bluuebunny/crossref_metadata_2025 huggingface dataset:
Bronchial Hyperresponsiveness to Methacholine Is Associated With Increased Common Carotid Intima-Media Thickness in Men
Authors: Zureik Mahmoud , Kony Sabine , Neukirch Catherine , Courbon Dominique , Leynaert Bénédicte , Vervloet Daniel , Ducimetière Pierre , Neukirch Françoise
Published: April 2004

Background—

Respiratory alterations have been associated with subsequent coronary heart diseases in numerous population-based studies. The underlying mechanisms remain largely unknown. The objective of this study was to examine the association between bronchial hyperresponsiveness (BHR) to methacholine (which reflects local inflammation in the bronchus) and common carotid intima-media thickness (CCA-IMT).

Methods and Results—

As part of the European Community Respiratory Health Survey follow-up, in Paris Center, we assessed BHR to methacholine (≥20% decrease in FEV1 for a maximum methacholine dose of 4 mg) and measured CCA-IMT by ultrasonography in 255 adults free of cardiovascular diseases aged 29 to 56 years (123 men, 132 women; mean age 44.5 years, 43.5% never smokers). In men, CCA-IMT mean value was higher in subjects with BHR than in those without (0.68±0.11 versus 0.62±0.09 mm,
P
=0.002). No association was found in women. Multivariate analysis confirmed the independent association between BHR and CCA-IMT in men (adjusted odds ratio for a 0.10-mm increase in CCA-IMT=2.1, 95% confidence interval: 1.1 to 4.3;
P
=0.02). These results remained similar after exclusion of asthmatic subjects (n=11). In each strata of smoking status (nonsmoker, ex-smoker, and current smokers), CCA-IMT mean values tended to be higher in subjects with BHR than in those without, although the difference between the 2 groups was more pronounced in current smokers.

Conclusions—

The results of the present study suggest that BHR is independently associated with CCA-IMT in men. The interrelationships between cardiovascular and respiratory alterations should be further investigated.
Decision Guidelines for Prophylactic Replacement of Björk-Shiley Convexo-Concave Heart Valves
Authors: van Gorp M.J. , Steyerberg E.W. , van der Graaf Y.
Published: April 2004

Background—

Because of risk of outlet strut fracture, prophylactic replacement should be considered for Björk-Shiley convexo-concave (BScc) valve recipients. We assessed the effects of epidemiological and decision-analytic guidelines on actual BScc valve replacement.

Methods and Results—

We performed a retrospective cohort study including all 2263 Dutch BScc patients with a mean follow-up of 11.3 years (range, 0 to 23 years). Outcomes were outlet strut fracture, mortality, and BScc valve replacement. For the surviving patients in 1992 (n=1330), we calculated the expected differences in life expectancy (LE) with and without BScc valve replacement according to decision guidelines developed in 1992. Differences in LE were compared with actual replacements. During 8 years of follow-up, there were 494 deaths (40%), and 11 patients had suffered outlet strut fracture. Of 1330 patients, 96 (10%) had undergone BScc valve replacement, particularly in years after introduction of initial and updated guidelines. One hundred seventeen patients (9%) had an estimated gain in LE after BScc valve replacement. These patients were more likely to undergo replacement than patients with an estimated loss of LE (hazard ratio, 6.6; 95% CI, 4.4 to 10;
P
<0.0001). A loss in LE after reoperation was predicted for 8 of 11 patients who experienced outlet strut fracture after guidelines were available.

Conclusions—

Valve replacement for BScc heart valve patients was largely in concordance with guidelines in the Netherlands. Individualized guidelines that are based on high-quality epidemiological data and are updated and implemented rigorously can influence clinical practice in complex decision problems.
Stent Thrombosis After Successful Sirolimus-Eluting Stent Implantation
Authors: Jeremias Allen , Sylvia Brett , Bridges Jonathan , Kirtane Ajay J. , Bigelow Brian , Pinto Duane S. , Ho Kalon K.L. , Cohen David J. , Garcia Lawrence A. , Cutlip Donald E. , Carrozza Joseph P.
Published: April 2004

Background—

Stent thrombosis (ST) is a rare but devastating complication of coronary stent implantation, occurring in 0.5% to 1.9% of patients with bare metal stents. The incidence of ST with drug-eluting stents is less well studied, particularly among patients outside of clinical trials.

Methods and Results—

The aim of this study was to evaluate the incidence and potential risk factors for ST in patients receiving sirolimus-eluting stents (SES) in the “real world” after commercial release in the United States in April 2003. All 652 patients who underwent SES implantation (776 lesions treated) at our institution between April and October 2003 were followed up prospectively after the procedure (median follow-up 100 days). During that period, 7 patients (1.1%, 95% CI 0.4% to 2.2%) developed ST within a range of 2 to 13 days, and 1 patient had an ST-elevation myocardial infarction on day 39 with evidence of thrombus within the SES at angiography. Patients with an ST had significantly smaller final nominal balloon diameters (2.75 versus 3.00 mm,
P
=0.04), and in 4 (57%) of the 7 patients with ST versus 1.7% of patients without ST (
P
<0.001), antiplatelet therapy had been discontinued after the procedure. Among the ST patients, 1 died and 5 had myocardial infarctions.

