bluuebunny/crossref_metadata_2025 huggingface dataset:
Etiology of Increased Enzymuria in Different Morphological Forms of Glomerulonephritis
Authors: Kuźniar Jakub , Marchewka Zofia , Lembas-Bogaczyk Jadwiga , Kuźniar Tomasz J. , Klinger Marian
Published: September 2004

Background: High urinary excretion of lysosomal enzymes is thought to reflect tubulointerstitial damage and is observed both in the acute and chronic phases of various morphological forms of glomerulonephritis (GN). It is related to the degree of proteinuria and secondary interstitial inflammatory process. N-acetyl-β-D-glucosaminidase (NAG) and β-glucuronidase (β-GR) are the most commonly used markers of tubulointerstitial injury. NAG and β-GR are also contained in azurophilic granulations of polymorphonuclear leukocytes (PMNs) and may be released during the activation of PMNs. Aims: The aim of this study was to elucidate the role of PMN degranulation in causing the increase of urinary excretion of lysosomal enzymes that is observed in glomerulonephritis. Material and Methods: We analyzed the urinary excretion of NAG, its B isoenzyme NAG-B, β-GR and leukocyte elastase (EL), in 91 patients with morphologically different primary and secondary glomerulopathies, and in 12 healthy controls. Results: Excretion of NAG, NAG-B and β-GR were statistically significantly higher in all GN patients in comparison to healthy controls. In the whole analyzed GN population significant correlations between amount of proteinuria and excretion of NAG, NAG-B and β-GR were ascertained. In subgroup analysis NAG excretion was significantly correlated with proteinuria in patients with diffuse proliferative GN (PGN), mesangiocapillary GN (MCGN), and minimal change disease (MCD). There was a significant correlation between NAG-B and proteinuria in MCD and PGN patients. There was a significant relationship of β-GR and EL with proteinuria and EL with NAG in the PGN group. Significant relationships between serum creatinine and excretion of EL but not NAG, NAG-B, or β-GR were observed in the whole examined group. Conclusions: Increased urinary excretion of elastase, with concomitant high proteinuria and NAG excretion in patients with proliferative GN may indicate that leukocyte degranulation is an additional source of enzymuria in the primary i.e. glomerular inflammatory process. Significant relationship between EL excretion and serum creatinine may indicate that EL released from PMN may also participate in the secondary i.e. interstitial injury that is decisive in the progression of GN.
Clinical Significance of Anticardiolipin and Anti-β2-Glycoprotein I Antibodies
Authors: Obermoser Gerlinde , Bitterlich Waltraud , Kunz Friedebert , Sepp Norbert T.
Published: September 2004

Background: Anticardiolipin (aCl) and anti-β2-glycoprotein I (anti-β2-gpI) antibodies are autoantibodies associated with the antiphospholipid syndrome (APS), which is characterized by both arterial and venous thrombosis and miscarriages. The scope of this study was to explore the clinical characteristics of patients with aCl and anti-β2-gpI antibodies. Methods: ACl were tested in 3,600 consecutive sera in our laboratory between January 1999 and June 2001. The clinical diagnosis and prevalence of thrombosis and pregnancy morbidity were retrospectively reviewed in aCl-positive patients. Furthermore, the frequency of anti-β2-gpI antibodies, lupus anticoagulant (LA), prolonged activated partial thromboplastin time (aPTT), and thrombocytopenia were investigated in aCl-positive patients. Results: 147 aCl-positive patients, 110 women and 37 men with a mean age of 41 years (range 7.8–82.5), were identified. 42 (28.6%) aCl-positive patients fulfilled the criteria for APS which was secondary to a connective tissue disorder in 8 patients. The frequency of anti-β2-gpI antibodies and LA, prolonged aPTT, and thrombocytopenia in aCl-positive patients was 23.8, 27.2, 25.7 and 9.2%, respectively. The presence of both aCl and anti-β2-gpI antibodies was strongly associated with clinical symptoms of APS (p = 0.007) compared to p = 0.008 for LA. Conclusion: Our data suggest that assessment of anti-β2-gpI antibodies in addition to aCl is a valuable diagnostic tool in the workup of patients with APS.
Canine Mast Cell Activation via Human IgG1 and IgG4
Authors: Sato Yoshitaka , Teshima Reiko , Nakamura Ryosuke , Takagi Kayoko , Sasaki Nobuo , Sawada Jun-ichi , Kitani Seiichi
Published: September 2004

Background: We have reported that canine mastocytoma-derived CM-MC cells are activated via canine IgG and express a high-affinity IgG receptor (canine FcγRI). The predicted amino acid sequence of the canine FcγRI α subunit was found to be 72% similar to that of humans. These results suggest that canine FcγRI have binding activity with human IgG and led us to investigate CM-MC activation via canine FcγRI and human IgG. Methods: The binding of human IgG to canine FcγRI was examined by flow cytometry using FITC-conjugated human IgG. [Ca2+]i increase or histamine release via canine FcγRI and the four human IgG subclasses was measured following aggregation of IgG-bound FcγRIs by anti-human IgG. To determine the binding activity of canine FcγRI with human IgG1 or IgG3, the displacement of 125I-labeled canine IgG from canine FcγRI was examined by unlabeled human IgG1 or IgG3. Results: The fluorescence intensity of CM-MC cells was markedly (about 50 times) elevated by incubation with FITC-human IgG compared with the fluorescence of the control cells. A significant (p < 0.01) calcium response and histamine release were observed following aggregation of canine FcγRIs bound with human IgG1 or IgG4. 125I-labeled canine IgG was displaced from canine FcγRI by preincubation with unlabeled total human IgG or human IgG1 dose-dependently, whereas no displacement was detected by preincubation with human IgG3. Conclusions: Canine FcγRI possesses a significant binding activity with human IgG1 or IgG4, while IgG2 or IgG3 did not significantly react with canine FcγRI on CM-MC cells.
Genetic Heterogeneity in Autosomal Dominant Pseudohypoaldosteronism Type I: Exclusion of Claudin-8 as a Candidate Gene
Authors: Huey Catherine L. , Riepe Felix G. , Sippell Wolfgang G. , Yu Alan S.L.
Published: September 2004

