria for inclusion were aneurysm treatment within 4 days after SAH. Trial medication (14 daily suppositories with 100 mg ASA or placebo) was started within 12 hours after aneurysm treatment. Analysis for the primary outcome event DIND was made according to the “on-treatment” principle and for the secondary outcome measures “poor outcome” and “nonexcellent outcome” according to the “intention-to-treat” principle.

Results—

Inclusion was stopped after the second interim analysis, when 161 of the planned 200 patients were included, because by then the chances of a positive effect were negligible. At the final analysis, ASA did not reduce the risk of DIND (hazard ratio, 1.83; 95% CI, 0.85 to 3.9). The relative risk reduction for poor outcome was 21% (relative risk, 0.79; 95% CI, 0.38 to 1.6).

Conclusions—

ASA given after aneurysm treatment does not appreciably reduce the occurrence of DIND.
Sex-Based Differences in the Effect of Intra-Arterial Treatment of Stroke
Authors: Hill Michael D. , Kent David M. , Hinchey Judith , Rowley Howard , Buchan Alastair M. , Wechsler Lawrence R. , Higashida Randall T. , Fischbein Nancy J. , Dillon William P. , Gent Michael , Firszt Carolyn M. , Schulz Gregory A. , Furlan Anthony J.
Published: August 2006

Background and Purpose—

Sex influences outcome after intravenous thrombolysis. In a combined analysis of the tissue plasminogen activator clinical trials, a sex-by-treatment interaction was observed. We sought to confirm that observation in an independent data set.

Methods—

Data were from the Pro-Urokinase for Acute Cerebral Thromboembolism-2 (PROACT-2) trial. Baseline factors were compared by sex. The primary outcome was an assessment of a sex-by-treatment interaction term within a logistic regression model, using a modified Rankin Scale score ≤2 at 90 days as the binary outcome. We also assessed whether there were differences in CT-scan appearance and recanalization at 2 hours post-treatment.

Results—

In the PROACT-2 study of intra-arterial stroke thrombolysis, in both women and men, prourokinase resulted in better outcomes than control. A sex by prourokinase treatment interaction was observed, with women showing a larger treatment effect (20% absolute benefit) compared with men (10% absolute benefit). The reason for this interaction is that thrombolytic treatment nullifies the worse outcome for untreated women compared with men. The reasons for effect modification do not include improved recanalization at 2 hours among women.

Conclusions—

Women with middle cerebral artery ischemic stroke benefit more from intra-arterial therapy. Further study of how sex affects stroke outcome is needed.
Tandem Internal Carotid Artery/Middle Cerebral Artery Occlusion
Authors: Rubiera Marta , Ribo Marc , Delgado-Mederos Raquel , Santamarina Esteban , Delgado Pilar , Montaner Joan , Alvarez-Sabín José , Molina Carlos A.
Published: August 2006

Background and Purpose—

Although tandem internal carotid artery/middle cerebral artery (MCA; TIM) occlusion has been associated with low recanalization rate after IV tissue plasminogen activator (tPA), its independent contribution on stroke outcome remains unknown. Moreover, whether the relative resistance to thrombolysis in tandem lesions varies depending on the location of MCA clot remains uncertain.

Methods—

Two hundred and twenty-one consecutive stroke patients with an acute MCA occlusion treated with IV tPA were studied. Emergent carotid artery ultrasound and transcranial Doppler (TCD) examinations were performed in all patients before treatment. Recanalization was assessed on TCD at 2 hours of tPA bolus. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and after 24 hours. Modifed Rankin Scale score was used to assess outcome at 3 months.

Results—

Median prebolus NIHSS score was 16 points. On TCD, 156 (71.6%) patients had a proximal and 65 (29.4%) a distal MCA occlusion. TIM occlusion was identified in 44 (19.9%) patients. Eighteen (41.9%) patients with and 123 (69.5%) without TIM lesions achieved an MCA recanalization (
P
=0.01). In a logistic regression model, hyperglycemia >140 mg/dL (odds ratio [OR] 3.3, 95% CI, 1.6 to 6.8) and the presence of TIM occlusion (OR 2.8, 95% CI, 1.1 to 6.9) emerged as independent predictors of absence of recanalization. However, the independent contribution of TIM lesions on poor response to thrombolysis varied depending on the location of MCA occlusion. TIM occlusion independently predicted resistance to thrombolysis in patients with proximal (OR 4.63, 95% CI, 1.79 to 11.96), but not in those with distal MCA occlusion. Patients with TIM occlusion had worse short- (
P
<0.0001) and long-term (
P
<0.0001) clinical outcome.