Conclusions—

In this single-center experience, the incidence of ST after SES implantation was ≈1%, which is within the expected range of bare metal stents. The discontinuation of antiplatelet therapy was strongly associated with the development of ST in this patient population.
Non–Polymer-Based Paclitaxel-Coated Coronary Stents for the Treatment of Patients With De Novo Coronary Lesions
Authors: Lansky Alexandra J. , Costa Ricardo A. , Mintz Gary S. , Tsuchiya Yoshihiro , Midei Mark , Cox David A. , O’Shaughnessy Charles , Applegate Robert A. , Cannon Louis A. , Mooney Michael , Farah Anthony , Tannenbaum Mark A. , Yakubov Steven , Kereiakes Dean J. , Wong S. Chiu , Kaplan Barry , Cristea Ecaterina , Stone Gregg W. , Leon Martin B. , Knopf William D. , O’Neill William W.
Published: April 2004

Background—

Paclitaxel, a microtubule-stabilizing compound with potent antitumor activity, has been shown to inhibit smooth muscle cell proliferation and migration. The DELIVER trial was a prospective, randomized, blinded, multicenter clinical evaluation of the non–polymer-based paclitaxel-coated ACHIEVE stent compared with the stainless steel Multi-Link (ML) PENTA stent.

Methods and Results—

A total of 1043 patients with focal de novo coronary lesions, <25 mm in length, in 2.5- to 4.0-mm vessels were randomized (ACHIEVE n=524; ML PENTA n=519). Angiographic follow-up was performed in a subset of 442 patients (ACHIEVE n=228; ML PENTA n=214). Prespecified end points were a 40% reduction in target-vessel failure at 9 months (primary clinical end point) and a 50% reduction in binary restenosis at 8 months (major secondary end point). Baseline clinical characteristics were comparable between the groups. Patients in ACHIEVE had more type C lesions and a larger reference diameter. At follow-up, stent late loss was 0.81 versus 0.98 mm (
P
=0.003), stent binary restenosis was 14.9% versus 20.6% (
P
=0.076), and target-vessel failure was 11.9% versus 14.5% (
P
=0.12) for ACHIEVE and ML PENTA, respectively.

Conclusions—

The ACHIEVE paclitaxel-coated stent decreased neointimal proliferation compared with the bare-metal PENTA stent; however, this reduction was insufficient to meet the prespecified primary end point of target-vessel failure and the secondary end point of binary restenosis.
Epicardial Activation of Left Ventricular Wall Prolongs QT Interval and Transmural Dispersion of Repolarization
Authors: Fish Jeffrey M. , Di Diego José M. , Nesterenko Vladislav , Antzelevitch Charles
Published: April 2004

Background—

Epicardial pacing of the left ventricle (LV) has been shown to prolong the QT interval and predispose to the development of torsade de pointes arrhythmias. The present study examines the cellular basis for QT prolongation and arrhythmogenesis after reversal of the direction of activation of the LV wall.

Methods and Results—

A transmural ECG and transmembrane action potentials were simultaneously recorded from epicardial, M, and endocardial cells of arterially perfused canine LV wedge preparations. QT interval increased from 297.6±3.9 to 314.0±5.7 ms (n=12;
P
<0.001) and transmural dispersion of repolarization (TDR) increased from 35.5±5.2 to 70.3±6.2 ms (n=12;
P
<0.001) as pacing was shifted from endocardium to epicardium. Conduction time between M and epicardial cells increased from 12.1±1.2 to 24.2±1.5 ms (n=12;
P
<0.001). Amplification of TDR was further accentuated in the presence of rapidly activating delayed rectifier potassium current blockers (E-4031 and cisapride), increasing from 50.5±7.6 to 86.1±6.2 ms (n=8;
P
<0.01). Torsade de pointes arrhythmias could be induced during epicardial, but not endocardial, pacing of LV in the presence of rapidly activating delayed rectifier potassium current blockade.

Conclusions—

Reversal of the direction of activation of the LV wall, as occurs during biventricular pacing, leads to a prominent increase in QT and TDR as a result of earlier repolarization of epicardium and delayed activation and repolarization of the midmyocardial M cells. The increase in TDR creates the substrate for the development of torsade de pointes under long-QT conditions.
Increased ACE 2 and Decreased ACE Protein in Renal Tubules From Diabetic Mice
Authors: Ye Minghao , Wysocki Jan , Naaz Parveen , Salabat Mohammad Reza , LaPointe Michael S. , Batlle Daniel
Published: April 2004

Unlike the ubiquitous angiotensin-converting enzyme (ACE), the ACE-related carboxypeptidase 2 (ACE 2) is predominantly expressed in the heart, kidney, and testis. ACE 2 degrades angiotensin (Ang) II to Ang (1–7) and Ang I to Ang (1–9). We investigated the expression of ACE and ACE 2 in a rodent model of type 2 diabetes. ACE and ACE 2 were measured in kidney and heart from 8-week-old no diabetic control (db/m) mice and diabetic (db/db) mice, which at this young age have obesity and hyperglycemia without nephropathy. In renal cortical tissue, ACE mRNA was reduced (db/db 0.31±0.06 versus db/m 0.99±0.05;
P
<0.005), whereas ACE 2 mRNA was not (db/db 0.94±0.05 versus db/m 1.03±0.11, NS). ACE protein was markedly reduced in kidney cortex of db/db mice (db/db 0.24±0.13 versus db/m 1.02±0.12;
P
<0.005), and this was associated with a corresponding decrease in renal ACE activity (db/db 12.7±3.7 versus db/m 61.6±4.4 mIU/mg protein;
P
<0.001). ACE 2 protein, by contrast, was increased in kidneys from diabetic mice (db/db 1.39±0.14 versus db/m 0.53±0.04;
P
<0.005). An increase in ACE 2 protein and a decrease in ACE protein, respectively, were also seen by immunostaining of renal cortical tubules from the db/db mice. In heart tissue, there were no significant differences between db/db and db/m mice in either ACE mRNA and protein or ACE 2 mRNA and protein. We conclude that in young db/db mice, ACE 2 protein in renal cortical tubules is increased, whereas ACE protein is decreased. We propose that the pattern of low ACE protein coupled with increased ACE 2 protein expression may be renoprotective in early stages of diabetes.
Prevalence and Magnitude of Classical Risk Factors for Stroke in a Cohort of 5092 Chinese Steelworkers Over 13.5 Years of Follow-up
Authors: Zhang Xiao-Fei , Attia John , D’Este Catherine , Yu Xue-Hai
Published: April 2004

Background and Purpose—

Stroke is the most common manifestation of cardiovascular disease (CVD) among Chinese men. This study addresses the prevalence and magnitude of classic CVD risk factors associated with total, ischemic, and hemorrhagic stroke in a Chinese cohort of at-risk men, compared with white populations. We also address which blood pressure index: systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP) is the best predictor of stroke.

