bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Inhaled Iloprost on Transpulmonary Gradient of Big Endothelin in Patients With Pulmonary Hypertension
Authors: Wilkens H. , Bauer M. , Forestier N. , König J. , Eichler A. , Schneider S. , Schäfers H.J. , Sybrecht G.W.
Published: March 2003

Background—

The pulmonary circulation is an important site for the production and clearance of endothelin (ET)-1, a potent vasoactive and mitogenic peptide. In healthy individuals, 40% to 50% of circulating ET-1 is removed on each passage through the lungs resulting in an arteriovenous ratio of <1, whereas many patients with pulmonary arterial hypertension (PAH) have ratios >1, indicating reduced clearance or increased release of endothelin. The influence of inhaled prostanoids on endothelin clearance is unknown.

Methods and Results—

In a prospective investigation, plasma concentrations of big endothelin-1 (big ET-1, Elisa) were measured in 15 patients with pulmonary hypertension undergoing right heart catheterization with iloprost inhalation (4 m, 11 f, aged 35 to 75 years, mean pulmonary arterial pressure (PAPm) 54±2.3 mm Hg, pulmonary vascular resistance (PVR) 1061±141 dyn × sec × cm
−5
). There was a significant transpulmonary gradient for big ET-1 with 31% ±11% higher concentrations in the radial artery than in the pulmonary artery (
P
<0.001). After inhalation of iloprost a significant decrease in the AV-ratio from 1.31±0.11 to 0.92±0.06 (
P
<0.007) was observed. The pulmonary net release of 3.10±0.65 pmol/min big ET-1 at baseline decreased to -1.24±1.32 pmol/min (
P
=0.013) within 15 minutes indicating a restored balance. Patients under long-term treatment with iloprost (n=7) tended to have a lower net release and AV-ratio for big ET-1 than patients without pretreatment.

Conclusion—

An increase in pulmonary clearance of big-ET could be a mechanism contributing to the beneficial effects of inhaled prostanoids in the treatment of PAH.
Value of Magnetic Resonance Imaging for the Noninvasive Detection of Stenosis in Coronary Artery Bypass Grafts and Recipient Coronary Arteries
Authors: Langerak Susan E. , Vliegen Hubert W. , Jukema J. Wouter , Kunz Patrik , Zwinderman Aeilko H. , Lamb Hildo J. , van der Wall Ernst E. , de Roos Albert
Published: March 2003

Background—

Magnetic resonance imaging (MRI) is a potential noninvasive diagnostic tool to detect coronary artery bypass graft stenosis, but its value in clinical practice remains to be established. We investigated the value of MRI in detecting stenotic grafts, including recipient vessels.

Methods and Results—

We screened for inclusion 173 consecutive patients who were scheduled for coronary angiography because of recurrent chest pain after coronary artery bypass grafting (CABG). We studied 69 eligible patients with 166 grafts (81 single vein, 44 sequential vein, and 41 arterial grafts). MRI with baseline and stress flow mapping was performed. Both scans were successful in 80% of grafts. Grafts were divided into groups with stenosis ≥50% (n=72) and ≥70% (n=48) in the graft or recipient vessels. Marginal logistic regression was used to predict the probability for the presence of stenosis per graft type using multiple MRI variables. Receiver operator characteristics (ROC) analysis was performed to assess the diagnostic value of MRI. Sensitivity (95% confidence interval)/specificity (95% confidence interval) in detecting single vein grafts with stenosis ≥50% and ≥70% were 94% (86 to 100)/63% (48 to 79) and 96% (87 to 100)/92% (84 to 100), respectively.

Conclusions—

MRI with flow mapping is useful for identifying grafts and recipient vessels with flow-limiting stenosis. Flow scans could be obtained in 80% of the grafts. This proof-of-concept study suggests that noninvasive MRI detection of stenotic grafts in patients who present with recurrent chest pain after CABG may be useful in selecting those in need of an invasive procedure.
Adjunctive Platelet Glycoprotein IIb/IIIa Receptor Inhibition With Tirofiban Before Primary Angioplasty Improves Angiographic Outcomes
Authors: Lee David P. , Herity Niall A. , Hiatt Bonnie L. , Fearon William F. , Rezaee Mehrdad , Carter Andrew J. , Huston Michelle , Schreiber Donald , DiBattiste Peter M. , Yeung Alan C.
Published: March 2003

Background—

Previous work has suggested that platelet glycoprotein IIb/IIIa receptor blockade may confer benefit in the treatment of acute myocardial infarction. The TIGER-PA pilot trial was a single-center randomized study to evaluate the safety, feasibility, and utility of early tirofiban administration before planned primary angioplasty in patients presenting with acute myocardial infarction.

Methods and Results—

A total of 100 patients presenting with acute myocardial infarction were randomized to either early administration of tirofiban in the emergency room or later administration in the catheterization laboratory. The primary outcome measures were initial TIMI grade flow, corrected TIMI frame counts, and TIMI grade myocardial perfusion (“blush”). Thirty-day major adverse cardiac events were also assessed. Angiographic outcomes demonstrate a significant improvement in initial TIMI grade flow, corrected TIMI frame counts, and TIMI grade myocardial perfusion when patients are given tirofiban in the emergency room before primary angioplasty. The rate of 30-day major adverse cardiac events suggests that early administration may be beneficial.