Conclusions—

TIM occlusion independently predicts poor outcome after IV thrombolysis. However, its impact varies depending on the location of MCA clot. Therefore, emergent carotid ultrasound plus TCD examinations may improve the selection of patients for more aggressive reperfusion strategies.
Plaque Echolucency Is Not Associated With the Risk of Stroke in Carotid Stenting
Authors: Reiter Markus , Bucek Robert A. , Effenberger Isabella , Boltuch Johanna , Lang Wilfried , Ahmadi Ramazanali , Minar Erich , Schillinger Martin
Published: August 2006

Background and Purpose—

Plaque characteristics are suggested to play a potentially important role as risk factors for poor outcome after carotid artery stenting (CAS). We therefore correlated objectively and subjectively determined carotid plaque morphology with neurological complications after CAS.

Methods—

We enrolled 698 consecutive patients undergoing elective CAS from a prospective single-center registry database and classified the preinterventional plaque status according to gray-scale median levels and the standardized Beletsky and Gray-Weale plaque scores. Patients were followed for 30-day neurological complications.

Results—

Neurological complications including transient ischemic attack, minor and major stroke occurred in 5.9% (41/698) of the patients. Median gray-scale median, Beletsky and Gray-Weale scores were 45 (interquartile range [IQR] 25 to 70), 3.0 (IQR 2.0 to 3.0) and 2.0 (IQR 2.0 to 3.0), respectively. None of the scores was significantly associated with adverse outcome adjusting for traditional risk factors, medication, preinterventional symptoms, degree of stenosis, contralateral occlusion and use of cerebral protection, neither with respect to all neurological complications nor with respect to stroke and death (all
P
>0.05).

Conclusions—

Plaque echolucency measured by objective and subjective grading did not identify patients with an increased risk of peri-interventional neurological events. Evaluation of plaque echolucency therefore cannot be recommended for risk stratification in CAS patients.
Prolonged bleeding-free period following prophylactic infusion of recombinant factor VIII reconstituted with pegylated liposomes
Authors: Spira Jack , Plyushch Olga P. , Andreeva Tatyana A. , Andreev Yury
Published: August 2006

Prophylactic treatment for hemophilia A involves infusion of factor VIII (FVIII) concentrates every 2 to 3 days. Liposomes can be efficacious vehicles for medicines, and surface modification by PEGylation can prolong liposome circulation time. When reconstituted with PEGylated liposomes (PEGLip's), recombinant FVIII binds noncovalently but with high affinity to the external liposome surface. This preparation showed prolongation of FVIII half-life and increased protection from bleeding in preclinical models. Here we report a blinded, controlled, crossover, multicenter clinical study that evaluated the time free from bleeding episodes in patients with hemophilia A during prophylaxis with standard rFVIII (no liposomes) or PEGLip rFVIII (PEGLip reconstituted) at 25 and 35 IU/kg doses. Of 24 enrolled patients, 23 were eligible for efficacy analysis. Mean number of days without bleeds was 7.2 ± 1.7 with standard rFVIII compared with 13.3 ± 4.8 with PEGLip rFVIII at the 35 IU/kg dose and 5.9 ± 1.7 with standard rFVIII versus 10.9 ± 2.9 with PEGLip rFVIII at the 25 IU/kg dose (P < .05 between treatment groups for each dose). PEGLip rFVIII was well tolerated. These data suggest that reconstitution of rFVIII with PEGLip's may reduce the frequency of treatment during prophylaxis.
Humoral immunity is the dominant barrier for allogeneic bone marrow engraftment in sensitized recipients
Authors: Xu Hong , Chilton Paula M. , Tanner Michael K. , Huang Yiming , Schanie Carrie L. , Dy-Liacco Mariano , Yan Jun , Ildstad Suzanne T.
Published: August 2006