Methods—

A cohort of 5092 male steelworkers (aged 18 to 74 years) recruited between 1974 to 1980 was followed up for an average of 13.5 years. The results showed that the risk ratios (RRs) of stroke associated with classic risk factors in this Asian population were not different than in whites, except for blood pressure. The RRs of total stroke for each 10mm Hg rise in SBP and DBP in this Asian group (1.4 and 1.8, respectively) were higher than in whites (1.2 to 1.3 and 1.2 to 1.5, respectively). The population attributable risk (PAR) for hypertension (160/95 mm Hg cutoff) to stroke was higher in Asians (ie, 31% for ischemic and 42% for hemorrhagic stroke) than in whites (25% and 34%, respectively).

Conclusion—

Our results indicate that hypertension is a greater risk factor for stroke in Asians than whites, especial for hemorrhagic stroke. The most predictive blood pressure (BP) index for stroke is MAP. However, the prevalence or magnitude of these traditional risk factors appears unlikely to explain the differing spectrum of CVD among Asians.
Cerebral Endothelial Expression of Adhesion Molecules in Mice with Chronic Graft-Versus-Host Disease
Authors: Sostak Petra , Reich Petra , Padovan Claudio S. , Gerbitz Armin , Holler Ernst , Straube Andreas
Published: April 2004

Background and Purpose—

Graft-versus-host disease (GvHD) is a major complication after allogeneic bone marrow transplantation (BMT). The theory that the central nervous system (in addition to the peripheral nervous system) participates in GvHD has been supported by detection of cerebral lymphomononuclear infiltrates in experimental GvHD and the observation of cerebral angiitis-like disease in patients with chronic GvHD.

Methods—

In a murine BMT model, we investigated the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on cerebral endothelium after allogeneic and syngeneic transplantation. Through the use of ICAM-1–knockout mice, the effect of ICAM-1 deficiency on cellular infiltration was evaluated. As an indicator of enhanced apoptotic cell death, we examined the cerebral expression of Fas antigen (Fas), the occurrence of the poly-ADP ribose polymerase p85 fragment, and the distribution of TUNEL positive–stained cells.

Results—

In close correlation with earlier findings of cerebral infiltration in the same animals, we found cerebral endothelial upregulation of ICAM-1 and especially of VCAM-1 in allogeneic recipients compared with syngeneic animals without GvHD and unmanipulated controls. In ICAM-1–knockout mice, leukocytic infiltration did not differ from that in wild-type animals. Neither cerebral histopathologic changes nor an apoptotic effect of cellular infiltrates on brain parenchyma could be detected.

Conclusions—

In this model of experimental GvHD, VCAM-1 may play a critical role in leukocyte recruitment into the central nervous system of animals with chronic GvHD.
Neurogenesis After Transient Global Ischemia in the Adult Hippocampus Visualized by Improved Retroviral Vector
Authors: Tanaka Ryota , Yamashiro Kazuo , Mochizuki Hideki , Cho Nei , Onodera Masafumi , Mizuno Yoshikuni , Urabe Takao
Published: April 2004

Background and Purpose—

Neurogenesis has been observed in the dentate gyrus of the adult hippocampus; however, the mechanisms involved in this process are still only partly understood. In this study, we visualized the proliferation, migration, and differentiation of neuronal progenitor cells in the dentate gyrus induced by ischemic stress using improved retroviral vector.

Methods—

Improved retroviral vector expressing enhanced green fluorescent protein (EGFP) as a transgene was injected into the dentate gyrus of adult Mongolian gerbils. After 48 hours, transient global ischemia (TGI) was induced by bilateral common carotid artery occlusion for 5 minutes using aneurysm clips. The morphological and immunohistological features of newly-generated cells in the dentate gyrus were analyzed at various times thereafter.

Results—

At 48 hours after viral injection, almost all EGFP-positive dividing cells were found in the subgranule layer (SGL). These cells proliferated and migrated to the granule cell layer (GCL), expressing the developing neuronal markers polysialic acid and doublecortin, and differentiated to neuronal nuclei–positive or calbindin-positive mature granule cells at 30 days after TGI or sham-operation. The number of GFP-positive cells in the GCL was significantly higher (
P
<0.05) in the ischemic animals at 30 days than in sham-operated gerbils.

Conclusions—

We saw neurogenesis in the adult dentate gyrus. Furthermore, we showed that ischemic stress promoted the proliferation and normal development of neurons at this site.
Impaired Endothelial Function of the Retinal Vasculature in Hypertensive Patients
Authors: Delles Christian , Michelson Georg , Harazny Joanna , Oehmer Sebastian , Hilgers Karl F. , Schmieder Roland E.
Published: April 2004

Background and Purpose—

Arterial hypertension constitutes a central factor in the pathogenesis of stroke. We examined endothelial function of the retinal vasculature as a model of the cerebral circulation.

