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Plasminogen Activator Inhibitor (plasminogen + activator_inhibitor)
Selected AbstractsMice Lacking the Plasminogen Activator Inhibitor 1 Are Protected from Trabecular Bone Loss Induced by Estrogen DeficiencyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2000E. Daci Abstract Bone turnover requires the interaction of several proteases during the resorption phase. Indirect evidence suggests that the plasminogen activator/plasmin pathway is involved in bone resorption and turnover, and recently we have shown that this cascade plays a role in the degradation of nonmineralized bone matrix in vitro. To elucidate the role of the plasminogen activator inhibitor 1 (PAI-1) in bone turnover in vivo, bone metabolism was analyzed in mice deficient in the expression of PAI-1 gene (PAI-1,/,) at baseline (8-week-old mice) and 4 weeks after ovariectomy (OVX) or sham operation (Sham) and compared with wild-type (WT) mice. PAI-1 inactivation was without any effect on bone metabolism at baseline or in Sham mice. However, significant differences were observed in the response of WT and PAI-1,/, mice to ovariectomy. The OVX WT mice showed, as expected, decreased trabecular bone volume (BV/TV) and increased osteoid surface (OS/BS) and bone formation rate (BFR), as assessed by histomorphometric analysis of the proximal tibial metaphysis. In contrast, no significant change in any of the histomorphometric variables studied was detected in PAI-1,/, mice after ovariectomy. As a result, the OVX PAI-1,/, had a significantly higher BV/TV, lower OS/BS, lower mineral apposition rate (MAR) and BFR when compared with the OVX WT mice. However, a comparable decrease in the cortical thickness was observed in OVX PAI-1,/, and WT mice. In addition, the cortical mineral content and density assessed in the distal femoral metaphysis by peripheral quantitative computed tomography (pQCT), decreased significantly after ovariectomy, without difference between PAI-1,/, mice and WT mice. In conclusion, basal bone turnover and bone mass are only minimally affected by PAI-1 inactivation. In conditions of estrogen deficiency, PAI-1 inactivation protects against trabecular bone loss but does not affect cortical bone loss, suggesting a site-specific role for PAI-1 in bone turnover. [source] 2-(2-Hydroxy-3-alkoxyphenyl)-1H-benzimidazole-5-carboxamidine Derivatives as Potent and Selective Urokinase-Type Plasminogen Activator Inhibitors.CHEMINFORM, Issue 48 2002Richard L. Mackman Abstract For Abstract see ChemInform Abstract in Full Text. [source] Favorable response of pediatric stem cell recipients to human protein C concentrate substitution for veno-occlusive diseasePEDIATRIC TRANSPLANTATION, Issue 1 2007S. W. Eber Abstract:, Plasminogen activator inhibitor 1 is known to be elevated in patients with hepatic VOD after intensive chemotherapy. To re-establish endogenous fibrinolysis and to inhibit thrombin formation, we used non-APC (zymogen) to normalize PAI-1 levels. As a consequence of thrombin formation inhibition and the consecutive inhibition of the coagulation cascade, this treatment is expected to reduce the elevated D-dimer level. Six pediatric stem cell recipients with moderate or severe VOD after busulfan or total body irradiation conditioning regimen are reported here who were therapy-refractory to defibrotide or rt-PA therapy. All patients had low levels of PC activity (16,39%). The administration of PC (60,240 IU/kg) led to a rapid and sustained rise in PC activity (target level >80%) with near normalization of prothrombin and partial thromboplastin time in all patients. Elevated PAI-1 levels declined. Five of the six patients showed a good clinical response with prompt resolution of clinical, sonographic, and laboratory signs of hepatic blood flow obstruction, while one patient with severe VOD, as well as concomitant liver GVHD and CMV disease, had a slow but detectable response to PC therapy. All patients survived. [source] Plasminogen activator inhibitor 1 gene polymorphisms and mirtazapine responses in Koreans with major depressionASIA-PACIFIC PSYCHIATRY, Issue 3 2009Hun Soo Chang PhD Abstract Introduction: Brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of mental disorders and in the mechanism of action of antidepressant medications. The mature form of BDNF is derived from proBDNF through tissue type plasminogen activator (tPA) and the plasminogen system in the brain, which is regulated by an endogenous inhibitor, plasminogen activator inhibitor (PAI). Therefore, PAI may be involved in the development of major depressive disorder (MDD) and its response to antidepressant treatment. The present study determined the relationship between the 4G/5G polymorphism in the PAI1 gene and the clinical outcome of mirtazapine treatment in 271 Korean MDD patients. Methods: We tested the association between the polymorphism and response to mirtazapine treatment or percentage decrease of the 21-item Hamilton Depression Rating (HAMD21) scores using multiple logistic and linear regression analysis. Results: PAI1 4G/5G genotypes and allele distributions were comparable between responders and non-responders during the treatment period. Similarly, linear regression showed no association between genotypes or alleles and the percentage decline in total HAMD21 with mirtazapine treatment. In the analysis of symptomatic subscores, the percentage decline in the psychic anxiety and delusion scores after 4 weeks of mirtazapine treatment showed a statistical trend to a difference among genotypes, although it was not statistically significance. Discussion: In this first pharmacogenetics study of the PAI1 4G/5G polymorphism and mirtazapine treatment response, our results do not support the hypothesis that this polymorphism is involved in the therapeutic response to mirtazapine. [source] Plasminogen activator inhibitor-1 and asthma: role in the pathogenesis and molecular regulationCLINICAL & EXPERIMENTAL ALLERGY, Issue 8 2009Z. Ma Summary Plasminogen activator inhibitor (PAI)-1 is a major inhibitor of the fibrinolytic system. PAI-1 levels are markedly increased in asthmatic airways, and mast cells (MCs), a pivotal cell type in the pathogenesis of asthma, are one of the main sources of PAI-1 production. Recent studies suggest that PAI-1 may promote the development of asthma by regulating airway remodelling, airway hyperresponsiveness (AHR), and allergic inflammation. The single guanosine nucleotide deletion/insertion polymorphism (4G/5G) at ,675 bp of the PAI-1 gene is the major genetic determinant