Background/Aims: Pseudohypoaldosteronism type I (PHAI) is an inherited disorder characterized by renal salt wasting, hyperkalemic metabolic acidosis, and hyperaldosteronism. Its known causes are mutations in the mineralocorticoid receptor and the epithelial sodium channel (ENaC), but there are reports of genetic heterogeneity. Claudin-8 is a tight junction protein that acts as a paracellular cation barrier in the distal nephron. The aim of this study was to test the hypothesis that mutations in claudin-8, which would be expected to induce a distal tubule cation leak, can be a cause of PHAI. Methods: We identified 10 patients with autosomal dominant PHAI in whom mutations in the mineralocorticoid receptor and ENaC had been excluded. The claudin-8 gene and upstream region was sequenced in all patients. Results: No disease-associated claudin-8 mutations were identified. A novel polymorphic allele in the 3′-untranslated region was identified in 2 patients, but was also found in 15% of individuals in a panel of normal controls. Conclusion: We present further evidence for locus heterogeneity in PHAI. Mutations in claudin-8 are unlikely to be a cause of PHAI. Further studies of other claudins in this disease are warranted.
Progression of Cisplatin-Induced Nephrotoxicity in a Carnitine-Depleted Rat Model
Authors: Sayed-Ahmed Mohamed M. , Eissa Maha A. , Kenawy Sanaa A. , Mostafa Nadia , Calvani Menotti , Osman Abdel-Moneim M.
Published: September 2004

Background: This study has been initiated to investigate whether endogenous carnitine depletion and/or carnitine deficiency is an additional risk factor and/or a mechanism in cisplatin-induced nephrotoxicity and to gain insights into the possibility of a mechanism-based protection by L-carnitine against this toxicity. Methods: 60 male Sprague-Dawley rats were divided into six groups of 10 animals each and received one of the following treatments: The first three groups were injected intraperitoneally with normal saline, L-carnitine (500 mg/kg), and D-carnitine (750 mg/kg), respectively, for 10 successive days. The 4th, 5th, and 6th groups were injected intraperitoneally with the same doses of normal saline, L-carnitine and D-carnitine, respectively, for 5 successive days before and after a single dose of cisplatin (7 mg/kg). Six days after cisplatin treatment, the animals were sacrificed, and serum as well as kidneys were isolated and analyzed. Results: A single dose of cisplatin resulted in a significant increase in blood urea nitrogen (BUN), serum creatinine, malondialdehyde (MDA) and nitric oxide (NO) and a significant decrease in total carnitine, reduced glutathione (GSH) and adenosine triphosphate (ATP) content in kidney tissues. Interestingly, L-carnitine supplementation attenuated cisplatin-induced nephrotoxicity manifested by normalizing the increase of serum creatinine, BUN, MDA and NO and the decrease in total carnitine, GSH and ATP content in kidney tissues. In the carnitine-depleted rat model, cisplatin induced a progressive increase in serum creatinine and BUN as well as a progressive reduction in total carnitine and ATP content in kidney tissue. Histopathological examination of kidney tissues confirmed the biochemical data, i.e. L-carnitine supplementation protected against cisplatin-induced kidney damage, whereas D-carnitine aggravated cisplatin-induced renal injury. Conclusion: Data from this study suggest that: (1) oxidative stress plays an important role in cisplatin-induced kidney damage; (2) carnitine deficiency should be viewed as an additional risk factor and/or a mechanism in cisplatin-induced renal dysfunction, and (3) L-carnitine supplementation attenuates cisplatin-induced renal dysfunction.
Pulse Pressure-Induced Transmural Fluid Flux Increases Bovine Aortic Smooth Muscle Cell Apoptosis in a Mitogen Activated Protein Kinase Dependent Manner
Authors: Birney Yvonne A. , Sweeney Catherine H. , Cappadona Charles R. , Sitzmann James V. , Cummins Philip M. , Redmond Eileen M. , Cahill Paul A.
Published: September 2004

Background: Mechanical forces associated with blood flow are critical in the regulation of vascular smooth muscle cell (VSMC) growth, migration, differentiation and apoptosis as fundamental features in the pathogenesis of vascular disease. We investigated the effect of pulse pressure on VSMC apoptosis. Methods: Using a perfused transcapillary co-culture system, bovine thoracic aortic SMC (BASMC) were exposed to increases in pulsatile flow (0.3–17 ml/min) and hence pulse pressure (amplitude of pulse 6–50 mm Hg) in the absence or presence of bovine aortic endothelial cells (BAEC). The extent of apoptosis was determined by measuring caspase-3 activity, the levels of pro- and anti-apoptotic Bcl-2 family proteins, FasL and cellular apoptosis susceptibility (CAS) protein expression and the extent of DNA fragmentation. Results: Changes in pulse pressure resulted in a significant force- and time-dependent increase in caspase-3 activity in BASMC. This effect was maximal after 6 h, independent of BAEC presence, and attenuated following inhibition of mitogen-activated protein kinase (MAPK) activity with PD98059. In parallel cultures, there was a significant increase in Bad and Bax expression, concomitant with an increase in DNA fragmentation, and a significant decrease in Bcl-2 and Bcl-XL expression. The pro-apoptotic effects of pulse pressure were specific for differentiated cells but independent of p53, inasmuch as FasL and CAS expression were enhanced in differentiated adult cells but decreased in de-differentiated embryonic cells in response to flow. Conclusions: These results suggest that pulse pressure promotes phenotypically distinct VSMC apoptosis in vitro in an endothelial-independent, MAPK-dependent, manner.
Characterization of Two Transgene Insertional Mutations at Pirouette, a Mouse Deafness Locus
Authors: Odeh Hana , Hagiwara Nobuko , Skynner Michael , Mitchem Kristina L. , Beyer Lisa A. , Allen Nicholas D. , Brilliant Murray H. , Lebart M.C. , Dolan David F. , Raphael Yehoash , Kohrman David C.
Published: September 2004