Methods—

Thirty-eight young subjects (19 hypertensive and 19 normotensive) were treated with the AT
1
-receptor blocker candesartan cilexetil and placebo, each over 7 days. Retinal capillary flow and blood flow velocity in the central retinal artery were assessed with scanning laser Doppler flowmetry and pulsed Doppler ultrasound, respectively.
N
G
-monomethyl-
l
-arginine (
l
-NMMA) was infused to inhibit nitric oxide (NO) synthesis. Diffuse luminance flicker was applied to stimulate NO release.

Results—

In normotensive subjects,
l
-NMMA decreased retinal capillary flow by 8.2%±13% (
P
<0.05) and flickering light increased mean blood flow velocity in the central retinal artery by 19%±29% (
P
<0.01). In contrast, no significant change to these provocative tests was seen in hypertensive subjects. Treatment with candesartan cilexetil restored a normal pattern of reactivity in retinal capillaries (
l
-NMMA: decrease in perfusion by 10%±17%,
P
<0.05) and the central retinal artery (flicker: increase in mean blood flow velocity by 42%±31%,
P
<0.001) in hypertensive patients.

Conclusions—

Endothelial function of the retinal vasculature is impaired in early essential hypertension but can be improved by AT
1
-receptor blockade.
Differences in Matrix Metalloproteinase-1 and Matrix Metalloproteinase-12 Transcript Levels Among Carotid Atherosclerotic Plaques With Different Histopathological Characteristics
Authors: Morgan Angharad R. , Rerkasem Kittipan , Gallagher Patrick J. , Zhang Baiping , Morris Gareth E. , Calder Philip C. , Grimble Robert F. , Eriksson Per , McPheat William L. , Shearman Clifford P. , Ye Shu
Published: April 2004

Background and Purpose—

Previous studies have shown that atherosclerotic lesions express a number of matrix metalloproteinases (MMPs). Here we investigated whether transcript levels of MMP-1, -3, -7, -9, and -12 in carotid atherosclerotic plaques were correlated with histological features and clinical manifestations.

Methods—

Atherosclerotic plaques (n=50) removed from patients undergoing carotid endarterectomy were classified histologically using a system proposed by Virmani et al, and MMP-1, -3, -7, -9, and -12 transcript levels in these tissues were quantified by real-time reverse-transcriptase polymerase chain reaction.

Results—

Compared to plaques with a thick fibrous cap, those with a thin cap had a 7.8-fold higher MMP-1 transcript level (
P
=0.006). MMP-3, -7, and -12 were 1.5-fold, 1.8-fold, and 2.1-fold, respectively, higher in thin cap plaques, but the differences did not reach statistical significance. MMP-12 transcript levels were significantly increased in ruptured plaques compared with lesions without cap disruption (
P
=0.001). MMP-9 transcript levels were similar among the different types of lesion. MMP-1 and -12 transcript levels were significantly higher in plaques from patients with amaurosis fugax, than in those from asymptomatic patients (
P
=0.029 and
P
=0.008 for MMP-1 and MMP-12, respectively), than in those from patients with stroke (
P
=0.027 and
P
=0.001, respectively), and than in those from patients with transient ischemic attack (
P
=0.046 and
P
=0.008, respectively).

Conclusions—

These data support a role of MMP-1 and -12 in determining atherosclerotic plaque stability.
Interobserver Variation of ASPECTS in Real Time
Authors: Coutts Shelagh B. , Demchuk Andrew M. , Barber Philip A. , Hu William Y. , Simon Jessica E. , Buchan Alastair M. , Hill Michael D.
Published: April 2004

Background—

The Alberta Stroke Program Early CT Score (ASPECTS) has been used to quantify early ischemic changes on computed tomography (CT) brain scans of acute stroke patients. We sought to assess the reliability of the score when performed in real time as compared with an expert rating performed at a later time point.

Methods—

Two hundred fourteen patients presenting with acute ischemic stroke or transient ischemic attack were prospectively recruited if they had a brain CT scan performed within 12 hours of symptom onset. Each scan was read for ASPECTS prospectively by the treating physician and later by 1 expert reader. A weighted kappa statistic was used to determine the interobserver agreement.

Results—

The median baseline National Institutes of Health Stroke Scale score was 5 (range: 0 to 32) and the median time to CT scan was 152 minutes (range: 22 to 769). The interobserver agreement between ASPECTS performed in real time and expert ASPECTS was substantial (κ
w
=0.69). The mean difference between real-time ASPECTS and expert ASPECTS was 0 (SD: 1.1).

Conclusions—

ASPECTS is a reliable clinical scale for rating early ischemic changes on CT when performed in real time.
Word Translation Disambiguation Using Bilingual Bootstrapping
Authors: Li Hang , Li Cong
Published: April 2004

This article proposes a new method for word translation disambiguation, one that uses a machine-learning technique called bilingual bootstrapping. In learning to disambiguate words to be translated, bilingual bootstrapping makes use of a small amount of classified data and a large amount of unclassified data in both the source and the target languages. It repeatedly constructs classifiers in the two languages in parallel and boosts the performance of the classifiers by classifying unclassified data in the two languages and by exchanging information regarding classified data between the two languages. Experimental results indicate that word translation disambiguation based on bilingual bootstrapping consistently and significantly outperforms existing methods that are based on monolingual bootstrapping.
Verb Class Disambiguation Using Informative Priors
Authors: Lapata Mirella , Brew Chris
Published: April 2004