of PAI-1 expression. Plasma PAI-1 level is higher in people with the 4G/4G genotype than in those with the 5G/5G genotype. A strong association between the 4G/5G polymorphism and the risk and the severity of asthma has been suggested. Levels of plasma IgE and PAI-1 and severity of AHR are greater in asthmatic patients with the 4G/4G genotype than in those with the 5G/5G genotype. The PAI-1 promoter with the 4G allele renders higher transcription activity than the PAI-1 promoter with the 5G allele in stimulated MCs. The molecular mechanism for the 4G allele-mediated higher PAI-1 expression is associated with greater binding of upstream stimulatory factor-1 to the E-box adjacent to the 4G site (E-4G) than to the E-5G. In summary, PAI-1 may play an important role in the pathogenesis of asthma. Further studies evaluating the mechanisms of PAI-1 action and regulation may lead to the development of a novel prognostic factor and therapeutic target for the treatment and prevention of asthma and other PAI-1-associated diseases. [source] Haemostatic management of intraoral bleeding in patients with congenital deficiency of ,2-plasmin inhibitor or plasminogen activator inhibitor-1HAEMOPHILIA, Issue 5 2004Y. Morimoto Summary., Haemostatic management of intraoral bleeding was investigated in patients with congenital ,2-plasmin inhibitor (,2-PI) deficiency or congenital plasminogen activator inhibitor- 1 (PAI-1) deficiency. When extracting teeth from patients with congenital ,2-PI deficiency, we advocate that 7.5,10 mg kg,1 of tranexamic acid be administered orally every 6 h, starting 3 h before surgery and continuing for about 7 days. For the treatment of continuous bleeding, such as post-extraction bleeding, 20 mg kg,1 of tranexamic acid should be administered intravenously, and after achieving local haemostasis 7.5 mg kg,1 of tranexamic acid should be administered orally every 6 h for several days. In addition, when treating haematoma caused by labial or gingival laceration or buccal or mandibular contusion, haemostasis should be achieved by administering 7.5,10 mg kg,1 of tranexamic acid every 6 h. Tranexamic acid can also be used for haemostatic management of intraoral bleeding in patients with congenital PAI-1 deficiency, but is less effective when compared with use in patients with congenital ,2-PI deficiency. Continuous infusion of 1.5 mg kg,1 h,1 of tranexamic acid is necessary for impacted tooth extraction requiring gingival incision or removal of local bone. [source] Hypoxia-inducible factor 1, is up-regulated by oncostatin M and participates in oncostatin M signaling,HEPATOLOGY, Issue 1 2009Stefan Vollmer The interleukin-6,type cytokine oncostatin M (OSM) acts via the Janus kinase/signal transducer and activator of transcription pathway as well as via activation of mitogen-activated protein kinases and is known to critically regulate processes such as liver development and regeneration, hematopoiesis, and angiogenesis, which are also determined by hypoxia with the hypoxia-inducible factor 1, (HIF1,) as a key component. Here we show that treatment of hepatocytes and hepatoma cells with OSM leads to an increased protein level of HIF1, under normoxic and hypoxic conditions. Furthermore, the OSM-dependent HIF1, increase is mediated via Janus kinase/signal transducer and activator of transcription 3 and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 pathways. OSM-mediated HIF1, up-regulation did not result from an increase in HIF1, protein stability but from increased transcription from the HIF1, gene. In addition, we show that the OSM-induced HIF1, gene transcription and the resulting enhanced HIF1, protein levels are important for the OSM-dependent vascular endothelial growth factor and plasminogen activator inhibitor 1 gene induction associated with several diseases. Conclusion: HIF1, levels increase significantly after treatment of hepatocytes and hepatoma cells with OSM, and HIF1, contributes to OSM downstream signaling events, pointing to a cross-talk between cytokine and hypoxia signaling in processes such as liver development and regeneration. (HEPATOLOGY 2009.) [source] Cholestasis enhances liver ischemia/reperfusion-induced coagulation activation in ratsHEPATOLOGY RESEARCH, Issue 2 2010Jaap J. Kloek Aim:, Cholestasis is associated with increased morbidity and mortality in patients undergoing major liver surgery. An additional risk is induced when vascular inflow occlusion is applied giving rise to liver ischemia/reperfusion (I/R) injury. The role of the coagulation system in this type of injury is elusive. The aim of the current study was to assess activation of coagulation following hepatic I/R injury in cholestatic rats. Methods:, Male Wistar rats were randomized into two groups and subjected to bile duct ligation (BDL) or sham laparotomy. After 7 days, both groups underwent 30 min partial liver ischemia. Animals were sacrificed before ischemia or after 6 h, 24 h, and 48 h reperfusion. Results:, Plasma AST and ALT levels were higher after I/R in cholestatic rats (P < 0.05). Hepatic necrosis, liver wet/dry ratio and neutrophil influx were increased in the BDL group up to 48 h reperfusion (P < 0.05). Liver synthetic function was decreased in the BDL group as reflected by prolonged prothrombin time after 6 h and 24 h reperfusion (P < 0.05). I/R in cholestatic rats resulted in a 12-fold vs. 7-fold (P < 0.01) increase in markers for thrombin generation and a 6-fold vs. 2-fold (P < 0.01) increase in fibrin degradation products (BDL vs. control, respectively). In addition, the cholestatic rats exhibited significantly decreased levels of antithrombin (AT) III and increased levels of the fibrinolytic inhibitor plasminogen activator inhibitor (PAI-1) during reperfusion. Conclusions:, Cholestasis significantly enhances I/R-induced hepatic damage and inflammation that concurs with an increased activation of coagulation and fibrinolysis. [source] Mice Lacking the Plasminogen Activator Inhibitor 1 Are Protected from Trabecular Bone Loss Induced by Estrogen DeficiencyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2000E. Daci Abstract Bone turnover requires the interaction of several proteases during the resorption phase. Indirect evidence suggests that the plasminogen activator/plasmin pathway is involved in bone resorption and turnover, and recently we have shown that this cascade plays a role in the degradation of nonmineralized bone matrix in vitro. To elucidate the role of the plasminogen activator inhibitor 1 (PAI-1) in bone turnover in vivo, bone metabolism was analyzed in