The mouse mutant ‘pirouette’ (pi) exhibits profound hearing loss and vestibular defects due to inheritance of a recessive mutation on chromosome 5. Dysfunction has been correlated with defects during maturation of sensory cells in the inner ear. As an initial step in characterizing pirouette at the genetic level, we have localized the candidate interval to a small region on central chromosome 5 by analysis of a congenic strain of pirouette mice. This region exhibits conserved synteny with human chromosome 4 and suggests that pirouette may be a genetic model of the human nonsyndromic deafness disorder DFNB25, which has been localized to 4p15.3–q12. In addition to the original spontaneous pirouette strain, we have identified and characterized 2 additional mouse strains with allelic mutations at the same locus. Analysis of the morphology in each of the 3 pirouette alleles indicated very similar early postnatal alterations in maturation of stereocilia and suggests that the gene affected in pirouette normally plays a role in building or maintaining these structures that are critical for sensory mechanotransduction.
Factor Analytical Study of the Short Version of the World Health Organization Quality of Life Instrument
Authors: Ohaeri Jude U. , Olusina Adewunmi K. , Al-Abassi Abdul-Hamid M.
Published: September 2004

The domains of the 26-item World Health Organization Quality of Life Instrument (WHOQOL-Bref) contain heterogeneous items and do not encompass the logical constructs of subjective quality of life (QOL). We compared the WHO 4-domain and 6-domain models of the WHOQOL-Bref with the 8-domain model that we obtained from factor analysis (FA). Data from 118 recently recovered Nigerian psychotic patients were used in confirmatory factor analysis (CFA) to assess goodness of fit and clarity of concept. Our FA model had superior goodness of fit for CFA and provided clarity of concept. Analysis of the WHOQOL-Bref should consider the domains from FA and include ‘overall QOL’ as an item and dependent variable. Subjective QOL is an aggregate of the following constructs: satisfaction with life circumstances; fulfillment of needs, and opportunity for experience in the milieu.
Prenatal Exposure to High Level of Glucocorticoids Increases the Susceptibility of Renal Proximal Tubular Cells to Apoptosis Induced by Uropathogenic Escherichia coli Toxins
Authors: Chen Ming , Bao Wenjie , Ceccatelli Sandra , Celsi Gianni
Published: September 2004

Prenatal exposure to excessive glucocorticoids may alter the developing fetus inducing metabolic and endocrine imbalance in various organs, including the kidney. This study aimed at evaluating whether prenatal exposure to high levels of glucocorticoids adversely affects renal cell survival and predisposes to renal cell death. Pregnant rats were injected with 0.1 mg/kg dexamethasone (DEX) i.p. from day 1 of gestation. Renal proximal tubular cells (PTCs) were prepared from 20-day-old offspring in the DEX (DEX cells) and control groups (CON cells). After 4 days’ culture, cells were exposed to uropathogenic Escherichia coli ARD6 toxins at concentrations known to induce apoptotic cell death. We found that cell death rate was significantly higher in DEX than in CON cells. Cells exhibited morphological and biochemical features of apoptosis. Conversely, the activity of the antioxidant enzyme catalase was significantly increased in renal cortex homogenate from 20-day-old DEX rats. The antioxidant vitamin E did not prevent apoptosis. These results indicate that prenatal exposure to high levels of glucocorticoids induces alterations in renal PTCs rendering them more sensitive to E. coli toxins via nonoxidative stress. With the increasing use of multiple doses of glucocorticoids in preterm infants, the possibility that antenatal glucocorticoids may lead to renal adverse consequences is of clinical relevance.
Tissue factor and tissue factor pathway inhibitor levels in trophoblast cells: implications for placental hemostasis
Authors: Brenner Benjamin , Katz Tamar , Miyagi Yohei , Lanir Naomi , Aharon Anat
Published: September 2004

The placenta is a highly vascularized organ with fetal and maternal blood supply. Syncytiotrophoblasts (STB), which line the placenta villous are possibly involved in local hemostatic mechanisms.The aim of this study was to evaluate the levels of tissue factor (TF) and its inhibitors, tissue factor pathway inhibitor (TFPI,TFPI-2), in STB model within hemostatic and inflammatory environments. Human primary STB cell cultures were characterized by vascular and hormonal markers. TF and TFPI mRNA expression, protein levels and activity were determined and compared to human umbilical vein endothelial cells (HUVEC). High levels of TF were demonstrated in STB cells compared to low levels in HUVEC. In contrast, STB expressed lower TFPI levels than HUVEC. LPS and TNFα increased the high constitutive TF in STB, whereas LPS and IL-1α further reduced TFPI levels. The procoagulant tendency of STB identified by us may reflect the physiological need for immediate inhibition of hemorrhage in the placental inter-villous spaces in basal and inflammatory conditions.This hemostatic balance may be critical for normal placental function and pregnancy outcome.
Blood coagulation kinetics: high throughput method for real-time reaction monitoring
Authors: Lo Ken , Diamond Scott
Published: September 2004