Levin's (1993) study of verb classes is a widely used resource for lexical semantics. In her framework, some verbs, such as give, exhibit no class ambiguity. But other verbs, such as write, have several alternative classes. We extend Levin's inventory to a simple statistical model of verb class ambiguity. Using this model we are able to generate preferences for ambiguous verbs without the use of a disambiguated corpus. We additionally show that these preferences are useful as priors for a verb sense disambiguator.
Cardiac toxicity of alemtuzumab in patients with mycosis fungoides/Sézary syndrome
Authors: Lenihan Daniel J. , Alencar Alvaro J. , Yang Deborah , Kurzrock Razelle , Keating Michael J. , Duvic Madeleine
Published: April 2004

Alemtuzumab is a monoclonal antibody to CD52 that has activity in T-cell leukemia and lymphoma. This study aims to describe the complications and outcomes of a subset of patients with mycosis fungoides/Sézary syndrome who were treated with alemtuzumab. Four of 8 patients, with no prior history of cardiac problems, developed significant cardiac toxicity (congestive heart failure or arrhythmia) that mostly improved after alemtuzumab discontinuation. The role of this agent in potentially inducing important cardiac side effects is suggested and argues for further investigation.
Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999
Authors: Peters Charles , Charnas Lawrence R. , Tan Ye , Ziegler Richard S. , Shapiro Elsa G. , DeFor Todd , Grewal Satkiran S. , Orchard Paul J. , Abel Susan L. , Goldman Anne I. , Ramsay Norma K. C. , Dusenbery Kathryn E. , Loes Daniel J. , Lockman Lawrence A. , Kato Shunichi , Aubourg Patrick R. , Moser Hugo W. , Krivit William
Published: April 2004

Cerebral X-linked adrenoleukodystrophy (X-ALD) is a disorder of very-long-chain fatty acid metabolism, adrenal insufficiency, and cerebral demyelination. Death occurs within 2 to 5 years of clinical onset without hematopoietic cell transplantation (HCT). One hundred twenty-six boys with X-ALD received HCT from 1982 to 1999. Survival, engraftment, and acute graft-versus-host disease were studied. Degree of disability associated with neurologic and neuropsychological function and cerebral demyelination were evaluated before and after HCT. Complete data were available and analyzed for 94 boys with cerebral X-ALD. The estimated 5- and 8-year survival was 56%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Demyelination involved parietal-occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. Overall 5-year survival of 92% in patients with 0 or 1 neurologic deficits and magnetic resonance imaging (MRI) severity score less than 9 before HCT was superior to survival for all others (45%; P < .01). Baseline neurologic and neuropsychological function, degree of disability, and neuroradiologic status predicted outcomes following HCT. In this first comprehensive report of the international HCT experience for X-ALD, we conclude that boys with early-stage disease benefit from HCT, whereas boys with advanced disease may be candidates for experimental therapies.
Human alloantibody anti-Mart interferes with Mac-1–dependent leukocyte adhesion
Authors: Sachs Ulrich J. H. , Chavakis Triantafyllos , Fung Lin , Lohrenz Alexander , Bux Jürgen , Reil Angelika , Ruf Andreas , Santoso Sentot
Published: April 2004

The CD11b/CD18 integrin plays a crucial role in cell-cell adhesion processes. Recently, we described a case of severe neonatal alloimmune neutropenia (NAIN) caused by an alloantibody against a variant of the CD11b subunit (Mart alloantigen). Allele-specific transfected cells allowed us to demonstrate that an H61R point mutation is directly responsible for the formation of Mart epitopes. No difference in the adhesion capability between H61 and R61 homozygous neutrophils was observed. Functional analysis showed that anti-Mart inhibited Mac-1–dependent adhesion of neutrophils and monocytic U937 cells to fibrinogen, intercellular adhesion molecule-1 (ICAM-1), receptor for advanced glycation end product (RAGE), and glycoprotein Ibα but not to junctional adhesion molecule-C or urokinase plasminogen activator receptor (uPAR). Accordingly, anti-Mart blocked neutrophil and U937 cell adhesion to endothelial cells and platelet-leukocyte aggregate formation in whole blood under high shear. Other sera of anti-Mart from mothers of infants without NAIN did not show inhibitory properties. We conclude that anti-Mart antibodies with different functional properties exist. This is supported by our findings that anti-Mart antibodies have different abilities to inhibit cell-cell adhesion, to enhance the respiratory burst of neutrophils, and to recognize different epitopes at the N-terminal region of CD11b. In conclusion, some anti-Mart alloantibodies interfere with Mac-1–dependent cellular functions of neutrophils, cause NAIN, and may be used as tools for studying Mac-1–dependent functions.
C/EBPα deficiency results in hyperproliferation of hematopoietic progenitor cells and disrupts macrophage development in vitro and in vivo
Authors: Heath Victoria , Suh Hyung Chan , Holman Matthew , Renn Katie , Gooya John M. , Parkin Sarah , Klarmann Kimberly D. , Ortiz Mariaestela , Johnson Peter , Keller Jonathan
Published: April 2004

CCAAT enhancer binding protein-α (C/EBPα) inhibits proliferation in multiple cell types; therefore, we evaluated whether C/EBPα-deficient hematopoietic progenitor cells (HPCs) have an increased proliferative potential in vitro and in vivo. In this study we demonstrate that C/EBPα-/- fetal liver (FL) progenitors are hyperproliferative, show decreased differentiation potential, and show increased self-renewal capacity in response to hematopoietic growth factors (HGFs). There are fewer committed bipotential progenitors in C/EBPα-/- FL, whereas multipotential progenitors are unaffected. HGF-dependent progenitor cell lines can be derived by directly culturing C/EBPα-/- FL cells in vitro Hyperproliferative spleen colonies and myelodysplastic syndrome (MDS) are observed in mice reconstituted with C/EBPα-/- FL cells, indicating progenitor hyperproliferation in vitro and in vivo. C/EBPα-/- FL lacked macrophage progenitors in vitro and had impaired ability to generate macrophages in vivo. These findings show that C/EBPα deficiency results in hyperproliferation of HPCs and a block in the ability of multipotential progenitors to differentiate into bipotential granulocyte/macrophage progenitors and their progeny. (Blood. 2004; 104:1639-1647)
Tumor necrosis factor-α blockade for the treatment of acute GVHD
Authors: Couriel Daniel , Saliba Rima , Hicks Krystal , Ippoliti Cindy , de Lima Marcos , Hosing Chitra , Khouri Issa , Andersson Borje , Gajewski James , Donato Michele , Anderlini Paolo , Kontoyiannis Dimitrios P. , Cohen Agueda , Martin Thomas , Giralt Sergio , Champlin Richard
Published: April 2004