Conclusions—

This pilot study suggests that early administration of tirofiban improves angiographic outcomes and is safe and feasible in patients undergoing primary angioplasty for acute myocardial infarction.
Correlation Between Anatomy and Electrical Activation in Canine Pulmonary Veins
Authors: Hamabe Akira , Okuyama Yuji , Miyauchi Yasushi , Zhou Shengmei , Pak Hui-Nam , Karagueuzian Hrayr S. , Fishbein Michael C. , Chen Peng-Sheng
Published: March 2003

Background—

The roles of complex muscle sleeve geometry and fiber orientation in the pulmonary veins (PVs) in wave-front propagation are poorly understood.

Methods and Results—

We mapped the left superior PV (LSPV, n=7) and left inferior PV (LIPV, n=4) of dogs with 420 bipolar electrodes (1-mm resolution) and performed detailed histological examination. In the anterior LSPV–left atrial (LA) junction, myocardial muscle fibers were oriented perpendicular to PV blood flow. A wedge filled with connective tissues led to a complete muscle separation or an abrupt increase in muscle thickness between the PV and LA (0.42±0.12 versus 2.0±0.31 mm,
P
<0.01). Distal LSPV pacing resulted in conduction block at the anterior PV-LA junction, with double potentials. In contrast, the posterior LSPV-LA junction showed gradual muscle thickening and a fiber orientation parallel to the blood flow. The maximum PV muscle thickness in the anterior PV-LA junction is thinner than that in the posterior junction (0.83±0.15 versus 1.3±0.38 mm,
P
<0.01). Distal LIPV pacing showed multiple PV-LA breakthroughs, with segmental conduction block in the anterior PV-LA junction. The conduction block corresponded to segmental PV-LA muscle disconnection. Complex fiber orientations in the PV muscle sleeves away from the PV-LA junction were responsible for intra-PV conduction delay or block during rapid PV pacing.

Conclusions—

We conclude that segmental muscle disconnection and differential muscle narrowing at PV-LA junctions and complex fiber orientations within the PV provide robust anatomical bases for conduction disturbance at the PV-LA junction and complex intra-PV conduction patterns.
Insulin-Stimulated Cyclic Guanosine Monophosphate Inhibits Vascular Smooth Muscle Cell Migration by Inhibiting Ca/Calmodulin-Dependent Protein Kinase II
Authors: Zhang Sui , Yang Yu , Kone Bruce C. , Allen Julius C. , Kahn Andrew M.
Published: March 2003

Background—

Insulin resistance is associated with vascular disease. Physiological concentrations of insulin inhibit cultured vascular smooth muscle cell (VSMC) migration in the presence of nitric oxide, and the failure to do so in insulin-resistant states may aggravate vascular disease. We sought to determine the molecular mechanisms by which insulin inhibits VSMC migration.

Methods and Results—

Insulin at 1 nmol/L stimulated cGMP production in cultured rat VSMCs that were induced to express inducible nitric oxide synthase (iNOS). VSMC migration was measured in a wound-closure assay, and the platelet-derived growth factor-AB (PDGF-AB)-stimulated component of VSMC migration after wounding was inhibited by insulin, 8-Br-cGMP, and 1-[
N
-0-bis(5-isoquinolinesulfonyl)-
N
-methyl-
l
-tyrosyl]-4-phenylpiperazine (KN-62), a selective inhibitor of calcium/calmodulin-dependent protein kinase II (CaM kinase II). Wounding alone or incubating cells with only PDGF-AB stimulated CaM kinase II activity in an insulin- and 8-Br-cGMP-inhibitable manner. Transfecting VSMCs with a constitutively active CaM kinase II mutant blocked the inhibition by insulin of both wound-induced and wound plus PDGF-AB-induced VSMC migration. High intracellular Ca
2+
([Ca]
i
)-stimulated CaM kinase II activity was inhibited by 8-Br-cGMP by an okadaic acid-sensitive mechanism.

Conclusions—

We conclude that in cultured rat VSMCs expressing iNOS, insulin, via stimulation of cGMP production, inhibits both wound alone-induced and the PDGF-AB-stimulated component of VSMC migration by inhibiting CaM kinase II activity. cGMP inhibits CaM kinase II at a post-[Ca]
i
step by a protein phosphatase-dependent mechanism.
Why Are Patients With Chronic Obstructive Pulmonary Disease at Increased Risk of Cardiovascular Diseases?
Authors: Sin Don D. , Man S.F. Paul
Published: March 2003

Background—

Chronic obstructive pulmonary disease (COPD) increases the risk of cardiovascular disease 2- to 3-fold. The factors responsible for this association remain largely unknown.

Methods and Results—

We analyzed data from participants, ≥50 years of age, of the Third National Health and Nutrition Examination Survey (n=6629) to determine whether C-reactive protein (CRP) and other systemic inflammatory markers are present in participants with chronic airflow obstruction and are associated with cardiac injury. Participants with severe airflow obstruction had circulating leukocyte, platelet, and fibrinogen levels that were 460/μL (95% confidence interval [CI], 30 to 890/μL), 39 510/μL (95% CI, 21 730 to 57 290/μL), and 41.63 mg/dL (95% CI, 19.87 to 63.39 mg/dL) higher, respectively, than in those without airflow obstruction. They were also 2.18 times (95% CI, 1.46 to 3.27) more likely to have an elevated circulating CRP level. Moderate airflow obstruction was associated with smaller but still significant increases in these levels. Moderate and severe airflow obstruction was associated with increased occurrence of ischemic changes on electrocardiograms of participants. In the presence of both highly elevated CRP and moderate or severe airflow obstruction, the Cardiac Infarction Injury Score was 2.68 and 5.88 U higher, respectively, than in those without airflow obstruction and with low CRP, which suggests an additive effect of CRP and COPD on the risk of cardiac injury.