A high throughput 384-well plate assay of blood function in 60 μl reactions with the fluorogenic thrombin substrate, boc-VPR-MCA, allowed for real-time monitoring of coagulation under a diverse set of reaction conditions. Using recalcified, citrated whole blood diluted 3-fold with corn trypsin inhibitor (to block Factor XIIa), addition of 0 to 13.8 pM of tissue factor (TF) reduced the time of maximal rate of thrombin production (Tmax) from 45 min to 11 min. Over this range of TF,Tmax was reduced from 35 min to 6 min by co-addition of 10 nM convulxin to activate platelets via GPVI. The maximal rate of thrombin production at Tmax was not a function of exogenously-added TF, Va, or reVIIa, but increased 30% with added convulxin. Addition of 0.07 to 0.7 pM TF along with convulxin produced small, but detectable reductions in Tmax. Addition of up to 0.67 nM reVIIa reduced Tmax by up to 53% in the range of 0.7 to 7 pM TF. Interestingly, platelet factor 4 (2.7 μM) caused a prolongation of Tmax from 45 min to 78 min at 0 TF, while protamine (1.8 μM) reduced Tmax to 30 min at 0 TF. Finally, combinatorial reaction studies with exogenously-added ADP, histamine, fMLP, indomethacin, anti-CD18, and fibrinogen revealed no unusual synergies amongst the agents, but demonstrated a striking procoagulant activity of added fibrinogen, due to protease contaminants in the “purified” fibrinogen. This high throughput approach allowed automated profiling of blood (50 reactions/ml of blood) to generate large data sets for testing cellular-proteomic kinetic models, screening drug interactions, and potentially monitoring subtle changes in the functional phenotype of a patient blood sample.
Paediatric cerebral sinus vein thrombosis
Authors: Waldman Dalia , Lubetsky Aharon , Kornbrut Nurit , Khalil Abdalla , Koren Ariel , Wolach Baruch , Fattal Aviva , Kapelushnik Joseph , Tamary Hannah , Yacobovitch Joanne , Raveh Eyal , Revel-Vilk Shoshana , Toren Amos , Brenner Benjamin , Kenet Gili
Published: September 2004

The etiology and pathophysiology of cerebral sinus venous thrombosis (CSVT) in the paediatric population is still poorly understood, and the role of thrombophilic risk factors remains to be elucidated. In our multi-center case-controlled study we studied 46 patients with CSVT diagnosed from April 1996 to December 2003, consecutively referred for thrombophilia work-up. The results of thrombophilia screen were compared to 112 healthy paediatric controls. Anticoagulant therapy was applied according to treating physicians’ decisions, and all cases were prospectively followed for a median of 4.1 years. Of 46 children, 8 had CSVT diagnosed in the neonatal period and therefore were analyzed separately. The prevalence of single thrombophilia markers and combinations of thrombophilic risk factors were similar among cases and controls. Among children with CSVT co-morbid systemic illness was present in most patients at diagnosis. Seven out of 8 children with idiopathic CSVT had thrombophilic risk factors as compared to 31/38 patients with co-morbid conditions. Anticoagulation was initiated in most patients, 11/46 patients continued therapy for a total of one year or more post event. Neither clinical presentation nor initial treatment decisions were affected by presence of thrombophilic risk factors in our study group. Thrombophilia prevalence was not increased in children with CSVT as compared to controls, however thrombophilia was more frequent among children with idiopathic CSVT. Thus, those selected patients would benefit most from thrombophilia work-up, required for long-term therapy considerations.
Tissue factor pathway inhibitor-2 (TFPI-2) recognizes the complement and kininogen binding protein gC1qR/p33 (gC1qR): implications for vascular inflammation
Authors: Petrovan Ramona , Ghebrehiwet Berhane , Ruf Wolfram , Peerschke Ellinor
Published: September 2004

Evidence is accumulating to suggest that TFPI-2 is involved in regulating pericellular proteases implicated in a variety of physiologic and pathologic processes including cancer cell invasion, vascular inflammation, and atherosclerosis. Recent immunohistochemical studies of advanced atherosclerotic lesions, demonstrated a similar tissue distribution for TFPI-2, High Molecular Weight Kininogen (HK), and gC1qR/p33 (gC1qR), a ubiquitously expressed, multicompartmental cellular protein involved in modulating complement, coagulation, and kinin cascades. Further studies to evaluate TFPI-2 interactions with gC1qR demonstrated direct interactions between gC1qR and TFPI-2 using immunoprecipitation and solid phase binding studies. Specific and saturable binding between TFPI-2 and gC1qR (estimated Kd: ∼ 70 nM) was observed by ELISA and surface plasmon resonance (Biacore) binding assays. Binding was inhibited by antibodies to gC1qR, and was strongly dependent on the Kunitz-2 domain of TFPI-2, as deletion of this domain reduced gC1qR-TFPI-2 interactions by approximately 75%. Deletion of gC1qR amino acids 74-95, involved in C1q binding, had no effect on gC1qR binding to TFPI-2, although antibodies to this region and purified C1q both inhibited binding, most likely via allosteric effects. In contrast, HK did not affect TFPI-2 binding to gC1qR. Binding of TFPI-2 to gC1qR produced statistically significant but modest reductions in TFPI-2 inhibition of plasmin, but had no effect on kallikrein inhibition in fluid phase chromogenic assays. Taken together, these data suggest that gC1qR may participate in tissue remodeling and inflammation by localizing TFPI-2 to the pericellular environment to modulate local protease activity and regulate HK activation.
Haplotype analysis of the matrix metalloproteinase 3 gene and myocardial infarction in a Chinese Han population
Authors: Zhou Xiaoyang , Huang Jianfeng , Chen Jianhong , Su Shaoyong , Chen Runsheng , Gu Dongfeng
Published: September 2004