Despite posttransplantation immunosuppressive therapy, acute graft-versus-host disease (GVHD) remains a major cause of sickness and death. Tumor necrosis factor-α (TNF-α) is implicated in the pathophysiology of GVHD at several steps in the process. Infliximab is a genetically constructed immunoglobulin G1 (IgG1) murine–human chimeric monoclonal antibody that binds the soluble subunit and the membrane-bound precursor of TNF-α, blocking its interaction with receptors and causing lysis of cells that produce TNF-α. In this study we retrospectively evaluated 134 patients who had steroid-refractory acute GVHD. Of these, 21 who received infliximab as a single agent were analyzed. The overall response rate was 67% (n = 14), and 13 patients (62%) experienced complete response (CR). Five patients (24%) did not respond, and 2 (10%) had progressive GVHD. None had a toxic reaction to infliximab. Ten patients (48%) had 18 fungal infections, including Aspergillus species in 7 and Candida species in 10. Seventeen patients (81%) had bacterial infections, including 32 gram-positive and 8 gram-negative infections. Viral infections, primarily cytomegalovirus reactivation, occurred in 14 patients (67%). The Kaplan-Meier estimate of overall survival was 38%. In conclusion, infliximab was well tolerated and active for the treatment of steroid-resistant acute GVHD, particularly with gastrointestinal tract involvement. Survival after steroid-resistant acute GVHD continues to be problematic. The possibility of excessive fungal and other infections must be explored further.
Cross-linking of FcγR triggers shedding of the hemoglobin-haptoglobin scavenger receptor CD163
Authors: Sulahian Timothy H , Pioli Patricia A , Wardwell Kathleen , Guyre Paul M
Published: April 2004

CD163, the hemoglobin (Hb)-haptoglobin scavenger receptor, is a monocyte/macrophage-restricted member of the scavenger receptor, cysteine-rich family of proteins. In addition to being expressed on the cell surface, a soluble form of CD163 has also been reported. Like tumor necrosis factor α (TNF-α), surface CD163 is proteolytically cleaved from the plasma membrane in response to lipopolysaccharide (LPS) stimulation. As cross-linking of the Fcγ receptor (FcγR) is similarly known to induce TNF-α shedding, the effect of FcγR stimulation on CD163 shedding was investigated. We found that FcγR stimulation resulted in a rapid release of surface CD163 into the supernatant that was blocked by inhibitors of protein kinase C and tyrosine kinases. Although LPS and FcγR stimulation in short-term cultures suppressed CD163 mRNA expression, long-term cultures of monocytes treated with LPS—but not with a FcγR cross-linking reagent—resulted in an interleukin-10-dependent recovery of surface CD163 expression. These studies suggest that the presence of immune complexes in infection or autoimmunity may radically alter the nature of CD163-dependent monocyte/macrophage processes. This may be particularly important in disease states in which immune complexes and high levels of free Hb are present, such as in autoimmune hemolytic anemia, transfusion reactions, or infections by hemolytic bacteria.
Short-term Flt3L treatment effectively mobilizes functional macaque dendritic cells
Authors: Teleshova Natalia , Jones Jennifer , Kenney Jessica , Purcell Jeanette , Bohm Rudolf , Gettie Agegnehu , Pope Melissa
Published: April 2004

In vivo administration of soluble Flt3L increases dendritic cell (DC) numbers to favor improved DC targeting of vaccine antigens, augmenting vaccine efficiency. In addition to confirming the effectiveness of human Flt3L in macaques, we strove to determine the optimal regimen to elevate numbers of functional DCs. Circulating DCs were identified within lineage−human leukocyte antigen-DR+ cells, which comprised CD11c−CD123+ plasmacytoid DCs (PDCs) and CD123− cells including CD11c+CD123− myeloid DCs as well as CD11c−CD123− cells. Traditionally, DCs have been monitored 1–2 days after 10- to 14-day treatments with Flt3L (100 μg/kg/day). We demonstrate that although standard treatment increased macaque DC percentages, as little as 5–7 days of treatment was sufficient, if not more effective at mobilizing DCs. Moreover, DC frequency continued to escalate over the ensuing days, peaking at ∼4 days post 7 days of treatment and ultimately decreasing thereafter. As expected, there was a more pronounced increase in the percentages and actual numbers of CD123− cells (CD11c+ and CD11c− subsets) compared with PDCs. Flt3L-mobilized DCs exhibited slightly increased CD80/CD86 expression but typically still that of immature DCs and were resilient to freeze-thawing. Overnight culture activated the cells, up-regulating CD80/CD86 expression as well as interleukin-12 release, typically being boosted by CD40L. This was even more apparent for enriched DC cultures. These data verify that peak mobilization of large numbers of functional macaque DCs occurs a few days, not immediately, after short-term Flt3L dosing. This has important implications for improved DC-targeting vaccine strategies to prevent infection with human immunodeficiency virus and other pathogens.
Insulin-Like Growth Factor (IGF)-Binding Protein-1 Is Highly Induced during Acute Carbon Tetrachloride Liver Injury and Potentiates the IGF-I-Stimulated Activation of Rat Hepatic Stellate Cells
Authors: Scharf Jens-Gerd , Dombrowski Frank , Novosyadlyy Ruslan , Eisenbach Christoph , Demori Ilaria , Kübler Bernd , Braulke Thomas
Published: April 2004