Conclusion—

Low-grade systemic inflammation was present in participants with moderate to severe airflow obstruction and was associated with increased risk of cardiac injury. This may in part explain the high rates of cardiovascular complications in COPD.
Inflammatory Markers and Risk of Heart Failure in Elderly Subjects Without Prior Myocardial Infarction
Authors: Vasan Ramachandran S. , Sullivan Lisa M. , Roubenoff Ronenn , Dinarello Charles A. , Harris Tamara , Benjamin Emelia J. , Sawyer Douglas B. , Levy Daniel , Wilson Peter W.F. , D’Agostino Ralph B.
Published: March 2003

Background—

Experimental studies support a key role for cytokines in left ventricular remodeling. In congestive heart failure (CHF) patients, elevated plasma cytokine levels are associated with worse functional status and adverse prognosis. It is unclear whether cytokine levels can predict the incidence of CHF in asymptomatic individuals.

Methods and Results—

We investigated the relations of serum interleukin-6 (IL-6), C-reactive protein (CRP), and spontaneous production of tumor necrosis factor-α (TNFα) by peripheral blood mononuclear cell (PBMC) to CHF incidence among 732 elderly Framingham Study subjects (mean age 78 years, 67% women) free of prior myocardial infarction and CHF. On follow-up (mean 5.2 years), 56 subjects (35 women) developed CHF. After adjustment for established risk factors, including the occurrence of myocardial infarction on follow-up, there was a 60 (PBMC TNFα) to 68% (serum IL-6) increase in risk of CHF per tertile increment in cytokine concentration (
P
=0.04, and 0.03, respectively, for trend). A serum CRP level ≥5 mg/dL was associated with a 2.8-fold increased risk of CHF (
P
=0.02). Subjects with elevated levels of all 3 biomarkers (serum IL-6 and PBMC TNFα >median values, CRP≥5 mg/dL) had a markedly increased risk of CHF (hazards ratio 4.07 [95% CI 1.34 to 12.37],
P
=0.01) compared with the other subjects.

Conclusions—

In our elderly, community-based sample, a single determination of serum inflammatory markers, particularly elevated IL-6, was associated with increased risk of CHF in people without prior myocardial infarction. Additional epidemiological investigations are warranted to confirm the contribution of inflammation to the pathogenesis of CHF in the general population.
Family History and Cardiovascular Risk in Familial Hypercholesterolemia
Authors: Wiegman Albert , Rodenburg Jessica , de Jongh Saskia , Defesche Joep C. , Bakker Henk D. , Kastelein John J.P. , Sijbrands Eric J.G.
Published: March 2003

Background—

Elevated LDL cholesterol (LDL-C) levels in childhood predict cardiovascular disease (CVD) later in life. Familial hypercholesterolemia (FH) represents the paradigm of this relation.

Methods and Results—

The objectives of this study were to (1) establish the LDL-C level that provides the most accurate diagnosis of FH in children from families with known FH and (2) assess whether lipoprotein variation in these children is associated with premature CVD in relatives. Foremost, however, it was our objective to identify children with FH who are at high risk and in need of early intervention. A total of 1034 consecutive children from FH kindreds were investigated. First, LDL-C levels >3.50 mmol/L had a 0.98 post-test probability (95% CI, 0.96 to 0.99) of predicting the presence of an LDL receptor mutation. Second, children with FH in the highest LDL-C tertile (>6.23 mmol/L) had a 1.7-times higher incidence (95% CI, 1.24 to 2.36) of having a parent with FH suffering from premature CVD (
P
=0.001). In addition, such a parent was found 1.8 times more often (95% CI, 1.20 to 2.59) among children with FH who had HDL-C <1.00 mmol/L (
P
=0.004). Last, children with FH whose lipoprotein(a) was >300 mg/L had a 1.45-times higher incidence (95% CI, 0.99 to 2.13) of having a parent with FH suffering from premature CVD (
P
=0.05).

Conclusions—

In FH families, LDL-C levels allow accurate diagnosis of FH in childhood. Moreover, increased LDL-C and lipoprotein(a) and decreased HDL-C levels in children identify FH kindreds with the highest CVD risk.
Mitral Annular Calcification Predicts Cardiovascular Morbidity and Mortality
Authors: Fox Caroline S. , Vasan Ramachandran S. , Parise Helen , Levy Daniel , O’Donnell Christopher J. , D’Agostino Ralph B. , Benjamin Emelia J.
Published: March 2003

Background—

Mitral annular calcification (MAC) has been associated with stroke in longitudinal, community-based cohorts and cardiovascular disease (CVD) outcomes in many small retrospective studies. Prospective data are limited on the relation of MAC with CVD morbidity and mortality.

Methods and Results—

We examined the association between MAC assessed by M-mode echocardiography and the incidence of CVD, CVD death, and all-cause death over 16 years of follow-up in the Framingham Heart Study subjects who attended a routine examination between 1979 and 1981. Cox proportional hazards models were used to estimate hazard ratios (HRs) associated with the presence of MAC for each outcome. Of 1197(445 male, 752 female) subjects who had adequate echocardiographic assessment, 14% had MAC. There were 307 incident CVD events and 621 deaths. In multivariable adjusted analyses, MAC was associated with an increased risk of incident CVD (HR, 1.5; 95% CI, 1.1, 2.0), CVD death (HR, 1.6; 95% CI, 1.1, 2.3), and all-cause death (HR, 1.3; 95% CI, 1.04, 1.6). For each 1-mm increase in MAC, the risk of incident CVD, CVD death, and all-cause death increased by ≈10%.