Matrix metalloproteinase (MMP) 3 plays an important role in the pathogenesis of myocardial infarction (MI). Up to now, there has been conflicting data regarding the possible contribution of the MMP3 -1612 5A/6A promoter polymorphism to MI. In this study, we have investigated the possible association of three polymorphisms (-1612 5A/6A, -376C/G, Glu45Lys) in the MMP3 gene with MI in a Chinese Han population. The polymorphisms were analyzed in 509 patients with MI, and in 518 healthy controls. The frequency of the 5A allele was 14% in the healthy controls, which is less than in Western populations (40%-52%). Logistic regression analyses of individual polymorphisms indicated that individuals carrying the -1612 5A allele had an increased risk of MI (odds ratio [OR] 1.75, 95% confidence interval [CI] 1.28 to 2.40), as did those carrying the -376 G allele (OR 1.78, 95% CI 1.33 to 2.38). The three polymorphisms studied were found to be in strong linkage disequilibria. Haplotype analyses showed that the 5A-G-Lys haplotype (-1612 5A, -376G and 45Lys) was independently associated with susceptibility to MI. Taken together, the effect of the MMP3 polymorphisms studied may be attributable to the -1612 5A/6A polymorphism. We conclude that the MMP3 -1612 5A/6A polymorphism is associated with MI in our population, implying that individuals of the 5A allele carriers have an increased risk of suffering MI.
Systemic thromboembolism in children
Authors: Kuhle Stefan , Massicotte Patricia , Chan Anthony , Adams Margaret , Abdolell Mohamed , de Veber Gabrielle , Mitchell Lesley
Published: September 2004

Thromboembolism (TE) has recently been recognized as a clinical entity in children. Determining the clinical characteristics of pediatric TE is an important first step in dealing with this new disorder. The paper summarizes 1776 consecutive children with systemic TE referred to 1-800-NO-CLOTS telephone consultation service. 1-800-NO-CLOTS is a free consultation service for clinicians managing pediatric TE. Patient information was collected immediately using standardized forms. In children with systemic TE, infants under one year of age (47%) including neonates (26%) represented the largest distinct pediatric age group. Age-related differences were seen in TE locations, associated conditions, and risk factors. However, venous TE was the most frequent manifestation (74%). Neonates and children with cardiac disorders were more likely to have an arterial TE than a venous TE Beyond the neonatal period, venous TE associated with a central line is more likely to occur than arterial TE. Children with ALL were 5.7 times more likely to have a venous TE than an arterial TE. TE were infrequent in otherwise healthy children with 90% of children having at least one risk factor. Central catheters were the single most common risk factor associated with TE, present in 2/3 of children. Ultrasound was most frequently employed for diagnosis of TE. Finally, there was marked heterogeneity in treatment of children with TE. In children, neonates form the largest single group with TE. TE usually occur only in the presence of one or more risk factors with catheters being the single most important factor.
Association between the Thr715Pro P-selectin gene polymorphism and soluble P-selectin levels in a multiethnic population in South London
Authors: Kerry Sally , Dong Yanbin , Strazzullo Pasquale , Cappuccio Francesco , Miller Michelle
Published: September 2004

The aim was to investigate whether the Thr715Pro P-selectin polymorphism is associated with soluble P-selectin (sP-selectin) levels in individuals from different ethnic groups. Plasma sPselectin and Thr715Pro (A/C) P-selectin gene polymorphism were measured in 237 white (106 females), 177 black African origin (92 females) and 201 South Asian (94 females) individuals living in England. All were free from coronary heart disease (CHD), stroke and other cardiovascular disease, diabetes, drug therapy for hypertension or high lipids, hormone replacement therapy or oral contraceptive pill. The Thr715Pro C allele was rare in blacks (0.8%) and intermediate in South Asians (3.0%) compared to whites (11.2%; p <0.001). sP-selectin levels were significantly lower in the individuals with the AC or CC compared to the AA genotype in both whites (-25% (95% C.I. -33.3 to -16.9); p <0.001) and South Asians (-25.2% (-40.5 to -6.1); p <0.012). There was insufficient power for this analysis in blacks. In conclusion, in whites and South Asians the C allele of the Thr715Pro P-selectin polymorphism is associated with lower sP-selectin levels. Lower levels of sP-selectin were not accounted for by this polymorphism in blacks, in whom the C allele was very rare.
Contamination of coagulation factor concentrates with human parvovirus B19 genotype 1 and 2
Authors: Schneider Beate , Becker Maria , Brackmann Hans-Hermann , Eis-Hübinger Anna
Published: September 2004

Human parvovirus B19 (B19) DNA has frequently been detected in plasma-derived coagulation factor concentrates. Furthermore, transmission of B19 infection was observed, indicating presence of the infectious virus despite routine viral inactivation/removal procedures during the manufacturing process. Recently, human parvovirus DNA isolates, variant from B19, have been identified resulting in classification of B19 virus into three distinct genotypes, with all viruses previously classified as B19 belonging to genotype 1. So far, there is no information available on contamination of clotting factor concentrates with genotype 2. Therefore, we analysed 202 different factor concentrate lots for genotype 1 and 2 DNA by PCR. Analysis of one hundred eighty-one lots representing 13 different products, administered over the last three years, was compared to 21 lots (8 products) used until the early 1980s which had not been treated by viral inactivation procedures. Genotype 1 DNA was detected in 77/181 (42.5%) currently administered lots, and 17/21 (81%) previously used lots. The level of genotype 1 DNA contamination was similar in currently and previously administered concentrates. Genotype 2 DNA was found in 5/202 (2.5%) lots, all of which were co-contaminated with genotype 1 DNA. DNA sequence analysis showed that the PCR-double positive concentrates contained typical genotype 1 and genotype 2 DNA. Because genotype 2 appears to cause a similar spectrum of diseases as genotype 1, simultaneous detection of genotype 2 by nucleic acid amplification testing (NAT), now widely applied to plasma pools for genotype 1, would give an added level of safety to blood products.
Oxidative status of platelets in normal and thalassemic blood
Authors: Amer Johnny , Fibach Eitan
Published: September 2004