mice deficient in the expression of PAI-1 gene (PAI-1,/,) at baseline (8-week-old mice) and 4 weeks after ovariectomy (OVX) or sham operation (Sham) and compared with wild-type (WT) mice. PAI-1 inactivation was without any effect on bone metabolism at baseline or in Sham mice. However, significant differences were observed in the response of WT and PAI-1,/, mice to ovariectomy. The OVX WT mice showed, as expected, decreased trabecular bone volume (BV/TV) and increased osteoid surface (OS/BS) and bone formation rate (BFR), as assessed by histomorphometric analysis of the proximal tibial metaphysis. In contrast, no significant change in any of the histomorphometric variables studied was detected in PAI-1,/, mice after ovariectomy. As a result, the OVX PAI-1,/, had a significantly higher BV/TV, lower OS/BS, lower mineral apposition rate (MAR) and BFR when compared with the OVX WT mice. However, a comparable decrease in the cortical thickness was observed in OVX PAI-1,/, and WT mice. In addition, the cortical mineral content and density assessed in the distal femoral metaphysis by peripheral quantitative computed tomography (pQCT), decreased significantly after ovariectomy, without difference between PAI-1,/, mice and WT mice. In conclusion, basal bone turnover and bone mass are only minimally affected by PAI-1 inactivation. In conditions of estrogen deficiency, PAI-1 inactivation protects against trabecular bone loss but does not affect cortical bone loss, suggesting a site-specific role for PAI-1 in bone turnover. [source] Inhibition of human breast cancer cell (MBA-MD-231) invasion by the Ea4-peptide of rainbow trout pro-IGF-IJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2006Sineenat Siri Abstract It was shown previously that Ea4-peptide of trout pro-IGF-I exerted mitogenic activity in non-transformed cells and inhibited colony formation in a soft agar medium of established human cancer cells. Here we report that the same peptide inhibits the invasion of human breast cancer cells (MDA-MB-231) through a matrigel membrane in a dose-dependent manner. The expression of urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI1) genes in MDA-MB-231 cells were downregulated by treatment with rtEa4-peptide. The inhibition of expression of these genes in response to rtEa4-peptide treatment was reduced to the control level when inhibitors for c-Jun N-terminal kinase 1/2 (JNK1/2), mitogen activated protein kinase kinase 1/2 (Mek1/2), p38 mitogen activated protein kinase (p38 MAPK), phosphatidylinositol 3-kinase (PI3K), and phosphokinase C (PKC) were used. These results suggest that inhibition of invasion of MDA-MB-231 cells by rtEa4-peptide may be mediated via the suppression of uPA, tPA, and PAI1 gene activities through signal transduction pathways. J. Cell. Biochem. 99: 1363,1373, 2006. © 2006 Wiley-Liss, Inc. [source] Transforming growth factor-,1-dependent activation of Smad2/3 and up-regulation of PAI-1 expression is negatively regulated by Src in SKOV-3 human ovarian cancer cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2004Kiyoshi Wakahara Abstract The net balance between urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1) has been implicated in tumor cell invasion and metastasis. To elucidate the mechanism of the transforming growth factor-,1 (TGF-,1)-dependent up-regulation of PAI-1 expression, we investigated which signaling pathway transduced by TGF-,1 is responsible for this effect. Here, we show (1) nontoxic concentrations of TGF-,1 up-regulates uPA expression in HRA and SKOV-3 human ovarian cancer cells, (2) TGF-,1 activates Smads (phosphorylation of Smad2 and nuclear translocation of Smad3) and subsequently up-regulates PAI-1 expression in HRA cells, whereas TGF-,1 neither activates Smads nor up-regulates PAI-1 in SKOV-3 cells, (3) pharmacological Src inhibitor PP2 or antisense (AS) c-Src oligodeoxynucleotide (ODN) treatment significantly induces TGF-,1-dependent activation of Smads, leading to PAI-1 synthesis, compared with controls, in SKOV-3 cells, (4) combination of TGF-,1 and PP2, which activates PAI-1 expression and reduces uPA expression in SKOV-3, results in decreased invasiveness, (5) pharmacological inhibitors for mitogen-activated protein kinase (MAPK) (PD98059) and phosphoinositide-3-kinase (PI3K) (LY294002 and wortmannin) or AS-PI3K ODN transfection do not affect TGF-,1-induced Smad signaling and up-regulation of PAI-1 expression in SKOV-3 cells pr treated with PP2, and (6) the induction of PAI-1 protein was partially inhibited by an inhibitor of Sp1-DNA binding, mithramycin, implicating, at least in part, Sp1 in the regulation of this gene by TGF-,1. In conclusion, TGF-,1-dependent activation of Smad2/3, leading to PAI-1 synthesis, may be negatively regulated by Src, but not its downstream targets MAPK and PI3K in SKOV-3 cells. These data also reflect the complex biological effect of uPA-PAI-1 system. © 2004 Wiley-Liss, Inc. [source] Tissue plasminogen activator (t-PA) and placental plasminogen activator inhibitor (PAI-2) in gingival crevicular fluid from patients with Papillon,Lefèvre syndromeJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 9 2004Christer Ullbro Abstract Objectives: Numerous patients with Papillon,Lefèvre syndrome (PLS) express a severe periodontal inflammation that results in premature loss of deciduous and permanent teeth. The plasminogen activating (PA) system is involved in physiological and pathological processes including epithelial healing, extracellular proteolysis and local inflammatory reactions. The aim of the study was to explore a possible role of the PA system in patients with PLS. Material and Methods: Samples of gingival crevicular fluid (GCF) were collected from areas with gingival infection in 20 patients with PLS and in 20 healthy controls. The concentration of tissue plasminogen activator (t-PA) and inhibitor (PAI-2) was measured with ELISA. Results: The median level of PAI-2 was significantly higher (p<0.01) in PLS patients than in the controls, while the median value of t-PA did not differ between the groups. No difference in t-PA or PAI-2 levels was found regarding age, gender or presence of active periodontal disease. Conclusion: The findings indicate an atypical activity of the PA system with a disturbed epithelial function in PLS patients, suggesting that the periodontal destruction seen in patients with PLS is secondary to a hereditary defect in the defense system. [source] Current Experimental Perspectives on the Clinical Progression of Alcoholic Liver DiseaseALCOHOLISM, Issue 10 2009Katja Breitkopf