Conclusions—

The independent association of MAC with incident CVD and CVD death underscores that cardiac calcification is a marker of increased CVD risk.
L-4F, an Apolipoprotein A-1 Mimetic, Restores Nitric Oxide and Superoxide Anion Balance in Low-Density Lipoprotein-Treated Endothelial Cells
Authors: Ou Zhijun , Ou Jingsong , Ackerman Allan W. , Oldham Keith T. , Pritchard Kirkwood A.
Published: March 2003

Background—

Low-density lipoprotein (LDL) impairs endothelial cell function by uncoupling endothelial nitric oxide synthase (eNOS) activity, which allows superoxide anion (O
2
·−
) to be generated rather than nitric oxide (·NO). Recent reports indicate that apolipoprotein (apo) A-1 mimetics inhibit the development of atherosclerotic lesions in LDL receptor-null mice. Here we hypothesize that L-4F, an apoA-1 mimetic that inhibits atherosclerosis induced by hypercholesterolemia, protects endothelial cell function by preventing LDL from uncoupling eNOS activity.

Methods and Results—

Bovine aortic endothelial cells were incubated with LDL±L-4F, and changes in A23187-stimulated ·NO and O
2
·−
generation were determined by ozone chemiluminescence and superoxide dismutase-inhibitable ferricytochrome c reduction, respectively. Western analysis of eNOS immunoprecipitates was used to determine effects of LDL and L-4F on heat shock protein 90 (hsp90) interactions with eNOS. LDL decreased ·NO production and increased eNOS-dependent O
2
·−
generation. Pretreatment of LDL with L-4F increased ·NO and decreased O
2
·−
generation. By itself, L-4F had no effect on O
2
·−
but did increase ·NO generation. Stimulation of endothelial cells incubated with LDL decreased the association of hsp90 with eNOS. Pretreatment of LDL with L-4F prevented a decrease in hsp90 association with eNOS and often enhanced association on stimulation.

Conclusions—

These data demonstrate that L-4F protects endothelial cell function by preventing LDL from uncoupling eNOS activity. L-4F allows endothelial cell to maintain coupled eNOS activity to generate ·NO even in the face of atherogenic concentrations of LDL.
Display of Fas Ligand Protein on Cardiac Vasculature as a Novel Means of Regulating Allograft Rejection
Authors: Askenasy Nadir , Yolcu Esma S. , Wang Zhiliang , Shirwan Haval
Published: March 2003

Background—

Fas ligand (FasL) is a potent death-inducing molecule with important functions in immune homeostasis and tolerance to self-antigens. The complex biological activities of FasL and its inefficient expression using conventional gene transfer approaches limit its use for immunomodulation to prevent allograft rejection. We have recently generated a chimeric FasL with core streptavidin (SA-FasL) with potent apoptotic activity and designed a novel approach to display it on the surface of several cell types via biotinylation. We herein tested whether SA-FasL can also be displayed on vascular endothelial cells in the heart and examined its effect on graft survival after transplantation into syngeneic and allogeneic hosts.

Methods and Results—

SA-FasL was efficiently displayed on the vasculature of BALB/c hearts with a half-life of 9 days in vivo. Transplantation of hearts displaying SA-FasL into syngeneic hosts resulted in indefinite graft survival without detectable toxicity to the grafts and hosts. In contrast, transplantation of allogeneic C57BL/10 hearts displaying SA-FasL into BALB/c recipients resulted in graft rejection, but in a delayed fashion as compared with control hearts (mean survival time=17.4±5 versus 9.6±1 days). Allograft survival was further extended to 21±2.6 and 24±3 days (
P
<0.05) by intravenous treatment of graft recipients with 1 dose of SA-FasL–decorated donor splenocytes on days 2 and 6 after transplantation, respectively.

Conclusions—

This study shows for the first time that exogenous proteins can be displayed on the endothelium of solid organs for therapeutic purposes. This approach provides a convenient and rapid means of displaying exogenous proteins on the surface of cells, tissues, and solid organs, with broad research and therapeutic implications.
High Temperature Surface Oxidation of Metallic Fibres for Hot Gas Filtration
Authors: Fei W. , Kuiry S. C. , Seal S. , Scammon K. , Quick N. , June M.
Published: March 2003

Metal hot gas filters made of Fe-Cr-Al alloy fibre media have been developed to meet the increasingly stringent requirement for hot gas filtration. High temperature oxidation behaviour of Fe-Cr-Al alloy fibre media consisting of a random non-woven feltlike structure was studied at a temperature of 1255 K in dry air. Two types of Fe-Cr-Al alloys, namely Hoskins 875 and Fe-Cr-Al-Mo were used in the present study. The oxidation kinetics was found to follow the parabolic law for thick fibres (25 μm). The scale morphology and chemical composition were studied by SEM/EDAX. Focused ion beam (FIB) was used to investigate the scale cross-section. X-ray photoelectron spectroscopy (XPS) and Auger electron spectroscopy (AES) studies confirmed that alumina scale forms on the surface of the Fe-Cr-Al alloy fibre media. Both fibres, 12 μm in diameter, showed short lifetimes at 1255 K. Fe-Cr-Al-Mo was found to have more oxidation resistance than Hoskins 875 at 1255 K.
A 6-month versus a 12-month surveillance for hepatocellular carcinoma in 559 hemophiliacs infected with the hepatitis C virus
Authors: Santagostino Elena , Colombo Massimo , Rivi Monica , Rumi Maria Grazia , Rocino Angiola , Linari Silvia , Mannucci Pier Mannuccio ,   for the the Study Group of the Association of Italian Hemophilia Centers
Published: March 2003

