bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulatory roles of androgens in cutaneous wound healing
Authors: Gilliver Stephen , Wu Fred , Ashcroft Gillian 
Published: October 2003

SummaryAlthough the effects of androgens on wound healing are poorly characterised, the androgen receptor is expressed by inflammatory cells, keratinocytes and fibroblasts during wound healing, suggesting that androgens may regulate inflammatory and/or repair processes. In fact, it appears that endogenous testosterone inhibits wound healing and promotes inflammation since castration of male mice or systemic treatment with the androgen receptor antagonist flutamide accelerates cutaneous wound healing and reduces the inflammatory response. The aim of this review is to summarise our current knowledge about the regulation of tissue repair processes by androgens.
Accumulation of radiolabelled platelets and fibrin on the carotid artery of rabbits after angioplasty: effects of heparin and dipyridamole
Authors: Lorenz Martin , Merk Herbert , Buchanan Michael , Eisert Wolfgang , van Ryn Joanne 
Published: October 2003

SummaryWe investigated the dynamic accumulation of platelets and fibrin after balloon injury of the carotid arteries in rabbits in vivo. In addition, effects of heparin and dipyridamole treatment were also tested. Autologous 99mTc-labelled platelet and 123I-labelled fibrin accumulation was measured at one minute intervals for 4 hours following balloon injury of the carotid artery. Platelet accumulation occurred rapidly, with a ~125% increase occurring within 30 min after injury. There was no further activity for up to 4 hours. This accumulation could be inhibited with an intravenous infusion of PGI2 (500 ng/kg/hr). Fibrin accumulation occurred slowly and continuously over the 4 hour measurement period. Injection of an anti-fibrin antibody inhibited fibrin accumulation. Heparin (25 U/kg/hr for 4 hrs) administration resulted in a significant 82 ± 19% and 68 ± 13% reduction in platelet and fibrin accumulation, respectively. This dose of heparin was associated with a 2-fold prolongation of the aPTT. Dipyridamole (0.45 mg/kg/hr for 4 hrs) resulted in a 46 ± 12% and 70 ± 25% reduction of platelet and fibrin accumulation, respectively. Thus, we demonstrated that the dynamics of platelet and fibrin accumulation following balloon injury in rabbits are very different. The vessel wall continues to be thrombogenic for fibrin up to 4 hours after injury even though platelet accumulation has ceased after one hour. We conclude that the local thrombotic events following balloon injury are complex and that not only platelets but also fibrin is important in regulating responses to injury.
High D-dimer levels predict cardiovascular events in patients with chronic atrial fibrillation during oral anticoagulant therapy
Authors: Mavri Alenka , Košmelj Katarina , Stegnar Mojca , Vene Nina 
Published: October 2003

SummaryAtrial fibrillation (AF) is associated with hemostatic abnormalities and increased risk of thrombotic cardiovascular events even during oral anticoagulant therapy (OAT). The aim of our study was to evaluate the predictive value of hemostatic markers for the risk of major cardiovascular events during OAT. The study group comprised 113 patients with chronic AF (70.2 ± 5.4 years old, 60% men), referred for OAT. Established clinical risk factors and levels of prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes (TAT), D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) antigen and activity, before and during OAT (after 3.9 ± 0.7 months; INR 2.57 ± 0.57) were determined. In all patients OAT significantly suppressed levels of F1+2 by 67%, TAT by 30% and D-dimer by 48% (all p <0.001). During an average follow-up of 44 months 22/111 (20%) patients suffered a combined cardiovascular event (stroke, myocardial infarction, peripheral vascular occlusion or vascular death). Patients with cardiovascular events were significantly older, had more frequent heart failure/systolic dysfunction and had significantly increased levels of D-dimer at entry (63 vs 39 ng/mL, p = 0.005) and during OAT (33 vs 18 ng/mL, p = 0.002), and of t-PA antigen at entry (14.3 vs 10.9 ng/mL, p = 0.02) and during OAT (15.0 vs 11.2 ng/mL, p = 0.05) (all values are medians). In multivariate Cox proportional hazard models, heart failure/systolic dysfunction (hazard ratio 2.91; 95% CI 1.17-7.26; p = 0.02), high levels of D-dimer on OAT (top vs. lower two quartiles) (hazard ratio 4.78, 95% CI 1.39-16.41; p = 0.01) and t-PA antigen levels (continuous variable) (hazard ratio 1.09; 95% CI 1.01-1.17; p = 0.02) were significantly associated with combined cardiovascular events.In conclusion, high levels of D-dimer and t-PA antigen during OAT are significant predictors of combined cardiovascular events in AF patients and, on this basis, could be useful additional markers of cardiovascular risk in such patients.
Cost-effectiveness of two models of management for patients on chronic warfarin therapy – a Markov model analysis
Authors: Chan Fredric , Wong Raymond , Cheng Gregory , You Joyce 
Published: October 2003