Chronic alcohol abuse is an important cause of morbidity and mortality throughout the world. Liver damage due to chronic alcohol intoxication initially leads to accumulation of lipids within the liver and with ongoing exposure this condition of steatosis may first progress to an inflammatory stage which leads the way for fibrogenesis and finally cirrhosis of the liver. While the earlier stages of the disease are considered reversible, cirrhotic destruction of the liver architecture beyond certain limits causes irreversible damage of the organ and often represents the basis for cancer development. This review will summarize current knowledge about the molecular mechanisms underlying the different stages of alcoholic liver disease (ALD). Recent observations have led to the identification of new molecular mechanisms and mediators of ALD. For example, plasminogen activator inhibitor 1 was shown to play a central role for steatosis, the anti-inflammatory adipokine, adiponectin profoundly regulates liver macrophage function and excessive hepatic deposition of iron is caused by chronic ethanol intoxication and increases the risk of hepatocellular carcinoma development. [source] Identification of a 251-bp Fragment of the PAI-1 Gene Promoter That Mediates the Ethanol-Induced Suppression of PAI-1 ExpressionALCOHOLISM, Issue 5 2001Hernan E. Grenett Background: Moderate alcohol consumption reduces the risk for coronary heart disease. This cardioprotection may be due to ethanol enhancement of fibrinolysis. Fibrinolysis involves the interaction of plasminogen activators (PAs) and the plasminogen activator inhibitor type-1 (PAI-1). Factor(s) that decrease endothelial cell (EC) PAI-1 expression increase fibrinolysis and may decrease the risk for cardiovascular disease. Methods: Five promoter deletion fragments were generated from a 1.1-kb PAI-1 promoter fragment and ligated to a luciferase reporter gene. Cultured human umbilical vein endothelial cells (HUVECs) were transiently transfected with these PAI-1 deletion constructs. A 251-base pair (bp) fragment of the PAI-1 promoter, positions ,800 to ,549, was cloned upstream of a heterologous promoter/enhancer. ECs luciferase activity was measured in the absence/presence of 20 mM ethanol. Electrophoresis mobility shift assays were performed with nuclear extracts from untreated and ethanol-treated ECs using this 251-bp fragment. Results: Deletion analysis showed a region between position ,800 and ,549 mediated ethanol repression of luciferase activity. This 251-bp promoter fragment also repressed the activity of a heterologous promoter/enhancer in the presence of ethanol. Using the labeled 251-bp fragment, nuclear extracts from ethanol-treated ECs contained two inducible bands and one enhanced band. Non-ethanol treated nuclear extracts also contained a band that was not observed in ethanol-treated samples. Competition using 100-fold molar excess of unlabeled probe abolished these four bands. Conclusions: Repression of PAI-I gene transcription in cultured HUVECs exposed to ethanol may involve the interaction of several transcription factors with binding sites localized between positions ,800 and ,549 of the PAI-1 gene promoter. [source] Ethanol-Induced Up-Regulation of the Urokinase Receptor In Cultured Human Endothelial CellsALCOHOLISM, Issue 2 2001Edlue M. Tabengwa Background: Moderate alcohol consumption has been correlated to reduced coronary artery disease (CAD) risk and mortality. This alcohol effect may be mediated in part by an increased endothelial cell (EC) fibrinolysis. ECs synthesize fibrinolytic proteins, tissue plasminogen activator (t-PA), urokinase type plasminogen activator (u-PA), and plasminogen activator inhibitor type-1(PAI-1). In addition, they synthesize and regulate receptors for fibrinolytic proteins, namely (t-PA and plasminogen receptor) Annexin II and u-PA receptor (u-PAR). These receptors play an important role in the regulated expression of receptor-bound plasminogen activator conversion of receptor-bound plasminogen to receptor-bound plasmin on the EC surface (surface-localized fibrinolytic activity). Therefore, systemic factors, such as ethanol, that affect the level, or activity or interaction of one or more of these components, resulting in the increased expression of surface-localized EC fibrinolytic activity, will be expected to reduce the risk for thrombosis, CAD, and myocardial infarction (MI). We have previously shown that low ethanol up-regulates t-PA and u-PA gene transcription, while it down-regulates PAI-1, hence resulting in increased (sustained, 24 hr) surface-localized EC fibrinolytic activity. The current studies were carried out to determine whether low ethanol increased u-PAR expression in cultured human umbilical cord vein ECs (HUVECs). Methods: Cultured HUVECs were preincubated (1 hr) in the absence/presence of ethanol (0.025,0.2%, v/v); u-PAR mRNA (RT-PCR), antigen (western blot), and activity (125I-u-PA ligand binding/Scatchard analysis) levels were then measured after 0,24 hr. To determine whether the ethanol-induced changes in the u-PAR expression were transcriptional, transient transfection studies were carried out using a u-PAR/luciferase promoter construct (pu-PAR120/luc [1.2-kb u-PAR promoter fragment ligated to a promoterless luciferase vector]). Results: uPAR mRNA levels increased 2- to 3-fold and antigen levels (western blot) increased 2- to 4-fold while u-PA binding activity increased 36% (1.25 vs. 1.7 , 105 sites/cell, Bmax) without significantly affecting the Kd (1,2 nM). Transient transfection of cultured HUVECs with a pu-PAR120/luc construct resulted in a 2- to 3-fold increase in promoter activity in ethanol-induced cultures, compared with controls. Conclusion: These combined results demonstrate that low ethanol (,0.1%, v/v) induces the up-regulation of u-PAR gene transcription, resulting in increased u-PAR ligand binding activity. These results also further identify/define the contribution and role of another fibrinolytic protein in the overall ethanol-induced increase in surface-localized EC fibrinolysis that may underlie and contribute, in part, to the cardioprotection attributed to moderate alcohol consumption. [source] Post-transcriptional regulation of plasminogen activator inhibitor-1 by intracellular iron in cultured human lung fibroblasts,interaction of an 81-kDa nuclear protein with the 3,-UTRJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2005K. S. RADHA Summary., The proteinase inhibitor, type-1 plasminogen activator inhibitor (PAI-1), is a major regulator of the plasminogen