Hepatocellular carcinoma (HCC) is an increasingly frequent cause of mortality in hemophiliacs with chronic viral hepatitis. Early diagnosis of the tumor at an initial stage is known to improve the outcome of HCC treatment. Because all HCC cases detected in a previous study based upon annual ultrasound (US) surveillance of hemophiliacs with elevated alanine aminotransferase levels were multinodular, this study was designed to evaluate if a more intense surveillance with US and alphafetoprotein (AFP) serum levels of all the patients infected with the hepatitis C virus (HCV) improved the identification of single nodule tumors. A multicenter cohort of 559 HCV-infected hemophiliacs was divided into 2 arms, one followed up at 6-month intervals and one at 12-month intervals depending on the choice and available facilities of each treatment center. During a 6-year surveillance period, HCC was diagnosed in 5 (2.4%) of 210 patients in the 6-month group and in 3 (0.9%) of 349 patients in the 12-month group. The overall incidence rate of HCC was 239 per 100 000 per year (397 per 100 000 per year in the 6-month group and 143 per 100 000 per year in the 12-month group; differences not statistically significant). By multivariate analysis, HCC risk was increased 12.9-fold with alcohol intake more than 80 g/d and 15.2-fold with AFP levels higher than 11 ng/mL. Liver-related death occurred in 8 cases (1.4%), including 3 with HCC. Still alive and tumor free after 24 to 34 months from diagnosis are 3 patients with multinodular tumors treated with repeat chemoembolization followed by orthotopic liver transplantation. In conclusion, 6-month surveillance with US did not increase the chances of detection of single nodule tumors, but it is reasonable to assume that successful treatment of multinodular tumors based upon debulking with chemoembolization and liver transplantation was facilitated by this approach. (Blood. 2003;102:78-82)
NMDA receptor–mediated regulation of human megakaryocytopoiesis
Authors: Hitchcock Ian S. , Skerry Timothy M. , Howard Martin R. , Genever Paul G.
Published: March 2003

Identification of the regulatory inputs that direct megakaryocytopoiesis and platelet production is essential for the development of novel therapeutic strategies for the treatment of thrombosis and related hematologic disorders. We have previously shown that primary human megakaryocytes express the N-methyl-d-aspartate acid (NMDA) receptor 1 (NR1) subunit of NMDA-type glutamate receptors, which appear to be pharmacologically similar to those identified at neuronal synapses, responsible for mediating excitatory neurotransmission in the central nervous system. However, the functional role of NMDA receptor signaling in megakaryocytopoiesis remains unclear. Here we provide evidence that demonstrates the fundamental importance of this signaling pathway during human megakaryocyte maturation in vitro. Reverse transcriptase–polymerase chain reaction (RT-PCR) analysis of RNA extracted from CD34+-derived megakaryocytes identified expression of NR2A and NR2D receptor subunits in these cells, as well as the NMDA receptor accessory proteins, Yotiao and postsynaptic density protein 95 (PSD-95). In functional studies, addition of a selective NMDA receptor antagonist, MK-801 inhibited proplatelet formation, without affecting proliferation or apoptosis. Exposure of CD34+ cells to MK-801 cultured for 14 days in the presence of thrombopoietin induced a decrease in expression of the megakaryocyte cell surface markers CD61, CD41a, and CD42a compared with controls. At an ultrastructural level, MK-801–treated cells lacked α-granules, demarcated membranes, and multilobed nuclei, which were prominent in untreated mature megakaryocyte controls. Using immunohistochemistry on sections of whole tibiae from c-Mpl knockout mice we demonstrated that megakaryocytic NMDA receptor expression was maintained following c-Mpl ablation. These data support a fundamental role for glutamate signaling in megakaryocytopoiesis and platelet production, which is likely to be independent of thrombopoietin-mediated effects.
Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease
Authors: O'Brien Lee A. , James Paula D. , Othman Maha , Berber Ergul , Cameron Cherie , Notley Colleen R. P. , Hegadorn Carol A. , Sutherland Jeffrey J. , Hough Christine , Rivard Georges E. , O'Shaunessey Denise , Lillicrap David ,   the Association of Hemophilia Clinic Directors of Canada
Published: March 2003

To date, no dominant mutation has been identified in a significant proportion of patients with type 1 von Willebrand disease (VWD). In this study, we examined 70 families as part of the Canadian Type 1 VWD Study. The entire VWF gene was sequenced for 1 index case, revealing 2 sequence variations: intron 30 (5312—19A>C) and exon 28 at Tyr1584Cys (4751A>G). The Tyr1584Cys variation was identified in 14.3% (10 of 70) of the families and was in phase with the 5312—19A>C variation in 7 (10.0%) families. Both variants were observed in 2 of 10 UK families with type 1 VWD, but neither variant was found in 200 and 100 healthy, unrelated persons, respectively. Mean von Willebrand factor antigen (VWF:Ag), VWF ristocetin cofactor (VWF:RCo), and factor VIII coagulant activity (FVIII:C) for the index cases in these families are 0.4 U/mL, 0.36 U/mL, and 0.54 U/mL, respectively, and VWF multimer patterns show no qualitative abnormalities. Aberrant VWF splicing was not observed in these patients, and both alleles of the VWF gene are expressed as RNA. Molecular dynamic simulation was performed on a homology model of the VWF-A2 domain containing the Tyr1584Cys mutation. This showed that no significant structural changes occur as a result of the substitution but that a new solvent-exposed reactive thiol group is apparent. Expression studies revealed that the Tyr1584Cys mutation results in increased intracellular retention of the VWF protein. We demonstrate that all the families with the Tyr1584Cys mutation share a common, evolved VWF haplotype, suggesting that this mutation is ancient. This is the first report of a mutation that segregates in a significant proportion of patients with type 1 VWD.
The NOD/SCID chimeric mouse model of human B cell development: studies on the VH4 family immunoglobulin repertoire and implications for SLE
Authors: Kolar G R , Capra J D
Published: March 2003