SummaryAllocation of additional resources for establishing or expanding anticoagulation clinic (AC) services is a significant concern for healthcare decision-makers when the payer is also the provider of the healthcare system. The majority of anticoagulated patients in Hong Kong are managed by routine medical care (RMC) instead of ACs, possibly due to the lack of local cost-effectiveness analysis of the AC setting. The aim was to compare the clinical and economic outcomes of anticoagulated patients who were managed by AC or RMC from the perspective of a public health organization in Hong Kong. A Markov model was designed to simulate, over 10 years, the economic and clinical outcomes of patients receiving chronic warfarin therapy managed by AC or RMC. The transition probabilities were derived from literature. Resource utilization was retrieved from patients managed by AC and RMC in Hong Kong. Sensitivity analysis was conducted to examine the robustness of the model. The total number of events per 100 patient-years and the direct medical cost per patient-year in the AC and RMC groups were 9.5 and USD 840, and, 19.3 and USD 1,179, respectively. The results of the model were sensitive to the variation of the probability of major bleeding in the AC group. In conclusion, the coordinated care provided by an anticoagulation clinic appears to be more cost-effective than routine medical care in the management of warfarin therapy from the perspective of public health organization in Hong Kong.
Animal models of vulnerable plaque
Authors: Jang Ik-Kyung , Khachigian Levon , Lowe Harry 
Published: October 2003

SummaryThere is increasing recognition of the importance of vulnerable plaque and acute plaque rupture leading to thrombosis, in the pathogenesis of acute coronary syndromes. This is fueling a number of developments, including novel imaging modalities and potential plaque stabilization therapies. However, to date, no animal model of vulnerable plaque or plaque rupture has been established. Recent developments, particularly using Apo E knockout mice, appear set to provide key breakthroughs. The present status of our understanding of plaque vulnerability is therefore discussed, with a discussion of these current advances in animal models.
Antithrombin reduces the ischemia/reperfusion-induced spinal cord injury in rats by attenuating inflammatory responses
Authors: Hirose Koji , Taoka Yuji , Uchiba Mitsuhiro , Nakano Kan-yu , Utoh Junichi , Kitamura Nobuo , Okajima Kenji 
Published: October 2003

SummaryAntithrombin (AT) reveals its antiinflammatory activity by promoting endothelial release of prostacyclin (PGI2) in vivo. Since neuroinflammation is critically involved in the development of ischemia/reperfusion (I/R)-induced spinal cord injury (SCI), it is possible that AT reduces the I/R-induced SCI by attenuating the inflammatory responses. We examined this possibility using rat model of I/R-induced SCI in the present study. AT significantly reduced the mortality and motor disturbances by inhibiting reduction of the number of motor neurons in animals subjected to SCI. Microinfarctions of the spinal cord seen after reperfusion were markedly reduced by AT. AT significantly enhanced the I/R-induced increases in spinal cord tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2. AT significantly inhibited the I/R-induced increases in spinal cord tissue levels of TNF-α, rat interleukin-8 and myeloperoxidase. In contrast,Trp49-modified AT did not show any protective effects. Pretreatment with indomethacin significantly reversed the protective effects of AT.An inactive derivative of factor Xa, which selectively inhibits thrombin generation, has been shown to fail to reduce SCI.Taken together, these observations strongly suggested that AT might reduce I/R-induced SCI mainly by the antiinflammatory effect through promotion of endothelial production of PGI2. These findings also suggested that AT might be a potential neuroprotective agent.
Evaluation of ADAMTS-13 activity in plasma using recombinant von Willebrand Factor A2 domain polypeptide as substrate
Authors: Whitelock Jody , Dong Jing-fei , Cruz Miguel 
Published: October 2003