Chronic platelet activation may be involved in thromboembolic complications, a leading cause of morbidity and mortality in β-thalassemia. Oxidative stress, with the generation of reactive oxygen species (ROS), is suspected to play a role in the pathophysiology of thalassemia and cardiovascular disorders. In the present study, we adapted flow cytometric techniques to measure oxidative state markers, ROS generation and reduced glutathione (GSH) content in platelets. Our results show that platelets obtained from β-thalassemic patients contain higher ROS and lower GSH levels than do platelets from normal donors, indicating a state of oxidative stress. In the absence of any known inherent abnormality in thalassemia platelets, this may be attributed to continuous exposure to oxidative insults from extra-platelet sources. We found that exposure of platelets to oxidants such as hydrogen peroxide and tertbutylhydroperoxide or to the platelet activators thrombin, calcium ionophore or phorbol myristate acetate stimulated the platelets’ oxidative stress.This was also increased by plasma of thalassemia patients, and decreased following treatment of the plasma with the iron-chelator Desferoxamin. Iron and hemin, the levels of which are augmented in plasma of thalassemia patients, stimulated the platelets’ oxidative stress.The oxidative status of the platelets was also affected by red blood cells (RBC); it was higher in normal platelets incubated with thalassemic RBC than with normal RBC. Normal RBC stimulated with hydrogen peroxide had a greater effect on platelets than did unstimulated RBC.The platelets’ oxidative stress was ameliorated by antioxidants such as N-acetyl-L-cysteine and vitamin C. Our findings indicate that in thalassemia, platelets undergo a state of oxidative stress, leading to their activation and potentially to thromboembolic consequences, and suggest that this hypercoagulable state might be treated with antioxidants.
Amino acid mutagenesis within ligand-binding loops in αv confers loss-of-function or gain-of-function phenotype on integrin αvβ3
Authors: Honda Shigenori , Kashiwagi Hirokazu , Kiyoi Teruo , Kato Hisashi , Kosugi Satoru , Shiraga Masamichi , Kurata Yoshiyuki , Tomiyama Yoshiaki
Published: September 2004

The crystal structure of αvβ3 in complex with a cyclic RGDcontaining ligand has recently been demonstrated. However, the functional significance of each residue within ligand binding loops has not been fully elucidated. Here, by employing alaninescanning mutagenesis, we have examined the functional role of ligand contact residues in αv. Tyr178 –> Ala substitution (Tyr178Ala) and Asp218Ala abolished a monovalent ligand, WOW-1 Fab binding as well as soluble fibrinogen binding, which is in perfect agreement with the crystallography. However, Asp150Ala showed no or only a modest inhibition of ligand binding. In contrast, Tyr substitution at Ala215 (Ala215Tyr) increased WOW-1 Fab binding, suggesting that the substitution increased the integrin affinity. The adhesion assay to immobilized fibrinogen showed essentially the same data as obtained using soluble ligands. Our present data indicate that Tyr178 and Asp218, but not Asp150 in αv is critically involved in ligand-binding and that Ala215 could regulate the affinity of αvβ3.
Platelets from Munc18c heterozygous mice exhibit normal stimulus-induced release
Authors: Schraw Todd , Crawford Garland , Ren Qiansheng , Choi Wangsun , Debbie C. , Pessin Jeffery , Whiteheart Sidney
Published: September 2004

A critical aspect of hemostasis is the release of clot-forming components from the three intra-platelet stores: dense core granules, α-granules and lysosomes. Exocytosis from these granules is mediated by soluble (SNAPs and NSF) and integralmembrane proteins (v- and t-SNAREs).Three SM (Sec1/Munc18) proteins are present in mouse platelets (Munc18a, 18b and 18c) and each potentially regulates exocytosis via modulation of their cognate syntaxin binding partner. To define the molecular machinery required for platelet exocytosis, we analyzed platelets from Munc18c heterozygous knockout mice. These platelets show a decrease in Munc18c but no apparent reduction in other secretory machinery components. No differences in the rates of aggregation or of secretion of [3H]-5HT (dense core granules), platelet factor 4 (α-granules), or hexosaminidase (lysosomes) were detected between platelets from Munc18c heterozygous knockout or wild-type mice. The platelets also show normal morphology. Contrary to a predicted requirement for Munc18c in platelet secretion, data reported here show that reducing Munc18c levels does not substantially alter platelet function. These data show that despite Munc18c’s role in platelet secretion, the lack of a secretion defect may be attributed to compensation by other Munc18 isoforms or that one allele is sufficient to maintain secretion under standard conditions.
Increased shear stress- and ristocetin-induced binding of von Willebrand factor to platelets in cord compared with adult plasma
Authors: Rehak Thomas , Cvirn Gerhard , Gallistl Siegfried , Leschnik Bettina , Köstenberger Martin , Katzer Helga , Ribitsch Volker , Muntean Wolfgang
Published: September 2004