We evaluated the relative contribution of the humoral and cellular arms of the immune response to bone marrow cells transplanted into sensitized recipients. We report here for the first time that humoral immunity contributes predominantly to allosensitization. Although the major role for nonmyeloablative conditioning is to control alloreactive host T cells in nonsensitized recipients, strikingly, none of the strategies directed primarily at T-cell alloreactivity enhanced engraftment in sensitized mice. In evaluating the mechanism behind this barrier, we found that humoral immunity plays a critical role in the rejection of allogeneic marrow in sensitized recipients. Adoptive transfer of as little as 25 μL serum from sensitized mice abrogated engraftment in secondary naive recipients. With the use of μMT mice as recipients, we found that T-cell-mediated immunity plays a secondary but still significant role in allorejection. Targeting of T cells in sensitized B-cell-deficient μMT mice enhanced alloengraftment. Moreover, both T- and B-cell tolerance were achieved in sensitized recipients when allochimerism was established, as evidenced by the acceptance of second donor skin grafts and loss of circulating donor-specific Abs. These findings have important implications for the management of sensitized transplant recipients and for xenotransplantation in which B-cell reactivity is a predominant barrier.
Differential effects of recombinant thrombopoietin and bone marrow stromal-conditioned media on neonatal versus adult megakaryocytes
Authors: Pastos Karen M. , Slayton William B. , Rimsza Lisa M. , Young Linda , Sola-Visner Martha C.
Published: August 2006

Umbilical cord blood (CB) is a valuable source of stem cells for transplantation, but CB transplantations are frequently complicated by delayed platelet engraftment. The reasons underlying this are unclear. We hypothesized that CB- and peripheral-blood (PB)–derived megakaryocytes (MKs) respond differently to the adult hematopoietic microenvironment and to thrombopoietin (Tpo). To test this, we cultured CB- and PB-CD34+ cells in adult bone marrow stromal conditioned media (CM) or unconditioned media (UCM) with increasing concentrations of recombinant Tpo and compared the effects of these conditions on CB-versus PB-MKs. PB-MKs reached highest ploidy in response to UCM + 100 ng/mL rTpo, and the addition of CM inhibited their maturation. In contrast, CB-MKs reached highest ploidy in CM without rTpo, and high rTpo concentrations (> 0.1 ng/mL) inhibited their maturation. This is the first evidence that human neonatal and adult MKs have substantially different biologic responses to Tpo and potentially to other cytokines.
AML1/Runx1 rescues Notch1-null mutation-induced deficiency of para-aortic splanchnopleural hematopoiesis
Authors: Nakagawa Masahiro , Ichikawa Motoshi , Kumano Keiki , Goyama Susumu , Kawazu Masahito , Asai Takashi , Ogawa Seishi , Kurokawa Mineo , Chiba Shigeru
Published: August 2006

The Notch1-RBP-Jκ and the transcription factor Runx1 pathways have been independently shown to be indispensable for the establishment of definitive hematopoiesis. Importantly, expression of Runx1 is down-regulated in the para-aortic splanchnopleural (P-Sp) region of Notch1- and Rbpsuh-null mice. Here we demonstrate that Notch1 up-regulates Runx1 expression and that the defective hematopoietic potential of Notch1-null P-Sp cells is successfully rescued in the OP9 culture system by retroviral transfer of Runx1. We also show that Hes1, a known effector of Notch signaling, potentiates Runx1-mediated transactivation. Together with the recent findings in zebrafish, Runx1 is postulated to be a cardinal down-stream mediator of Notch signaling in hematopoietic development throughout vertebrates. Our findings also suggest that Notch signaling may modulate both expression and transcriptional activity of Runx1.
Negative regulation of primitive hematopoiesis by the FGF signaling pathway
Authors: Nakazawa Fumie , Nagai Hiroki , Shin Masahiro , Sheng Guojun
Published: August 2006

Hematopoiesis is controlled by multiple signaling molecules during embryonic and postnatal development. The function of the fibroblast growth factor (FGF) pathway in this process is unclear. Here we show that FGF plays a key role in the regulation of primitive hematopoiesis in chicks. Using hemoglobin mRNA expression as a sensitive marker, we demonstrate that timing of blood differentiation can be separated from that of initial mesoderm patterning and subsequent migration. High FGF activity inhibits primitive blood differentiation and promotes endothelial cell fate. Conversely, inhibition of FGFR activity leads to ectopic blood formation and down-regulation of endothelial markers. Expression and functional analyses indicate that FGFR2 is the key receptor mediating these effects. The FGF pathway regulates primitive hematopoiesis by modulating Gata1 expression level and activity. We propose that the FGF pathway mediates repression of globin gene expression and that its removal is essential before terminal differentiation can occur.
An inventory of mucin genes in the chicken genome shows that the mucin domain of Muc13 is encoded by multiple exons and that ovomucin is part of a locus of related gel-forming mucins
Authors: Lang Tiange , Hansson Gunnar C , Samuelsson Tore
Published: August 2006