The use of the NOD=SCID mouse as a transplant recipient for human cord blood B cell progenitorsas a tool for investigations into the development of human B cells has become an exciting reality. The characteristics of the immunoglobulin repertoire in such a model is important to investigate, as it is possiblethat normal or skewed representationscould be produced.Here we reviewour current work in which we describe a normal VH4 repertoire produced in this chimeric mouse model and describe the differences in combinatorial diversity between the human cells that were isolated from the bone marrow and spleen. The implications of this model for studies of systemic lupus erythematosus are also discussed.
Joseph Mecke: an appreciation
Authors: Mecke Joseph
Published: March 2003

Joseph Mecke, Professor of Mathematics at the Friedrich Schiller University, Jena, celebrates his 65th birthday on 18 February 2003. To commemorate this happy occasion, the signatories invited some colleagues, friends and former students to honour Joseph as a mathematician, teacher and research worker by submitting research articles to this issue of Advances in Applied Probability. We trust that the following papers will pay homage to the influence he has exerted in point process theory and stochastic geometry during his distinguished career.
Bayesian analysis of deformed tessellation models
Authors: Blackwell Paul G. , Møller Jesper
Published: March 2003

We define a class of tessellation models based on perturbing or deforming standard tessellations such as the Voronoi tessellation. We show how distributions over this class of ‘deformed’ tessellations can be used to define prior distributions for models based on tessellations, and how inference for such models can be carried out using Markov chain Monte Carlo methods; stability properties of the algorithms are investigated. Our approach applies not only to fixed dimension problems, but also to variable dimension problems, in which the number of cells in the tessellation is unknown. We illustrate our methods with two real examples. The first relates to reconstructing animal territories, represented by the individual cells of a tessellation, from observation of an inhomogeneous Poisson point process. The second example involves the analysis of an image of a cross-section through a sample of metal, with the tessellation modelling the micro-crystalline structure of the metal.
Estimation of mean particle volume using the set covariance function
Authors: Cabo Annoesjka , Baddeley Adrian
Published: March 2003

Our aim is to estimate the volume-weighted mean of the volumes of three-dimensional ‘particles’ (compact, not-necessarily-convex subsets) from plane sections of the particle population. The standard stereological technique is to place test lines in the plane section, and measure cubed intercept lengths with the two-dimensional particle profiles. This paper discusses more efficient estimators obtained by integrating over all possible placements of the test line. We prove that these estimators have smaller variance than the line transect estimators, and indeed are related to them by the Rao-Blackwell process. In the improved estimators, the cubed intercept length is replaced by a moment of the distance between two points in the section profile. This can be computed as a moment of the set covariance function, which in turn is computable using the fast Fourier transform. We also derive an isoperimetric-type inequality between the improved estimator and the area-weighted 3/2th moment of the profile areas. Finally, we present two practical applications to particles of silicon carbide and to synaptic boutons in brain tissue. We estimate the variance of the technique and the gain in efficiency over line transect techniques; the efficiency improvement appears to be as much as one order of magnitude.
A new graph related to the directions of nearest neighbours in a point process
Authors: Chiu S. N. , Molchanov I. S.
Published: March 2003

This paper introduces a new graph constructed from a point process. The idea is to connect a point with its nearest neighbour, then to the second nearest and continue this process until the point belongs to the interior of the convex hull of these nearest neighbours. The number of such neighbours is called the degree of a point. We derive the distribution of the degree of the typical point in a Poisson process, prove a central limit theorem for the sum of degrees, and propose an edge-corrected estimator of the distribution of the degree that is unbiased for a stationary Poisson process. Simulation studies show that this degree is a useful concept that allows the separation of clustering and repulsive behaviour of point processes.
Decomposition of gamma-distributed domains constructed from Poisson point processes
Authors: Cowan Richard , Quine Malcolm , Zuyev Sergei
Published: March 2003

A known gamma-type result for the Poisson process states that certain domains defined through configuration of the points (or ‘particles’) of the process have volumes which are gamma distributed. By proving the corresponding sequential gamma-type result, we show that in some cases such a domain allows for decomposition into subdomains each having independent exponentially distributed volumes. We consider other examples—based on the Voronoi and Delaunay tessellations—where a natural decomposition does not produce subdomains with exponentially distributed volumes. A simple algorithm for the construction of a typical Voronoi flower arises in this work. In our theoretical development, we generalize the classical theorem of Slivnyak, relating it to the strong Markov property of the Poisson process and to a result of Mecke and Muche (1995). This new theorem has interest beyond the specific problems being considered here.
Distance measurements on processes of flats
Authors: Hug Daniel , Last Günter , Weil Wolfgang
Published: March 2003