Multiple indications do exist that the extensive neonatal platelet adhesion and aggregation, and the shorter closure time of neonatal compared with adult whole blood in the platelet function analyzer 100 are attributable to the physiological high plasma concentrations and high concentrations of unusually large von Willebrand factor (vWf) multimers in neonates. However, to date the direct experimental evidence is lacking. Therefore, we compared in the present study the ability of neonatal vWf to bind to platelets to that of adult vWf. Platelet-poor plasma of neonatal or adult origin, containing antibody-stained vWf, was incubated with neonatal or adult platelet suspension. Subsequently, vWf-platelet interaction was induced by exposing the mixture to shear stress by means of a cone/plate measuring system or by incubating the mixture with ristocetin. Finally, samples were analyzed in a FAC Scan flow cytometer. Detected fluorescence intensities directly correlate with the amount of vWf attached to the platelet surface. We found that significantly higher amounts of neonatal vWf were attached to platelets in the presence of shear stress or ristocetin.This efficient neonatal vWf-platelet interaction is an effect intrinsic to the neonatal vWf, and not to the neonatal platelet: the amount of neonatal vWf attached to neonatal platelets was not different from the amount of neonatal vWf attached to adult platelets. Furthermore, decreasing the vWf content in cord plasma to adult level resulted in significantly suppressed vWf-platelet attachment in the presence of ristocetin, indicating that the high neonatal vWf level contributes to the efficient vWf-platelet binding in neonates.
The factor VII activating protease G511E (Marburg) variant and cardiovascular risk
Authors: Miller George , E.Webb Karen , Cooper Jackie , Humphries Steve , Ireland Helen
Published: September 2004

A previous study had shown a strong relationship between a variant in factor VII activating protease (FSAP G511E) and advanced carotid atheroma. In-vitro, the variant has reduced fibrinolytic but normal pro-coagulant activity, which may constitute a prothrombotic state. The current study has addressed risk for coronary heart disease in a prospective study of cardio-vascular disorders (Northwick Park Heart Study II). An interactive effect upon risk was found between the 511E allele and elevated levels of cholesterol and triglyceride. Fibrinogen could substitute for triglyceride levels in this risk-interaction analysis. The findings support the proposal that the FSAP 511E allele exacerbates atherosclerosis or its clinical sequelae.
Disruption of Endothelial-Cell Caveolin-1α/Raft Scaffolding During Development of Monocrotaline-Induced Pulmonary Hypertension
Authors: Mathew Rajamma , Huang Jing , Shah Mehul , Patel Kirit , Gewitz Michael , Sehgal Pravin B.
Published: September 2004

Background—

In the monocrotaline (MCT)-treated rat, there is marked stimulation of DNA synthesis and megalocytosis of pulmonary arterial endothelial cells (PAECs) within 3 to 4 days, followed by pulmonary hypertension (PH) 10 to 14 days later. Growing evidence implicates caveolin-1 (cav-1) in plasma membrane rafts as a negative regulator of promitogenic signaling. We have investigated the integrity and function of endothelial cell–selective cav-1α/raft signaling in MCT-induced PH.

Methods and Results—

Although PH and right ventricular hypertrophy developed by 2 weeks after MCT, a reduction in cav-1α levels in the lung was apparent within 48 hours, declining to ≈30% by 2 weeks, accompanied by an increase in activation of the promitogenic transcription factor STAT3 (PY-STAT3). Immunofluorescence studies showed a selective loss of cav-1α and platelet endothelial cell adhesion molecule-1 in the PAEC layer within 48 hours after MCT but an increase in PY-STAT3. PAECs with cav-1α loss displayed high PY-STAT3 and nuclear immunostaining for proliferating cell nuclear antigen (PCNA). Biochemical studies showed a loss of cav-1α from the detergent-resistant lipid raft fraction concomitant with hyperactivation of STAT3. Moreover, cultured PAECs treated with MCT-pyrrole for 48 hours developed megalocytosis associated with hypo-oligomerization and reduction of cav-1α, hyperactivation of STAT3 and ERK1/2 signaling, and stimulation of DNA synthesis.

Conclusions—

MCT-induced disruption of cav-1α chaperone and scaffolding function in PAECs likely accounts for diverse alterations in endothelial cell signaling in this model of PH.
High-Dose Atorvastatin Reduces Total Plasma Levels of Oxidized Phospholipids and Immune Complexes Present on Apolipoprotein B-100 in Patients With Acute Coronary Syndromes in the MIRACL Trial
Authors: Tsimikas Sotirios , Witztum Joseph L. , Miller Elizabeth R. , Sasiela William J. , Szarek Michael , Olsson Anders G. , Schwartz Gregory G.
Published: September 2004

Background—

Oxidized phospholipids (OxPL) are present within atherosclerotic plaques and bound by lipoprotein (a) [Lp(a)] in plasma. This study evaluated the impact of atorvastatin on oxidized LDL (OxLDL) in patients with acute coronary syndromes (ACS).

Methods and Results—

OxLDL-E06 (OxPL content on apolipoprotein B-100 [apoB] detected by antibody E06), apoB-100 immune complexes (apoB-IC), OxLDL autoantibodies, and Lp(a) levels were measured in 2341 patients at baseline and after 16 weeks of treatment with atorvastatin 80 mg/d or placebo. The OxLDL-E06 and apoB-IC data are reported per apoB-100 particle (OxPL/apoB, IC/apoB) and as total levels on all apoB-100 particles (total apoB-OxPL and total apoB-IC [eg, OxPL/apoB or IC/apoB×apoB-100 levels]). Compared with baseline values, atorvastatin reduced apoB-100 (−33%), total apoB-OxPL (−29.7%), total apoB-IC IgG (−29.5%), and IgM (−25.7%) (
P
<0.0001 for all), whereas no change or an increase was observed with placebo. When normalized per apoB-100, compared with placebo, atorvastatin increased OxPL/apoB (9.5% versus −3.9%,
P
<0.0001) and Lp(a) (8.8% versus −0.7%, (
P
<0.0001). A strong correlation was noted between OxPL/apoB and Lp(a) (
R
=0.85,
P
<0.0001), consistent with previous data that Lp(a) binds OxPL.