activator system involved in plasmin formation and fibrinolysis. The present study explores the effects of intracellular iron on the expression of PAI-1 and associated cell-surface plasmin activity in human lung fibroblasts; and reports the presence of a novel iron-responsive protein. ELISA revealed a dose-dependent increase in PAI-1 antigen levels expressed in the conditioned medium of cells treated with deferoxamine, in the three cell lines studied. A concomitant increase in mRNA levels was also observed by Northern analyses. Presaturation with ferric citrate quenched the effect of deferoxamine. Experiments with transcription and translation inhibitors on TIG 3-20 cells demonstrated that intracellular iron modulated PAI-1 expression at the post-transcriptional level with the requirement of de-novo protein synthesis. Electrophoretic mobility shift assay and UV crosslinking assays revealed the presence of an ,,81-kDa nuclear protein that interacted with the 3,-UTR of PAI-1 mRNA in an iron-sensitive manner. Finally, we demonstrated that the increased PAI-1 is functional in suppressing cell-surface plasmin activity, a process that can affect wound healing and tissue remodeling. [source] The G20210A prothrombin-gene mutation and the plasminogen activator inhibitor (PAI-1) 5G/5G genotype are associated with early onset of severe preeclampsiaJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2005A. GERHARDT Summary., Hereditary risk determinants of venous thrombosis have been reported to be associated with severe preeclampsia. So far there are no data to support whether these risk determinants are related to the time of onset of severe preeclampsia. We used a case,control design, studying 97 women with severe preeclampsia in previous pregnancies and 277 normal women, to assess hereditary risk factors of venous thrombosis as risk determinants for severe preeclampsia. A case-only design comprising solely the 97 women with a history of preeclampsia was used to evaluate these risk factors as risk determinants for early onset of severe preeclampsia. Using the case,control design, there was no significant risk association of the hereditary risk factors with severe preeclampsia [factor V Leiden, odds ratio (OR) 0.9, 95% confidence interval (CI) 0.4, 2.2; prothrombin mutation, OR 1.9, 95% CI 0.5, 7.0; methylentetrahydrofolate reductase 677TT genotype, OR 0.8, 95% CI 0.4, 1.8; plasminogen activator inhibitor (PAI-1) 4G/4G genotype, OR 1.2, 95% CI 0.7, 2.1; PAI-1 5G/5G genotype, OR 1.0, 95% CI 0.5, 1.8]. However, the onset of severe preeclampsia was significantly earlier in women with the G20210A prothrombin gene mutation (24.5 weeks vs. 30.1 weeks, P = 0.046) and in women with the PAI-1 5G/5G genotype (25.7 weeks vs. 30.8 weeks, P = 0.024). Hereditary risk factors for venous thrombosis do not predispose for severe preeclampsia. However, women who are carriers of the G20210A prothrombin gene mutation and the PAI-1 5G/5G genotype are at risk for early onset of severe preeclampsia. It appears that these risk factors do not induce the pathomechanism but accelerate the course of preeclampsia. [source] Tissue- and agonist-specific regulation of human and murine plasminogen activator inhibitor-1 promoters in transgenic miceJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 11 2003M. Eren Summary., Numerous studies have described regulatory factors and sequences that control transcriptional responses in vitro. However, there is a paucity of information on the qualitative and quantitative regulation of heterologous promoters using transgenic strategies. In order to investigate the physiological regulation of human plasminogen activator inhibitor type-1 (hPAI-1) expression in vivo compared to murine PAI-1 (mPAI-1) and to test the physiological relevance of regulatory mechanisms described in vitro, we generated transgenic mice expressing enhanced green fluorescent protein (EGFP) driven by the proximal ,2.9 kb of the hPAI-1 promoter. Transgenic animals were treated with Ang II, TGF-,1 and lipopolysaccharide (LPS) to compare the relative activation of the human and murine PAI-1 promoters. Ang II increased EGFP expression most effectively in brain, kidney and spleen, while mPAI-1 expression was quantitatively enhanced most prominently in heart and spleen. TGF-,1 failed to induce activation of the hPAI-1 promoter but potently stimulated mPAI-1 in kidney and spleen. LPS administration triggered robust expression of mPAI-1 in liver, kidney, pancreas, spleen and lung, while EGFP was induced only modestly in heart and kidney. These results indicate that the transcriptional response of the endogenous mPAI-1 promoter varies widely in terms of location and magnitude of response to specific stimuli. Moreover, the physiological regulation of PAI-1 expression likely involves a complex interaction of transcription factors and DNA sequences that are not adequately replicated by in vitro functional studies focused on the proximal ,2.9 kb promoter. [source] Combined type-1 plasminogen activator inhibitor and NOD2/CARD15 genotyping predicts complicated Crohn's disease behaviourALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2007M. ALVAREZ-LOBOS Summary Background NOD2/CARD15 gene variants have not been universally associated with stricturing behaviour in Crohn's disease. Other behaviour modifying genes could explain these results. Aim To study the combined influence of NOD2/CARD15 variants and 4G/4G genotype of type-1 plasminogen activator inhibitor (PAI-1) gene on Crohn's disease behaviour. Methods One hundred and seventy Crohn's disease patients were studied prospectively, with a mean follow-up of 7± 6 years. Disease behaviour was registered by using two criteria: the Vienna classification and a non-hierarchical classification based on the behavioural Vienna categories. Results In the multivariate analysis for stricturing behaviour according to the Vienna categories, only absence of colonic disease (OR, 4.0; 95% CI: 1.49,11.1; P = 0.006) was an independent predictive factor. However, in the multivariate analysis for stricturing disease applying a non-hierarchical criteria, ileal disease (OR, 4.19; 95% CI: 1.30,13.5; P = 0.01), and carrying both NOD2/CARD15 variants and the 4G/4G PAI-1 genotype (OR, 5.02; 95% CI: 1.44,17.48; P = 0.01) were independent predictive factors. In the multivariate analysis for penetrating behaviour, the 4G/4G PAI-1 (OR, 3.10; 95% CI: 1.54,6.23; P = 0.001) and male sex (OR, 2.44; 95% CI: 1.30,4.60; P = 0.005) were independent predictive factors irrespective of criteria applied. Conclusions