Hepatic stellate cells (HSC) play a pivotal role in hepatic tissue repair and fibrogenesis. IGF-I has been considered a mitogenic signal for activation and proliferation of HSC in vitro. In the present study IGF-I and IGF-binding protein (IGFBP) gene expression was studied in a model of acute liver injury induced by a single intragastric dose of carbon tetrachloride (CCl4) in adult rats. Northern blot analysis revealed a marked increase in IGFBP-1 mRNA levels, with a maximum between 3 and 9 h after CCl4 application, whereas steady state mRNA levels of IGF-I were only moderately altered. In situ hybridization experiments demonstrated that this increase in IGFBP-1 mRNA was due to a strong expression of IGFBP-1 in the perivenous region 6–12 h after CCl4 application, extending to the midzonal region of the acinus within 24–48 h. Consequently, a prominent immunostaining for IGFBP-1 was observed in perivenous areas, with a maximum 24–48 h after intoxication. Preincubation of early cultured HSC with a nonphosphorylated IGFBP-1 from human amniotic fluid resulted in a 3.4-fold increase in IGF-I-induced DNA synthesis. The mitogenic effect of IGF-I was also potentiated when HSC were cocultivated with IGFBP-1-overexpressing BHK-21 cells compared with nontransfected cells. These data suggest that IGFBP-1 released during the early steps of liver tissue damage and repair may interact with HSC and potentiate the sensitivity of IGF-I to mitogenic signals.
VEGFA is necessary for chondrocyte survival during bone development
Authors: Zelzer Elazar , Mamluk Roni , Ferrara Napoleone , Johnson Randall S. , Schipani Ernestina , Olsen Bjorn R.
Published: April 2004

To directly examine the role of vascular endothelial growth factor (VEGFA)in cartilage development, we conditionally knocked out Vegfa in chondrocytes, using the Col2a1 promoter to drive expression of Cre recombinase. Our study of Vegfa conditional knockout (CKO) mice provides new in-vivo evidence for two important functions of VEGFA in bone formation. First, VEGFA plays a significant role in both early and late stages of cartilage vascularization, since Vegfa CKO mice showed delayed invasion of blood vessels into primary ossification centers and delayed removal of terminal hypertrophic chondrocytes. Second, VEGFA is crucial for chondrocyte survival, since massive cell death was seen in joint and epiphyseal regions of Vegfa CKO endochondral bones. Chondrocytes in these regions were found to upregulate expression of Vegfa in wild-type mice at the time when massive cell death occurred in the Vegfa CKO mice. The expression of the VEGFA receptors Npr1 and Npr2 in epiphyseal chondrocytes and lack of blood vessel reduction in the vicinity of the cartilaginous elements in the Vegfa CKO mice raise the possibility that the observed cell death is the result of a direct involvement of VEGFA in chondrocyte survival. Interestingly, the extensive cell death seen in Vegfa CKO null bones had a striking similarity to the cell death phenotype observed when hypoxia-inducible factor 1α (Hif1a)expression was abolished in developing cartilage. This similarity of cell death phenotypes and the deficient VEGFA production in Hif1a null epiphyseal chondrocytes demonstrate that HIF1α and VEGFA are components of a key pathway to support chondrocyte survival during embryonic bone development.
BMP receptor IA is required in mammalian neural crest cells for development of the cardiac outflow tract and ventricular myocardium
Authors: Stottmann Rolf W. , Choi Murim , Mishina Yuji , Meyers Erik N. , Klingensmith John
Published: April 2004

The neural crest is a multipotent, migratory cell population arising from the border of the neural and surface ectoderm. In mouse, the initial migratory neural crest cells occur at the five-somite stage. Bone morphogenetic proteins(BMPs), particularly BMP2 and BMP4, have been implicated as regulators of neural crest cell induction, maintenance, migration, differentiation and survival. Mouse has three known BMP2/4 type I receptors, of which Bmpr1a is expressed in the neural tube sufficiently early to be involved in neural crest development from the outset; however, earlier roles in other domains obscure its requirement in the neural crest. We have ablated Bmpr1a specifically in the neural crest, beginning at the five-somite stage. We find that most aspects of neural crest development occur normally;suggesting that BMPRIA is unnecessary for many aspects of early neural crest biology. However, mutant embryos display a shortened cardiac outflow tract with defective septation, a process known to require neural crest cells and to be essential for perinatal viability. Surprisingly, these embryos die in mid-gestation from acute heart failure, with reduced proliferation of ventricular myocardium. The myocardial defect may involve reduced BMP signaling in a novel, minor population of neural crest derivatives in the epicardium, a known source of ventricular myocardial proliferation signals. These results demonstrate that BMP2/4 signaling in mammalian neural crest derivatives is essential for outflow tract development and may regulate a crucial proliferation signal for the ventricular myocardium.
Extra-embryonic vasculature development is regulated by the transcription factor HAND1
Authors: Morikawa Yuka , Cserjesi Peter
Published: April 2004