Background

Mucins are large glycoproteins that cover epithelial surfaces of the body. All mucins contain at least one PTS domain, a region rich in proline, threonine and serine. Mucins are also characterized by von Willebrand D (VWD) domains or SEA domains. We have developed computational methods to identify mucin genes and proteins based on these properties of the proteins. Using such methods we are able to characterize different organisms where genome sequence is available with respect to their mucin repertoire.

Results

We have here made a comprehensive analysis of potential mucins encoded by the chicken (Gallus gallus) genome. Three transmembrane mucins (Muc4, Muc13, and Muc16) and four gel-forming mucins (Muc6, Muc2, Muc5ac, and Muc5b) were identified. The gel-forming mucins are encoded within a locus similar to the corresponding human mucins. However, the chicken has an additional gene inserted between Muc2 and Muc5ac that encodes the the α-subunit of ovomucin, a protein similar to Muc2, but it is lacking a PTS domain. We also show that the β-subunit of ovomucin is the orthologue of human MUC6. The transmembrane Muc13 gene is in chicken as well as in mammals adjacent to the HEG (heart of glass) gene. HEG has PTS, EGF and transmembrane domains like Muc13, suggesting that these two proteins are evolutionary related. Unlike previously known mucins, the PTS domain of Muc13 is encoded by multiple exons, where each exon encodes a repeat unit of the PTS domain.

Conclusion

We report new mucin homologues in chicken and this information will aid in understanding the evolution of mucins in vertebrates. The fact that ovomucin, a protein not found in mammals, was located in the same locus as other gel-forming mucins provides strong support that these proteins are evolutionary related. Furthermore, a relationship of HEG and the transmembrane Muc13 is suggested on the basis of their biochemical properties and their presence in the same locus. Finally, our finding that the chicken Muc13 is distributed between multiple exons raises the interesting possibility that the length of the PTS domain could be controlled by alternative splicing.
Normal hematopoiesis after conditional targeting of RXRα in murine hematopoietic stem/progenitor cells
Authors: Ricote Mercedes , Snyder Cynthia S , Leung Ho-Yin , Chen Ju , Chien Kenneth R , Glass Christopher K
Published: August 2006

Because of the retinoic acid receptor-α (RARα) gene’s involvement in acute promyelocytic leukemia, the important role of RARs in hematopoiesis is now well established. However, relatively few studies of hematopoiesis have focused on the role of the retinoid X receptors (RXRs), the obligate heterodimeric partners of the RARs. We sought to establish whether conditional targeting of RXRα in early hematopoietic progenitors, ideally to the level of the hematopoietic stem cell (HSC), would compromise hematopoiesis. For hematopoietic targeting of RXRα, we characterized IFN-inducible MxCre mice for use in studying the role of RXRα in hematopoiesis. We established that MxCre executes recombination of loxP-flanked RXRα in hematopoietic progenitors immunophenotypically enriched for HSC, leading to widespread and sustained targeting of RXRα in hematopoietic cells. However, we found no evidence of hematologic compromise in mice lacking RXRα, suggesting that RXRα is dispensable for normal murine hematopoiesis. Nonetheless, RXRα null bone marrow cells cultured in methylcellulose form colonies more efficiently than bone marrow cells obtained from control mice. This result suggests that although RXRα is not required for murine hematopoiesis, there may be hematopoietic signaling pathways that respond selectively to RXRα or settings in which combined expression of RXR (α, β, and γ) is limiting.
The bone marrow constitutes a reservoir of pericyte progenitors
Authors: Lamagna Chrystelle , Bergers Gabriele
Published: August 2006