Distance measurements are useful tools in stochastic geometry. For a Boolean modelZin ℝd, the classical contact distribution functions allow the estimation of important geometric parameters ofZ. In two previous papers, several types of generalized contact distributions have been investigated and applied to stationary and nonstationary Boolean models. Here, we consider random setsZwhich are generated as the union sets of Poisson processesXofk-flats,k∈ {0, …,d-1}, and study distances from a fixed point or a fixed convex body toZ. In addition, we also consider the distances from a given flat or a flag consisting of flats to the individual members ofXand investigate the associated process of nearest points in the flats ofX. In particular, we discuss to which extent the directional distribution ofXis determined by this point process. Some of our results are presented for more general stationary processes of flats.
Ising models and multiresolution quad-trees
Authors: Kendall W. S. , Wilson R. G.
Published: March 2003

We study percolation and Ising models defined on generalizations of quad-trees used in multiresolution image analysis. These can be viewed as trees for which each mother vertex has
2d daughter vertices, and for which daughter vertices are linked together in d-dimensional Euclidean configurations. Retention probabilities and interaction strengths differ according to whether the relevant bond is between mother and daughter or between neighbours. Bounds are established which locate phase transitions and show the existence of a coexistence phase for the percolation model. Results are extended to the corresponding Ising model using the Fortuin-Kasteleyn random-cluster representation.
Limits of sequences of stationary planar tessellations
Authors: Nagel Werner , Weiss Viola
Published: March 2003

In order to increase the variety of feasible models for random stationary tessellations (mosaics), two operations acting on tessellations are studied: superposition and iteration (the latter is also referred to as nesting). The superposition of two planar tessellations is the superposition of the edges of the cells of both tessellations. The iteration of tessellations means that one tessellation is chosen as a ‘frame’ tessellation. The single cells of this ‘frame’ are simultaneously and independently subdivided by cut-outs of tessellations of an independent and identically distributed sequence of tessellations. In the present paper, we investigate the limits for sequences of tessellations that are generated by consecutive application of superposition or iteration respectively. Sequences of (renormalised) superpositions of stationary planar tessellations converge weakly to Poisson line tessellations. For consecutive iteration the notion of stability of distributions is adapted and necessary conditions are formulated for those tessellations which may occur as limits.
Nonstationary Poisson hyperplanes and their induced tessellations
Authors: Schneider Rolf
Published: March 2003

Results about stationary Poisson hyperplane processes and the induced hyperplane mosaics are extended to the case where, instead of stationarity, it is only assumed that the intensity measure has a (possibly continuous) density with respect to some translation-invariant measure. Intensities and quermass densities, which are constant in the stationary case, are then replaced by functions. In a similar way, the associated zonoid (Matheron's Steiner convex set) is generalized.
On the integral of geometric Brownian motion
Authors: Schröder Michael
Published: March 2003

This paper studies the law of any real powers of the integral of geometric Brownian motion over finite time intervals. As its main results, an apparently new integral representation is derived and its interrelations with the integral representations for these laws originating by Yor and by Dufresne are established. In fact, our representation is found to furnish what seems to be a natural bridge between these other two representations. Our results are obtained by enhancing the Hartman-WatsonAnsatzof Yor, based on Bessel processes and the Laplace transform, by complex analytic techniques. Systematizing this idea in order to overcome the limits of Yor's theory seems to be the main methodological contribution of the paper.
On Dufresne's relation between the probability laws of exponential functionals of Brownian motions with different drifts
Authors: Matsumoto Hiroyuki , Yor Marc
Published: March 2003

Denote by αt(μ)the probability law ofAt(μ)= ∫0texp(2(Bs+μs))dsfor a Brownian motion {Bs,s≥ 0}. It is well known that αt(μ)is of interest in a number of domains, e.g. mathematical finance, diffusion processes in random environments, stochastic analysis on hyperbolic spaces and so on, but that it has complicated expressions. Recently, Dufresne obtained some remarkably simple expressions for αt(0)and αt(1), as well as an equally remarkable relationship between αt(μ)and αt(ν)for two different drifts μ and ν. In this paper, hinging on previous results about αt(μ), we give different proofs of Dufresne's results and present extensions of them for theprocesses{At(μ),t≥ 0}.
Recursive filters for a partially observable system subject to random failure
Authors: Lin Daming , Makis Viliam
Published: March 2003

We consider a failure-prone system which operates in continuous time and is subject to condition monitoring at discrete time epochs. It is assumed that the state of the system evolves as a continuous-time Markov process with a finite state space. The observation process is stochastically related to the state process which is unobservable, except for the failure state. Combining the failure information and the information obtained from condition monitoring, and using the change of measure approach, we derive a general recursive filter, and, as special cases, we obtain recursive formulae for the state estimation and other quantities of interest. Up-dated parameter estimates are obtained using the EM algorithm. Some practical prediction problems are discussed and an illustrative example is given using a real dataset.
Compound Poisson approximations for sums of discrete nonlattice variables
Authors: Čekanavičius V. , Wang Y. H.
Published: March 2003

Sums of independent random variables concentrated on the same finite discrete, not necessarily lattice, set of points are approximated by compound Poisson distributions and signed compound Poisson measures. Such approximations can be more accurate than the normal distribution. Short asymptotic expansions are constructed.
Thick and thin points for random recursive fractals
Authors: Hambly B. M. , Jones O. D.
Published: March 2003

We consider random recursive fractals and prove fine results about their local behaviour. We show that for a class of random recursive fractals the usual multifractal spectrum is trivial in that all points have the same local dimension. However, by examining the local behaviour of the measure at typical points in the set, we establish the size of fine fluctuations in the measure. The results are proved using a large deviation principle for a class of general branching processes which extends the known large deviation estimates for the supercritical Galton-Watson process.
On the N-tower problem and related problems
Authors: Bruss F. Thomas , Louchard Guy , Turner John W.
Published: March 2003