Conclusions—

After atorvastatin treatment, total OxPL on all apoB-100 particles was decreased. However, there was enrichment of OxPL on a smaller pool of apoB-100 particles, in parallel with similar increases in Lp(a), suggesting binding by Lp(a). These data support the hypothesis that atorvastatin promotes mobilization and clearance of proinflammatory OxPL, which may contribute to a reduction in ischemic events after ACS.
Differential Effects of Apolipoprotein A-I–Mimetic Peptide on Evolving and Established Atherosclerosis in Apolipoprotein E-Null Mice
Authors: Li Xiaojun , Chyu Kuang-Yuh , Neto Jose R. Faria , Yano Juliana , Nathwani Nitya , Ferreira Carmel , Dimayuga Paul C. , Cercek Bojan , Kaul Sanjay , Shah Prediman K.
Published: September 2004

Background—

Apolipoprotein (apo) A-I and apoA-I–mimetic peptides showed promise to prevent atherosclerosis development. Using a bypassed vein graft model in apoE-null mice, we evaluated the effects of oral or intraperitoneal administration of an apoA-I–mimetic peptide on evolving atherosclerotic lesions in the vein graft and compared such effects on the established atherosclerotic lesions in aortic sinus in the same mice.

Methods and Results—

We used apoE-null mice in which a segment of inferior vena cava was grafted into the right carotid artery at 16 weeks of age. Native aortic atherosclerotic lesions (established atherosclerosis) and vein-graft atherosclerotic lesions (evolving atherosclerosis) were assessed 4 weeks after daily oral (0.3 mg/mL) or intraperitoneal (50 μg in 200 μL saline) administration of an apoA-I–mimetic peptide, D4F. Mice receiving saline or water without D4F served as controls. Both oral and intraperitoneal administration of D4F reduced vein-graft atherosclerotic (evolving lesions) plaque size by 43% and 42%, plaque lipid by 70% and 49%, and macrophage immunoreactivity by 63% and 62%, respectively, compared with controls. In contrast, D4F had no effect on the native aortic sinus atherosclerotic lesions (established lesions).

Conclusions—

Oral and intraperitoneal administration of the apoA-I–mimetic peptide D4F significantly reduced rapidly evolving atherosclerotic lesions in vein grafts but not established atherosclerotic lesions in aortic sinus. These observations suggest that the type of atherosclerotic lesions and the time of initiation during the course of lesion evolution modulate the beneficial effects of apoA-I–mimetic peptides on atherosclerosis.
Economic-Demographic Effects of Immigration: Results from a Dynamic Spatial Microsimulation Model
Authors: Rephann Terance J. , Holm Einar
Published: September 2004

Sweden has a liberal immigration policy compared to other developed countries. However, this policy has been reexamined in recent years. This article examines the economic-demographic effects of immigration using a dynamic spatial microsimulation model called SVERIGE (System for Visualizing Economic and Regional Influences Governing the Environment). It presents simulations that vary three key characteristics of immigration:(1) magnitude, (2) ethnicorigins, and (3) settlement characteristics. Outcome variables examined include immigration, emigration, births, population, migration, labor force participation, and average earnings. Preliminary and illustrative results suggest that large immigration flows can be accommodated by a country with modest economic-demographic effects. Also, the characteristics of immigrants, including initial settlement choice, affect outcomes in different ways.
Is Distance Really Dead? Comparing Industrial Location Patterns over Time in Canada
Authors: Polèse Mario , Shearmur Richard
Published: September 2004

This article presents a model for comparing industrial location patterns over time, applied to Canadian data for 1971 and 1996. The Canadian economy is divided into eighteen industrial sectors (manufacturing and services), of which eight are examined in detail. The analysis addresses several questions. Do observed location models for given industries follow predictable patterns? How stable are those patterns over time? Has the relative sensitivity to “distance” of given industries changed over time? Can significant breaks in location patterns be observed over time? The authors consider the possible impact of information technology on location. If “distance is dying,” as is sometimes argued, this should be reflected in changing location patterns. The results show a high degree of stability over time, suggesting that distance is still very much alive.
Time Out and Drop Out
Authors: ÿian Hogne
Published: September 2004

By way of focusing on two partly opposing temporalizations found in different social practices of young persons out of work, some central aspects of the relation between individualism and linear time are discussed, in particular in relation to the question of self-identity. It is concluded that if linear time should have any analytical value in the study of late modernity it should refer to the social practices and ideology of individualism and neither to the orchestrating of collectives nor to unidirectionality and irreversibility.
Social Perception of Time, Distance and High-Speed Transportation
Authors: Klein Olivier
Published: September 2004

The aim of this article is to throw light on the link between high-speed means of transportation - especially the TGV - and the present-day temporal structures of society. The first part describes how the industrial timeis born out of industrial capitalism and its conceptions of the work. This model changes but it is still very topical, regarding certain important aspects of contemporary socioeconomic structures. Nevertheless, this permanence can’t explain the whole current evolutions. The second part shows how high-speed travel behaviours - considering only professional purposes - also reveal some mains breaks with the model of industrial time. The third part of the article looks into the model of fragmented time, which appears gradually surimposed to industrial time. Finally, the fourth part presents the concepts of high speed as an opportunityand high speed as a necessity. This dual reading of the ways in which we can deal with the distance in high speed means of transportation appears adapted to the double temporal structure which prevails today.
‘Times’ and Images of Others in an Amis Village, Taiwan
Authors: Huang Shiun-wey
Published: September 2004

Why different ‘times’ (or different ‘categories of objectified time’) coexist among the Amis in Iwan? I argue that the Amis’ images of others provide an answer to it. For the Amis in that village, four significant others have relations with them. This article explores how the images of others reflect in the time dimension. In sum, attempting to combine their own cultural traditions with certain cultural elements of ‘superior’ others, and strive for a better future is the important cultural mechanism of the Amis.