Adult bone marrow is a rich reservoir of hematopoietic and mesenchymal stem and progenitor cells. Mobilization and recruitment of bone marrow-derived cells to injured or ischemic tissue or tumors endorse the initiation and maintenance of angiogenic processes in the adult by incorporating endothelial progenitor cells (EPC) into the developing vasculature and by recruiting accessory hematopoietic cells. Recent data have now revealed that the origin of bone marrow-derived vascular cells is not restricted to endothelial cells but also includes pericytes—the perivascular support cells. Several laboratories have now reported the existence of pericyte progenitor cells, and these cells, like EPC, can be mobilized and recruited to the remodeling vasculature under ischemic conditions and in tumors. This review focuses on pericytes in vessel formation and on recent discoveries about their bone marrow origin in the adult.
Identification and characterization of a human monoclonal antagonistic antibody AL-57 that preferentially binds the high-affinity form of lymphocyte function-associated antigen-1
Authors: Huang Lili , Shimaoka Motomu , Rondon Isaac J , Roy Illa , Chang Qing , Po Melody , Dransfield Daniel T , Ladner Robert C , Edge Albert S B , Salas Azucena , Wood Clive R , Springer Timothy A , Cohen Edward H
Published: August 2006

LFA-1 (αLβ2) mediates cell-cell and cell-extracellular matrix adhesions essential for immune and inflammatory responses. One critical mechanism regulating LFA-1 activity is the conformational change of the ligand-binding αL I domain from low-affinity (LA), closed form, to the high-affinity (HA), open form. Most known integrin antagonists bind both forms. Antagonists specific for the HA αL I domain have not been described. Here, we report the identification and characterization of a human antibody AL-57, which binds to the αL I domain in a HA but not LA conformation. AL-57 was discovered by selection from a human Fab-displaying library using a locked-open HA I domain as target. AL-57 Fab-phage bound HA I domain-expressing K562 cells (HA cells) in a Mg2+-dependent manner. AL-57 IgG also bound HA cells and PBMCs, activated by Mg2+/EGTA, PMA, or DTT. The binding profile of AL-57 IgG on PBMCs was the same as that of ICAM-1, the main ligand of LFA-1. In contrast, an anti-αL murine mAb MHM24 did not distinguish between the HA and LA forms. Moreover, AL-57 IgG blocked ICAM-1 binding to HA cells with a potency greater than MHM24. It also inhibited ICAM-1 binding to PBMCs, blocked adhesion of HA cells to keratinocytes, and inhibited PHA-induced lymphocyte proliferation with potencies comparable with MHM24. These results indicate that specifically targeting the HA I domain is sufficient to inhibit LFA-1-mediated, adhesive functions. AL-57 represents a therapeutic candidate for treatment of inflammatory and autoimmune diseases.
A selective small molecule agonist of the melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice
Authors: Kang Liya , McIntyre Kim W , Gillooly Kathleen M , Yang Yifan , Haycock John , Roberts Stephen , Khanna Ashish , Herpin Timothy F , Yu Guixue , Wu Ximao , Morton George C , Tuerdi Huji , Koplowitz Barry , Walker Stephen G , Wardwell-Swanson Judy , Macor John E , Lawrence R Michael , Carlson Kenneth E
Published: August 2006

It is well established that melanocortins are peptides that have potent anti-inflammatory activity. Recent research has focused on understanding which of the known melanocortin receptors mediates the anti-inflammatory actions of the melanocortins. The aim of this study was to assess the anti-inflammatory activity of a synthetic MC-1R agonist. BMS-470539 is a potent, selective, full agonist of human and murine MC-1R with EC50 values in a cAMP accumulation assay of 16.8 and 11.6 nM, respectively. BMS-470539 dose-dependently inhibited TNF-α-induced activation of a NF-κB transcriptional reporter in human melanoma cells, which endogenously express MC-1R. In vivo studies with BMS-470539 demonstrated that subcutaneous administration of BMS-470539 resulted in a dose-dependent inhibition of LPS-induced TNF-α production in BALB/c mice. In this model, the compound had an ED50 of approximately 10 μmol/kg and a pharmacodynamic half-life of ∼8 h. Pharmacokinetic analysis of the compound indicated that the compound had a t1/2 of 1.7 h. In a model of lung inflammation, administration of 15 μmol/kg BMS-470539 resulted in a 45% reduction in LPS-induced leukocyte infiltration (an infiltrate comprised primarily of neutrophils). The compound was also effective in a model of delayed-type hypersensitivity, reducing paw swelling by 59%, comparable with that seen with 5 mg/kg dexamethasone. These studies demonstrate that a selective small molecule agonist of the melanocortin-1 receptor is a potent anti-inflammatory agent in vivo and provides compelling evidence for the involvement of this receptor in the modulation of inflammation.
Glucocorticoid Up-Regulates Transforming Growth Factor-β (TGF-β) Type II Receptor and Enhances TGF-β Signaling in Human Prostate Cancer PC-3 Cells
Authors: Li Zongbin , Chen Yuxia , Cao Dongmei , Wang Yan , Chen Guangchun , Zhang Shimin , Lu Jian
Published: August 2006