SummaryThe metalloprotease ADAMTS-13 cleaves von Willebrand factor (VWF), and is absent or severely reduced in the plasma of patients with thrombotic thrombocytopenia purpura (TTP). Under physiologic flowing conditions, the enzyme cleaves endothelial cell-derived ultra-large VWF multimers at the Y842/M843 peptide bond located in the A2 domain, where many mutations associated with Type 2A VWD cluster. These VWF mutants are more susceptible for cleavage activity, decreasing the large VWF multimers in the plasma. The susceptibility of a recombinant VWF-A2 domain to ADAMTS-13 and the potential application in detecting enzyme activity were investigated. In vitro, fluid phase cleavage of VWF by ADAMTS-13 requires denaturing conditions and prolonged incubation in order to estimate enzyme activity. We have measured ADAMTS-13 activity based on enzyme cleavage of a recombinant VWF-A2 domain under non-denaturing conditions. In our assay, enzyme activity was absent in plasma from congenital and acquired TTP patient, and blocked by each EDTA, monoclonal antibody VP-1 (peptide-specific antibody against residues 828-842 of VWF), and an ADAMTS-13 antibody purified from plasma of an acquired TTP patient. This novel recombinant VWF-A2 protein has potential utility as matrix for a rapid clinical measurement of plasma ADAMTS-13 activity.
Fibrinogen Bβ polymorphisms do not directly contribute to an altered in vitro clot structure in humans
Authors: Brennan Stephen , George Peter , Maghzal Ghassan 
Published: October 2003

SummaryFibrinogen Bβ polymorphisms, such as the -455 G/A and the Arg448Lys amino acid substitution, have been shown to increase the risk of atherothrombotic disease. Although these polymorphisms are related to fibrinogen concentrations, their effect on fibrin clot structure has not been extensively studied. We examined the frequency of the fibrinogen Bβ -455 G/A polymorphism in a group of myocardial infarction (MI) patients. There was no association between this polymorphism and MI. However, we found that patients homozygous for the rare -455 A allele had a higher average age at first MI. A similar result was found for individuals homozygous for the Bβ 448 Lys allele who also had a higher age at first MI.We subsequently studied the clotting properties of purified Arg448 and Lys448 fibrinogens in vitro and found that these fibrinogens did not significantly differ in their polymerisation, fibrinolysis kinetics or in their clot permeation properties. Mass spectrometry analysis of endoproteinase Asp-N digests of Bβ chains revealed that the Lys448 and the Arg448 chains were expressed in approximately equal proportions in a heterozygote Arg448Lys individual. Our results demonstrate that the fibrinogen Bβ –455 G/A polymorphism is not associated with myocardial infarction and furthermore the closely linked Bβ Arg448Lys protein coding variation does not have an influence on the function nor the structure of the protein in a purified system.
Characterization of the human protein S gene promoter: a possible role of transcription factors Sp1 and HNF3 in liver
Authors: Tatewaki Hideki , Tsuda Hiroko , Kanaji Taisuke , Yokoyama Kazunari , Hamasaki Naotaka 
Published: October 2003

SummaryProtein S is a vitamin-K-dependent plasma glycoprotein that serves as a cofactor for activated protein C in the protein C anticoagulation pathway, which regulates blood coagulation by inactivating factors Va and VIIIa. Mechanisms regulating the expression of the protein S gene remain unknown to date. The aim of this study was to characterize the cis-acting DNA elements of the human protein S gene in liver.We found that liver cell lines (HepG2 and PLC) transcribed the human protein S gene to mRNA, whereas non-liver cell lines (HEK293 and HeLa cells) either transcribed the gene weakly or not at all. Isolation and analysis of tissue-specific gene expression in HepG2 and HeLa cells of the 5’-flanking region from-6183 to +294 of the protein S gene indicated that the consensus binding motifs to HNF3 and Sp1 or MAZ transcription factors in the flanking region are essential for protein S gene expression. Exogenous expression of the Sp1 gene augmented the protein S-reporter gene expression in HepG2 or PLC cells but had no effect in HeLa cells. Taken together, we would conclude that transcription factors of HNF3, MAZ, and Sp1 are required for high-level expression of the protein S gene in hepatic cells, but in non-hepatic cells such as HeLa cells, an unknown factor(s) binds to the Sp1 region and disturbs the action of Sp1 and MAZ.
Interaction of high molecular weight kininogen binding proteins on endothelial cells
Authors: Tholanikunnel Baby , Ghebrehiwet Berhane , Kaplan Allen , Joseph Kusumam 
Published: October 2003