Consider N towers each made up of a number of counters. At each step a tower is chosen at random, a counter removed which is then added to another tower also chosen at random. The probability distribution for the time needed to empty one of the towers is obtained in the case N = 3. Arguments are set forward as to why no simple formulae can be expected for N > 3. An asymptotic expression for the mean time before one of the towers becomes empty is derived in the case of four towers when they all initially contain a comparably large number of counters. We then study related problems, in particular the ruin problem for three players. Here we use simple martingale methodology as well as a solution proposed by T. S. Ferguson for a slightly modified problem. Throughout the paper it is our main objective to shed light on the reasons why the case N > 3 is so substantially different from the case N ≤ 3.
The telomerase-associated protein p43 is involved in anchoring telomerase in the nucleus
Authors: Möllenbeck Matthias , Postberg Jan , Paeschke Katrin , Rossbach Michael , Jönsson Franziska , Lipps Hans J.
Published: March 2003

Telomere replication of eukaryotic chromosomes is achieved by a specialized enzyme, the telomerase. Although the biochemistry of end-replication is well understood, little is known about the organization of the end-replication machinery, its regulation throughout the cell cycle or the biological function of the telomerase-associated proteins. Here we investigate the function of the telomerase-associated protein p43 within the macronucleus of the ciliated protozoa Euplotes. It has been shown that p43 binds in vitro to the RNA subunit of telomerase and shares homology with the La autoantigen family. It therefore has been suggested that it is involved in the assembly and/or nuclear retention of telomerase. We show that the p43-telomerase complex is bound to a subnuclear structure in vivo and is resistant to electroelution. Upon inhibition of p43 or telomerase expression by RNAi, which in this study was used for the first time in spirotrichs, this complex is no longer retained in the nucleus.

Further analysis revealed that the p43-telomerase complex is bound to the nuclear matrix in vivo and that after inhibition of p43 expression, telomerase is released from this structure, strongly suggesting that p43 is involved in anchoring of telomerase in the nucleus. This is the first in vivo demonstration of the biological function of this telomerase-associated component involved in telomere replication and allows us to propose a model for the organization of the end-replication machinery in the eukaryotic cell.
Isolation of hepatoblasts based on the expression of Dlk/Pref-1
Authors: Tanimizu Naoki , Nishikawa Mitsuo , Saito Hiroki , Tsujimura Tohru , Miyajima Atsushi
Published: March 2003

Hepatoblasts are common progenitors for hepatocytes and biliary epithelial cells, although their nature remains largely unknown. In order to isolate and to characterize hepatoblasts, we searched for cell surface antigens expressed in mouse fetal hepatic cells by the signal sequence trap method and found that Dlk, also known as Pref-1, was strongly expressed in fetal liver. Immunohistochemical as well as northern analysis indicated that Dlk was highly expressed in the E10.5 liver bud. The strong expression continued until the E16.5 stage and was significantly downregulated thereafter. Using a monoclonal antibody against Dlk, we isolated Dlk+ cells either by a fluorescence-activated cell sorter or by an automatic magnetic cell sorter. Dlk+ cells isolated from fetal livers expressed albumin and formed colonies when cultured at low density with HGF and EGF for 5 days. Over 60% of colonies derived from E14.5 Dlk+ cells contained both albumin+ and cytokeratin 19+ cells, indicating that a majority of colony-forming Dlk+ cells are able to differentiate into both hepatocyte and biliary epithelial cell lineages. In addition,numerous microvilli were observed by electronmicroscopic analysis in most of those cultured cells, also indicating differentiation of Dlk+ cells under this condition. Furthermore, 7% of the colony-forming Dlk+cells were not only bipotential but also highly proliferative, forming a large colony containing more than 100 cells during 5 days of culture. By transplantation of Dlk+ cells into the spleen, donor-derived hepatocytes were found in the recipient liver, indicating that Dlk+cells differentiated into hepatocytes in vivo. These results indicate that Dlk+ cells are hepatoblasts and that Dlk is a useful marker to enrich highly proliferative hepatoblasts from fetal liver.
Furin interacts with proMT1-MMP and integrin αV at specialized domains of renal cell plasma membrane
Authors: Mayer Gaétan , Boileau Guy , Bendayan Moïse
Published: March 2003

Matrix metalloproteinases (MMPs) and integrins are essential for cell and extracellular matrix homeostasis. Both membrane type-1 MMP (MT1-MMP) and the integrin αV subunit are fully activated upon cleavage at a furin recognition site. Furin is shuttled to the cell surface through the trans-Golgi network and endosomal system, and its only known role on plasma membrane consists in activation of opportunistic pathogenic entities. Here, we report findings about the interaction of furin with MT1-MMP and the integrinαV at the cell surface. By using in vivo gene delivery, western blotting and immunogold electron microscopy, we provide evidence of significant pools of furin and proMT1-MMP along the surface of cells lining basement membranes. Moreover, furin and integrin αV are frequently found associated with the slit diaphragm of renal podocytes and around endothelial fenestrations. ProMT1-MMP, by contrast, is concentrated at the slit diaphragm. Coimmunoprecipitations and double immunogold labelings indicate that furin interacts with proMT1-MMP and αV at points of insertion of the slit diaphragm. Our results suggest that these focalized complexes could trigger basement membrane proteolysis either directly by activation of proMT1-MMP or indirectly by promoting activation of proMMP2.