Combined PAI-1 and NOD2/CARD15 genotyping predict complicated Crohn's disease. Patients with these variants could benefit from early interventions. [source] Regulation of type I plasminogen activator inhibitor in human gingival fibroblasts with cyclosporine AORAL DISEASES, Issue 4 2010Y-C Ho Oral Diseases (2010) 16, 396,401 Objectives:, Cyclosporine A (CsA) is used as an immunosuppressive agent and its prominent side effect is the induction of gingival overgrowth. Type I plasminogen activator inhibitor (PAI-1) has shown to play an important role in CsA-induced gingival overgrowth. However, little is known about whether factors can modulate CsA-induced PAI-1 expression. Methods:, Cytotoxicity, reverse transcriptase-polymerase chain reaction, and enzyme-linked immunosorbent assay were used to investigate the effects of Human gingival fibroblasts (HGFs) exposed to CsA. In addition, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, interlukin-1,, tumor necrosis factor-,, mitogen-activated protein kinase kinase (MEK) inhibitor U0126, signal-regulated protein kinase (ERK) inhibitor PD98059 and cell-permeable glutathione precursor N -acetyl- L -cysteine (NAC) were added to test how they modulated the effects of CsA-induced PAI-1 expression. Results:, The concentration of CsA higher than 500 ng ml,1 demonstrated cytotoxicity to HGFs (P < 0.05). Periodontal pathogens as well as proinflammatory cytokines were found to increase the CsA-induced PAI-1 mRNA and protein expression (P < 0.05). Pharmacological agents NAC, U0126, and PD98059 were found to decrease the CsA-induced PAI-1 mRNA and protein expression (P < 0.05). Conclusions:, Cyclosporine A (CsA) may predispose to gingival overgrowth under inflammatory environments. The regulation of PAI-1 expression induced by CsA might be critically related with the intracellular glutathione and the ERK-MAPK pathway. [source] Prospective study of hemostatic alterations in children with acute lymphoblastic leukemia,AMERICAN JOURNAL OF HEMATOLOGY, Issue 5 2010Paola Giordano In a group of newly diagnosed acute lymphocytic leukemia (ALL) children we evaluated a number of hemostatic and inflammatory markers at diagnosis and at different time points during chemotherapy for the remission induction to identify alterations in the plasma levels of prothrombotic markers before and during the course of chemotherapy. The following plasma markers were evaluated: thrombin-antithrombin complex (TAT), D-Dimer, plasminogen activator inhibitor 1 (PAI-1), antithrombin, fibrinogen, von Willebrand factor (VWF) antigen and high molecular weight VWF (HMW-VWF) multimers, P-selectin, tumor necrosis factor alpha (TNF-,), and interleukin 6 (IL-6). Plasma samples were collected at the following time points: at T0 (baseline) and T1 (+24 days of therapy), T2 (+36 days therapy), and T3 (+64 days therapy). The results show that, at diagnosis, ALL children presented with laboratory signs of increased thrombin generation and fibrin formation (i.e. high TAT and D-dimer levels), fibrinolysis inhibition (i.e. high PAI-1 level), endothelial activation (i.e., high HMW-VWF and soluble P-selectin levels) and inflammation (i.e. high TNF-alpha and IL-6 levels). After starting induction therapy, the thrombin generation markers and inflammatory cytokines significantly decreased. To the opposite, PAI-1 and P-selectin significantly increased, suggesting an insult by chemotherapy on the vascular endothelium. These effects were more evident during steroid administration. Symptomatic venous thromboembolism (VTE) episodes developed in two cases during induction therapy, which did not allow the evaluation of the predictive value for VTE of laboratory markers. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc. [source] Impact of genetic variation on perioperative bleedingAMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2008Jochen D. Muehlschlegel Variation in bleeding in the perioperative period is a complex and multifactorial event associated with immediate and delayed consequences for the patient and health care resources. Little is known about the complex genetic influences on perioperative bleeding. With the discovery of multiple variations in the human genome and ever-growing databases of well-phenotyped surgical patients, better identification of patients at risk of bleeding is becoming a reality. In this review, polymorphisms in the platelet receptor genes, plasminogen activator inhibitor, and angiotensin genes among others will be discussed. We will explore the nature, effects, and implications of the genetics that influence perioperative bleeding above and beyond surgical bleeding, particularly in cardiac surgery. Am. J. Hematol., 2008. © 2008 Wiley-Liss, Inc. [source] Regulation of plasminogen activator inhibitor 1 expression in human osteoarthritic chondrocytes by fluid shear stress: Role of protein kinase C,ARTHRITIS & RHEUMATISM, Issue 8 2009Chih-Chang Yeh Objective To test a fluid flow system for the investigation of the influence of shear stress on expression of plasminogen activator inhibitor 1 (PAI-1) in human osteoarthritic (OA) articular chondrocytes (from lesional and nonlesional sites) and human SW-1353 chondrocytes. Methods Human SW-1353 chondrocytes and OA and normal human articular chondrocytes were cultured on type II collagen,coated glass plates under static conditions or placed in a flow chamber to form a closed fluid-circulation system for exposure to different levels of shear stress (2,20 dyn/cm2). Real-time polymerase chain reaction was used to analyze PAI-1 gene expression, and protein kinase C (PKC) inhibitors and small interfering RNA were used to investigate the mechanism of shear stress,induced signal transduction in SW-1353 and OA (lesional and nonlesional) articular chondrocytes. Results There was a significant reduction in PAI-1 expression in OA chondrocytes obtained from lesional sites compared with those obtained from nonlesional sites. In SW-1353 chondrocytes subjected to 2 hours of shear flow, moderate shear stresses (5 and 10 dyn/cm2) generated significant PAI-1 expression, which was regulated through PKC, phosphorylation and Sp-1 activation. These levels of shear stress also increased PAI-1 expression in articular chondrocytes from nonlesional sites and from normal healthy cartilage through the activation of PKC, and Sp-1 signal transduction, but no effect of these levels of fluid shear stress was observed on OA chondrocytes from lesional sites. Conclusion OA chondrocytes from lesional sites and those from nonlesional sites of human cartilage have