SummaryCell surface proteins reported to participate in the binding and activation of the plasma kinin-forming cascade includes gC1qR, cytokeratin 1 and u-PAR. Each of these proteins binds high molecular weight kininogen (HK) as well as Factor XII. The studies on the interaction of these proteins, using dot-blot analysis, revealed that cytokeratin 1 binds to both gC1qR and u-PAR while gC1qR and u-PAR do not bind to each other. The binding properties of these proteins were further analyzed by gel filtration. When biotinylated cytokeratin 1 was incubated with either gC1qR or u-PAR and gel filtered, a new, higher molecular weight peak containing biotin was observed indicating complex formation. The protein shift was also similar to the biotin shift. Further, immunoprecipitation of solubilized endothelial cell plasma membrane proteins with anti-gC1qR recovered both gC1qR and cytokeratin 1, but not u-PAR. Immunoprecipitation with anti-u-PAR recovered only u-PAR and cytokeratin 1. By competitive ELISA, gC1qR inhibits u-PAR from binding to cytokeratin 1; u-PAR inhibits gC1qR binding to a lesser extent and requires a 10-fold molar excess. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular complexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored.
A new fossil species of Euleptes from the early Miocene of Montaigu, France (Reptilia, Gekkonidae)
Authors: Müller Johannes 
Published: October 2003

AbstractA new fossil leaf-toed gecko, Euleptes gallica sp. nov., is described from the early Miocene locality Montaigu, France. The species is the third record of leaf-toed geckos in the early Miocene of Europe. A palaeobiogeographical interpretation suggests that the modern form is a relic endemite of the western Mediterranean region which survived the extinction of its congeneric relatives by being isolated on the Corso-Sardinian microplate, which left its former position at the beginning of the Miocene.
Prior chemotherapy and allograft CD34+ dose impact donor engraftment following nonmyeloablative allogeneic stem cell transplantation in patients with solid tumors
Authors: Carvallo Cristian , Geller Nancy , Kurlander Roger , Srinivasan Ramaprasad , Mena Othon , Igarashi Takehito , Griffith Linda M. , Linehan W. Marston , Childs Richard W. 
Published: October 2003

Abstract
Significant engraftment variability occurs among patients following nonmyeloablative hematopoietic cell transplantation. We analyzed the impact of multiple factors on donor myeloid and T-cell engraftment in 36 patients with metastatic tumors undergoing cyclophosphamide/fludarabine-based conditioning. Higher CD34+ doses facilitated donor myeloid engraftment, while prior chemotherapy exposure facilitated both donor myeloid and T-cell engraftment. At day 30, median donor T-cell and myeloid chimerism was 98% and 76%, respectively, in those patients with prior chemotherapy versus 88% (P = .008) and 26% (P &lt; .0001) in chemotherapy-naive patients. Donor myeloid chimerism at day 45 was predicted by prior chemotherapy exposure and the log10 of the CD34+ dose (adjusted coefficient of determination [R2] = .47; P &lt; .0001), while chemotherapy alone impacted donor T-cell engraftment. Patients with prior chemotherapy were more likely to develop acute grades II to IV graft-versus-host disease (GVHD; 8/18) compared with chemotherapy-naive patients (2/18; P = .031). Thus, tailoring the intensity of nonmyeloablative conditioning based on prior chemotherapy exposure is an important consideration in trial design.
Total correction of hemophilia A mice with canine FVIII using an AAV 8 serotype
Authors: Sarkar Rita , Tetreault Renee , Gao Guangping , Wang Lili , Bell Peter , Chandler Randy , Wilson James M. , Kazazian Haig H. 
Published: October 2003