Previous studies have shown that dexamethasone (Dex) induces the expression of TGF-β1 in androgen-independent prostate cancer both in vitro and in vivo. However, it is not clear whether Dex has a direct effect on the expression of TGF-β receptors. In this study, using the androgen-independent human prostate cancer cell line, PC-3 cells, we demonstrated that Dex increased the expression of TGF-β receptor type II (TβRII), but not TGF-β receptor type I (TβRI) in a time- and dose-dependent manner. The up-regulation of TβRII expression by Dex was mediated by glucocorticoid receptor and occurred at the transcriptional level. Dex also enhanced TGF-β1 signaling and increased the expression of cyclin-dependent kinase inhibitors p15INK4B (p15) and p27KIP1 (p27), which are the target genes of TGF-β1 and have been identified as inducers of cell cycle arrest at the G1 checkpoint. The antiproliferative effect of Dex was partially blocked by anti-TβRII antibody, indicating that elevated TβRII and TGF-β1 signaling were involved in the antiproliferative effect of Dex. Because the TGF-β1 pathway could not fully explain the antiproliferative effect of Dex, we further examined the effects of Dex on the transcriptional activity of nuclear factor-κB (NF-κB) and the expression of IL-6 and found that Dex suppressed the transcriptional activity of NF-κB and IL-6 mRNA expression in PC-3 cells. These results demonstrated that glucocorticoid inhibited the proliferation of PC-3 cells not only through enhancing growth-inhibitory TGF-β1 signaling, but also through suppressing transcriptional activities of NF-κB.
Orphanin FQ/Nociceptin Is a Physiological Regulator of Prolactin Secretion in Female Rats
Authors: Chesterfield Matthew , Janik James , Murphree Emily , Lynn Courtney , Schmidt Erin , Callahan Phyllis
Published: August 2006

Orphanin FQ/nociceptin (OFQ/N), the most recently identified endogenous opioid peptide, stimulates prolactin secretion in both male and female rats. OFQ/N, however, did not elicit this stimulatory effect through the μ-, δ-, or κ-opiate receptor subtype. The role OFQ/N plays in prolactin regulation under physiological conditions and its mechanism of action are not known. The purpose of these studies was to determine the physiological significance and pharmacological specificity of the prolactin secretory response to OFQ/N. In addition, the role of the tuberoinfundibular dopaminergic (TIDA) neurons in mediating this response was examined. Opioid receptor-like-1 (ORL-1) receptors were blocked by pretreatment with compound B (Comp B), a purported OFQ/N antagonist, or receptor synthesis was disrupted by pretreatment with ORL-1 receptor antisense oligonucleotides. The prolactin secretory response to OFQ/N administration in diestrous females was measured. Furthermore, the suckling-induced prolactin response was also determined after Comp B pretreatment. TIDA neuronal activity was quantified in diestrous female rats to determine whether OFQ/N stimulates prolactin release by inhibiting TIDA neurons. OFQ/N significantly inhibited the TIDA neurons by 1 min, preceding the prolactin secretory response. Both Comp B and antisense pretreatment blocked the stimulatory effects of OFQ/N on prolactin release, and Comp B abolished the suckling-induced prolactin response. These studies indicate that OFQ/N is a potent stimulus for prolactin secretion in female rats and that it mediates this effect by rapid and transient inhibition of TIDA neuronal activity. Furthermore, OFQ/N plays a physiologically significant role in the regulation of prolactin secretion during lactation, and it mediates its effects via actions at the ORL-1 receptor subtype.