differential responses to shear stress with regard to PAI-1 gene expression, and therefore diverse functional consequences can be observed. [source] Relationship between elevated cerebrospinal fluid levels of plasminogen activator inhibitor 1 and neuronal destruction in patients with neuropsychiatric systemic lupus erythematosusARTHRITIS & RHEUMATISM, Issue 7 2009Jakub Kwieci Objective A homeostatic imbalance between coagulation and fibrinolysis might occur intrathecally in neuropsychiatric systemic lupus erythematosus (NPSLE). However, there are no published data on levels of fibrinolytic factors in the cerebrospinal fluid (CSF) of patients with NPSLE. The present study was undertaken to assess CSF levels of fibrinolytic molecules, including urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), D-dimer, and plasminogen activator inhibitor 1 (PAI-1), in SLE patients with clinically verified neuropsychiatric involvement and to compare these levels with those in SLE patients without neuropsychiatric involvement and in healthy subjects. Methods Levels of uPA, tPA, and PAI-1 were assessed in CSF from 94 patients with SLE (33 who had NPSLE, 56 who did not have NPSLE, and 5 who were positive for antiphospholipid antibody [not included in the NPSLE or non-NPSLE group]) and from 53 age-matched controls. Patients were evaluated clinically, with magnetic resonance imaging of the brain, analyses of neuronal/glial degradation products in CSF, and neuropsychiatric testing. Results In the group of patients with NPSLE, intrathecal PAI-1 levels were significantly elevated compared with levels in SLE patients without overt neuropsychiatric involvement (P < 0.05) and in healthy controls (P < 0.001). In contrast, intrathecal levels of uPA did not differ significantly. Intrathecal levels of PAI-1 correlated significantly with CSF levels of interleukin-6 (IL-6) (r = 0.34, P < 0.001) and IL-8 (r = 0.33, P < 0.001). Importantly, increased PAI-1 and D-dimer levels were observed in SLE patients who had pathologically elevated levels of glial fibrillary acidic protein, neurofilament triplet protein, and tau protein in CSF. Conclusion Intrathecal release of PAI-1 is increased in patients with NPSLE. This results in impaired fibrinolysis, which might contribute to neuronal and astrocytic damage in NPSLE. [source] Plasminogen activator inhibitor 1 gene polymorphisms and mirtazapine responses in Koreans with major depressionASIA-PACIFIC PSYCHIATRY, Issue 3 2009Hun Soo Chang PhD Abstract Introduction: Brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of mental disorders and in the mechanism of action of antidepressant medications. The mature form of BDNF is derived from proBDNF through tissue type plasminogen activator (tPA) and the plasminogen system in the brain, which is regulated by an endogenous inhibitor, plasminogen activator inhibitor (PAI). Therefore, PAI may be involved in the development of major depressive disorder (MDD) and its response to antidepressant treatment. The present study determined the relationship between the 4G/5G polymorphism in the PAI1 gene and the clinical outcome of mirtazapine treatment in 271 Korean MDD patients. Methods: We tested the association between the polymorphism and response to mirtazapine treatment or percentage decrease of the 21-item Hamilton Depression Rating (HAMD21) scores using multiple logistic and linear regression analysis. Results: PAI1 4G/5G genotypes and allele distributions were comparable between responders and non-responders during the treatment period. Similarly, linear regression showed no association between genotypes or alleles and the percentage decline in total HAMD21 with mirtazapine treatment. In the analysis of symptomatic subscores, the percentage decline in the psychic anxiety and delusion scores after 4 weeks of mirtazapine treatment showed a statistical trend to a difference among genotypes, although it was not statistically significance. Discussion: In this first pharmacogenetics study of the PAI1 4G/5G polymorphism and mirtazapine treatment response, our results do not support the hypothesis that this polymorphism is involved in the therapeutic response to mirtazapine. [source] Fibrinolytic risk factor clustering and insulin resistance in healthy male relatives of men with intermittent claudication,BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 3 2006D. J. Parry Background: Raised fibrinolytic factors predict cardiovascular risk in healthy subjects. The aim of this study was to measure fibrinolytic factors and insulin resistance in healthy male first-degree relatives of men with intermittent claudication younger than 65 years. Methods: The study compared 165 healthy first-degree relatives with 165 age-, sex- and race-matched control subjects free from a personal or family history of premature cardiovascular disease. Primary outcome measures were plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (tPA) and D-dimer levels. Insulin resistance was estimated by Homeostasis Model Assessment. Clinical and biochemical risk factors were measured and subjects genotyped for the PAI-1 4G/5G polymorphism. Results: First-degree relatives had significantly higher mean PAI-1 (10·23 versus 7·85 ng/ml; P = 0·024), tPA (9·98 versus 8·29 ng/ml; P < 0·001) and D-dimer levels (56·6 versus 46·1 ng/ml; P = 0·004). They also had significantly higher insulin resistance (1·85 versus 1·53; P < 0·001) and clustered multiple atherogenic risk factors. On multivariate analysis the association between both tPA and D-dimer levels and relative status was independent of other variables. Conclusion: Raised levels of PAI-1, tPA, D-dimer and estimated insulin resistance were present in the healthy male first-degree relatives of men with intermittent claudication. These data support the hypothesis of fibrinolytic risk factor clustering in this high-risk population. Copyright © 2006 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] Genotype,phenotype relationships in an investigation of the role of proteases in abdominal aortic aneurysm expansionBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 11 2005P. Eriksson Background: The aim of the study was to investigate the effect of functional polymorphisms in promoters of matrix metalloproteinase (MMP) 2, MMP-3, MMP-9, MMP-12 and plasminogen activator inhibitor (PAI) 1 genes on the growth rate of small abdominal aortic aneurysms (AAA). Methods: Some 455 individuals with a small AAA (4·0,5·5 cm) were monitored for aneurysm growth by ultrasonography (mean follow-up 2·6 years). They also provided a DNA sample for