Abstract
Despite the popularity of adeno-associated virus 2 (AAV2) as a vehicle for gene transfer, its efficacy for liver-directed gene therapy in hemophilia A or B has been suboptimal. Here we evaluated AAV serotypes 2, 5, 7, and 8 in gene therapy of factor VIII (FVIII) deficiency in a hemophilia A mouse model and found that AAV8 was superior to the other 3 serotypes. We expressed canine B domain-deleted FVIII cDNA either in a single vector or in 2 separate AAV vectors containing the heavy- and light-chain cDNAs. We also evaluated AAV8 against AAV2 in intraportal and tail vein injections. AAV8 gave 100% correction of plasma FVIII activity irrespective of the vector type or route of administration.
Clinical Utility of an Immunoradiometric Assay for Parathyroid Hormone (1–84) in Primary Hyperparathyroidism
Authors: Silverberg Shonni J. , Gao Ping , Brown Ijeoma , LoGerfo Paul , Cantor Tom L. , Bilezikian John P. 
Published: October 2003

Abstract
The reliable diagnosis of primary hyperparathyroidism depends on the measurement of PTH. The PTH assays in widespread use measure not only the hormone but also hormone fragments, thus limiting the clinical utility of the assays. A new immunoradiometric assay (IRMA) using an antigenic determinant at the extreme amino-terminal of the PTH molecule detects only full-length PTH (1–84). We compared three PTH assays and determined the presence of PTH (1–84) and PTH fragments in serum and parathyroid adenomas of patients with primary hyperparathyroidism. We studied 56 patients with primary hyperparathyroidism. PTH levels were increased in 63% using the midmolecule RIA; in 73% in the “intact” IRMA; and in 96% in the PTH (1–84)-IRMA. The PTH (1–84)-IRMA correlated with the other assays (midmolecule RIA R = +0.736; P &lt; 0.0001; “intact”-IRMA R = +0.951; P &lt; 0.0001) and indices of disease activity (serum calcium R = +0.511, P &lt; 0.0001; alkaline phosphatase R = +0.489, P = 0.001; and radius bone density R = −0.366, P &lt; 0.01). In 21 consecutive patients undergoing parathyroidectomy, 18 had parathyroid adenomas. Intact PTH was higher than PTH (1–84)-IRMA in both serum and glandular homogenates from these patients. Similar proportions of PTH (1–84) and hormone fragments were found in both adenomas [66 ± 3% of “intact” PTH-reflected PTH (1–84) and sera (73 ± 2% of “intact” PTH reflected PTH (1–84)]. We conclude that the PTH (1–84)-IRMA offers improved diagnostic sensitivity in patients with primary hyperparathyroidism than other currently available assays. This study also provides evidence that both PTH (1–84) and PTH fragments are produced in parathyroid adenomas and that peripheral metabolism of hormone and fragment does not alter the proportion of bioactive hormone.
Octreotide Abolishes the Acute Decrease in Bone Turnover in Response to Oral Glucose
Authors: Clowes Jackie A. , Allen Heather C. , Prentis Donna M. , Eastell Richard , Blumsohn Aubrey 
Published: October 2003

AbstractFeeding or oral intake of glucose results in an acute suppression of bone turnover. This does not appear to be mediated by insulin. Several gastrointestinal hormones modulate bone turnover in vitro and may mediate this response. We examined whether inhibiting the production of gastrointestinal hormones using octreotide could block glucose-mediated suppression of bone turnover. Fifteen subjects were each studied on four occasions in a randomized, single-blind, crossover study after receiving 1) oral placebo, iv saline; 2) oral glucose, iv saline; 3) oral glucose, iv octreotide; or 4) iv octreotide alone. We measured serum C-terminal telopeptide of type I collagen, urinary N-terminal telopeptide of type I collagen, osteocalcin, procollagen type I N-terminal propeptide, PTH, insulin, ionized calcium, and glucose over 4 h. All bone turnover markers decreased significantly after oral glucose (P &lt; 0.001). At 120 min serum C-terminal telopeptide decreased by 45 ± 2%, urinary N-terminal telopeptide by 31 ± 7%, osteocalcin by 16 ± 1%, and procollagen type I N-terminal propeptide by 8 ± 1%. There was no significant decrease in bone turnover in response to oral glucose during octreotide infusion. Octreotide alone resulted in a significant increase in all bone turnover markers (P &lt; 0.05) and PTH (P &lt; 0.01). We conclude that octreotide completely abolishes the bone turnover response to glucose intake and increases PTH secretion. The apparent bone turnover response to feeding is probably mediated by an octreotide-inhibitable endocrine factor.