The basic helix-loop-helix (bHLH) transcription factor HAND1 (also called eHAND) is expressed in numerous tissues during development including the heart, limbs, neural crest derivatives and extra-embryonic membranes. To investigate the role of Hand1 during development, we generated a Hand1 knockout mouse. Hand1-null mice survived to the nine somite stage at which time they succumbed to numerous developmental defects. One striking defect in Hand1-null embryos was the accumulation of hematopoietic cells between the yolk sac and the amnion because of defects in the yolk sac vasculature. In Hand1-null yolk sacs, vasculogenesis occurs but vascular refinement was arrested. Analysis of angiogenic genes in extra-embryonic membranes showed that most are expressed at normal levels in Hand1-null embryos but several, including Vegf, Ang1 and ephrin B2, and gene components of the Notch pathway are upregulated. In the absence of Hand1 the expression of the bHLH factor Hand2 is also enhanced. Although HAND1 and HAND2 share many structural features, and Hand2 is required for vasculature development in yolk sacs, enhanced expression of Hand2 is insufficient to compensate for the loss of Hand1. The most striking aspect of the vascular defect in Hand1 mutant yolk sacs is the abnormal distribution of smooth muscle cells. During normal angiogenesis,vascular smooth muscle precursors are recruited to the peri-endothelial tissue before differentiation, however, in Hand1 null yolk sacs, smooth muscle cells are not recruited but differentiate in clusters distributed throughout the mesoderm. These data indicate that Hand1 is required for angiogenesis and vascular smooth muscle recruitment in the yolk sac.
TheC. elegansheterochronic genelin-46affects developmental timing at two larval stages and encodes a relative of the scaffolding protein gephyrin
Authors: Pepper Anita S.-R. , McCane Jill E. , Kemper Kevin , Yeung Denise Au , Lee Rosalind C. , Ambros Victor , Moss Eric G.
Published: April 2004

The succession of developmental events in the C. elegans larva is governed by the heterochronic genes. When mutated, these genes cause either precocious or retarded developmental phenotypes, in which stage-specific patterns of cell division and differentiation are either skipped or reiterated, respectively. We identified a new heterochronic gene, lin-46, from mutations that suppress the precocious phenotypes caused by mutations in the heterochronic genes lin-14 and lin-28. lin-46 mutants on their own display retarded phenotypes in which cell division patterns are reiterated and differentiation is prevented in certain cell lineages. Our analysis indicates that lin-46 acts at a step immediately downstream of lin-28, affecting both the regulation of the heterochronic gene pathway and execution of stage-specific developmental events at two stages: the third larval stage and adult. We also show that lin-46 is required prior to the third stage for normal adult cell fates, suggesting that it acts once to control fates at both stages, and that it affects adult fates through the let-7 branch of the heterochronic pathway. Interestingly, lin-46 encodes a protein homologous to MoeA of bacteria and the C-terminal domain of mammalian gephyrin, a multifunctional scaffolding protein. Our findings suggest that the LIN-46 protein acts as a scaffold for a multiprotein assembly that controls developmental timing, and expand the known roles of gephyrin-related proteins to development.
Valuing the benefits of a health intervention using three different approaches to contingent valuation: re-treatment of mosquito bed-nets in Nigeria
Authors: Onwujekwe Obinna , Fox-Rushby Julia , Hanson Kara
Published: April 2004

Objectives: To determine the level of willingness to pay (WTP) for re-treatment of mosquito nets and to compare the theoretical validity of WTP estimates from three contingent valuation question formats: the bidding game, binary with follow-up technique, and a novel structured haggling technique that mimicked price-taking behaviour in the study area.

Methods: WTP was elicited from randomly selected respondents from three villages in Southeast Nigeria, using pretested interviewer-administered questionnaires. Respondents' WTP for insecticide-treated nets (ITNs) was first elicited before their WTP for re-treatment of ITNs. Ordinary least-squares regression was used to assess theoretical validity.

Results: More than 95% of the respondents were willing to pay for re-treatment. The mean WTP was 37.1 Naira, 43.4 Naira and 49.2 Naira in the bidding game, binary with follow-up and structured haggling groups, respectively (US$1.00 = 120 Naira). The WTP estimates elicited across the three question formats were statistically different ( P < 0.01). Ordinary least-squares estimation showed that WTP was positively related to many variables, especially stated WTP for ITNs ( P < 0.05). Structured haggling generated the highest number of statistically significant variables to explain WTP.

Conclusions: The three contingent valuation approaches generated different distributions of WTP for net retreatment, possibly due to their inherent differences. Structured haggling generated the most theoretically valid estimates of WTP. The levels of WTP identified suggest that user fees exceeding 50 Naira per net re-treatment may discourage demand for the service. This is an important challenge for ITN programmes.
Design of Large Space Structures with Imperfection Using ANN-Based Simulator
Authors: Horr A. M. , Asadsajadi S. R. , Safi M.
Published: April 2004

Based on the advanced computational plasticity and an artificial neural network (ANN) simulator, a new design strategy has been presented for large space structures with imperfections. Nonlinear system identification approach has also been greatly spread among the researchers and engineers in the past few years. The neural network simulators as a non-parametric system identification approach present a robust and efficient way to simulate the nonlinear behaviour of engineering systems. In the paper herein an artificial neural network (ANN) simulator, a general back error propagating perceptron, is use to simulate random imperfection for nonlinear dynamic analysis of large space structures. It is also desirable to search for a procedure for wind pressure calculation with accuracy and reliability. In this respect, attention is paid to the advanced computational fluid dynamics (CFD). The use of the advanced CFD analysis can help engineers to estimate the wind pressure for the design of large space structures with complex geometries. The characteristics of the new design method have been shown graphically using a full documented numerical example, which highlights the efficiency of the new simulation method. The purpose of this paper is to present a new design method, which takes into account the effects of imperfection on the resulting dynamic responses of large space structures under gravity, temperature and wind loadings.