analysis of the ,1306 C > T, ,1171 5A > 6A, ,1562 C > T, ,82 A > G and ,675 4G > 5G alleles of MMP-2, MMP-3, MMP-9, MMP-12 and PAI-1, respectively. Mean linear AAA growth rates were calculated by flexible modelling; the sample size was sufficient to detect variants that influenced the growth rate by 25 per cent. Results: For MMP-2, MMP-9 and MMP-12 genotypes, growth rates were similar to the mean linear growth rate of 3·08 mm per year. For MMP-3, growth rates were 3·05 (for 5A5A), 3·19 (for 5A6A) and 2·90 (for 6A6A) mm per year. For PAI-1, patients with 4G4G, 4G5G and 5G5G genotypes had growth rates of 3·18, 2·92 and 3·47 mm per year, respectively, for aneurysms with a baseline diameter of 45·1, 44·6 and 46·2 mm. The increased growth rate for patients with PAI-1 5G5G genotype was not statistically significant (P = 0·061), although these patients had the lowest plasma PAI-1 concentrations (P = 0·018). Conclusion: There was no evidence that any specific MMP polymorphism had a clinically significant effect on AAA expansion. The plasminogen system may have a small but clinically significant role in AAA development. Much larger studies would be needed to evaluate genes of smaller effect. Copyright © 2005 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] Telomere length in relation to insulin resistance, inflammation and obesity among Arab youthACTA PAEDIATRICA, Issue 6 2010OS Al-Attas Abstract Aim:, The aim of this study was to determine the associations of telomere length to markers of obesity, insulin resistance and inflammation in Saudi children. Methods:, A total of 69 boys and 79 girls, aged 5,12 years, participated in this cross-sectional study. Anthropometrics were measured. Serum glucose and lipid profile were measured using routine laboratory methods. Serum insulin, leptin, adiponectin, resistin, tumour necrosis factor-alpha and active plasminogen activator inhibitor 1 were quantified using customized multiplex assay kits. C-reactive protein and angiotensin II were quantified using ELISA. Leucocyte telomere length was examined by quantitative real time PCR utilizing IQ cycler. Results:, Mean telomere length was significantly shorter in obese boys compared with their lean counterparts (p = 0.049), not in girls. It was not associated to insulin resistance, adipocytokines and markers of inflammation. In girls, the significant predictor of telomere length was waist circumference, explaining 24% of variance (p = 0.041) while in boys, systolic blood pressure explained 84% of the variance (p = 0.01). Conclusion: Childhood obesity in boys corresponds to shorter leucocyte telomere length which is not evident in girls. The association of leucocyte telomere length to blood pressure and waist circumference in children suggests clinical implications as to the contribution of these parameters in premature ageing. [source] Accelerated plasminogen activator inhibitor may prevent late restenosis after coronary stenting in acute myocardial infarctionCLINICAL CARDIOLOGY, Issue 3 2003Teruo Inoue M.D. Abstract Background: Although acceleration of plasma plasminogen activator inhibitor-1 (PAI-1) level after emergent coronary angioplasty in acute myocardial infarction (AMI) has been documented, its pathophysiologic role is still unknown. Hypothesis: This study was designed to elucidate the role of PAI-1 in the development of restenosis after primary coronary stenting in AMI. Methods: We selected for this study 66 patients with AMI, who underwent primary coronary stenting for infarct-related coronary artery lesions in an emergent situation. In all patients, plasma PAI-1 level was measured at admission, and at 3 h, 24 h, 48 h, and 1 month after coronary stenting. Results: At admission, the PAI-1 level was equivalent in 24 patients who experienced restenosis and in 42 patients without restenosis (28 ± 4 vs. 29 ± 4 ng/ml). In patients with restenosis, the levels did not change during the course after coronary stenting. In patients without restenosis, however, the level significantly increased at 3 h (48 ± 9 ng/ml, p < 0.001), 24 h (42 ± 9, p < 0.01), and 48 h (38 ± 7, p < 0.05) after coronary stenting, and was restored to the level equivalent to that at admission (27 ± 2 ng/ml) 1 month after coronary stenting. The PAI-1 level at 3 h after coronary stenting in patients without restenosis was significantly higher (p < 0.05) than the level (33 ± 6 ng/ml) in patients with restenosis. Multiple logistic regression analysis indicated that the PAI-1 level 3 h after coronary stenting was an independent predictor of restenosis (Wald x2 = 3.826, p = 0.019, odds ratio 0.921, 95% confidence interval 0.866-0.961). Conclusion: Accelerated PAI-1 after coronary stenting in patients with AMI may protect against the development of late restenosis. [source] Apolipoprotein E and Paraoxonase 1 polymorphisms are associated with lower serum thyroid hormones in postmenopausal womenCLINICAL ENDOCRINOLOGY, Issue 2 2009Irene Lambrinoudaki Summary Objective, Autoimmune thyroiditis and overt or subclinical hypothyroidism have been associated with increased prevalence of cardiovascular disease (CVD). Design, Cross-sectional investigation of the association between gene polymorphisms related to CVD with thyroid function and autoimmunity. Patients, In total 84 healthy postmenopausal women aged 49,69 years. Measurements, FT3, FT4, anti-TPO and anti-TG were assessed in the sera of participants. The following polymorphisms were assessed from peripheral lymphocyte DNA: Apolipoprotein E E2/E3/E4, paraoxonase 1 A/B, Glycoprotein IIIa leu33pro, MTHFR ala222val, ApoBarg3500gln, plasminogen activator inhibitor 1 4G/5G, cholesterol 7-, hydroxylase A204C and cholesterol ester transfer protein B1/B2. Results, A statistically significant correlation was found between Apolipoprotein E and paraoxonase1 polymorphisms and serum thyroid hormones: carriers of the E2 or E4 allele of the ApoE gene had lower levels of FT4 (P = 0·0005) than women with the E3/E3 genotype. Carriers of the B allele of paraoxonase 1 gene had lower levels of FT3 compared to women with the wild-type genotype (P = 0·047). A statistically significant positive association (P = 0·049) was also observed between anti-TG antibodies and the presence of the E2 allele of the Apolipoprotein E gene. Conclusions, Polymorphisms of apolipoprotein E and paraoxonase 1 are associated with different levels of thyroid hormone and anti-Tg antibody levels in the study population in this pilot study. The mechanism underlying this association remains to be elucidated. [source] | |||||||||||||||||||||||||