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Biomedical subjects

S Sasayama

Publications and source records attributed to S Sasayama.

At least 127 records · Page 7Linked to original sources
PubMed1999

Hepatocyte growth factor is a major mediator in heparin-induced angiogenesis.

Heparin has a potent angiogenic effect in experimental animals and patients with ischemic diseases; however, the precise mechanism behind this angiogenesis remains to be clarified. The aim of this study was to determine whether the administration of heparin affects the levels of heparin-binding angiogenic factors in human plasma, and to identify the molecule responsible for heparin-induced angiogenesis. Plasma levels of hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) were measured before and after administration of 100 U, 3,000 U or 10,000 U of heparin in patients with coronary artery disease. Administration of 3,000 U or 10,000 U of heparin caused significant increases in plasma HGF (40- and 54-fold, respectively), in absence of obvious increases in bFGF and VEGF levels. Furthermore, compared with the serum collected before heparin administration, the serum collected after heparin administration had more prominent growth-promoting and vascular tube-inducing properties on endothelial cells, and these increased activities were completely inhibited by neutralization of HGF, whereas neutralization of bFGF and VEGF had no effect. These findings suggest that HGF plays a significant role in heparin-induced angiogenesis.

Aged↗
PubMed1999

The role of endothelin-converting enzyme-1 in the development of alpha1-adrenergic-stimulated hypertrophy in cultured neonatal rat cardiac myocytes.

BACKGROUND: Accumulating evidence suggests that the local synthesis of endothelin-1 (ET-1) plays a role in the development of heart failure in vivo. We investigated the role of endothelin-converting enzyme-1 (ECE-1), which mediates the conversion of big ET-1 to mature ET-1, in the development of alpha1-adrenergic-stimulated hypertrophy in cultured neonatal rat cardiac myocytes. METHODS AND RESULTS: Phenylephrine (PE) induced the expression of ET-1 in rat cardiac myocytes and accelerated the conversion of big ET-1 to ET-1. The ECE-1 mRNA levels were markedly increased 3 hours after PE stimulation (3.6-fold compared with saline stimulation, P<0.005). A specific ECE-1 antagonist, FR901533, inhibited the PE-stimulated increase in protein synthesis rate by 45% (P<0.05). As genetic markers for the hypertrophic response, FR901533 inhibited the PE-stimulated transcriptional activities of the 3.5-kb beta-myosin heavy chain promoter by 79% (P<0.01) but did not affect that of the 3.4-kb atrial natriuretic factor (ANF) promoter. In Bio14.6 Syrian cardiomyopathic hamsters, ventricular ET-1 and ANF mRNA levels did not correlate at 2 different stages. CONCLUSIONS: ET-1-independent pathways may mediate activation of the ANF gene program in ventricular myocytes both in vitro and in vivo. These results also indicate that the conversion of big ET-1 to ET-1 in rat cardiac myocytes is required for the development of alpha1-adrenergic-stimulated hypertrophy and beta-myosin heavy chain gene transcription.

Adrenergic alpha-Agonists↗
PubMed1999

Determinants of collateral development in patients with acute myocardial infarction.

BACKGROUND: The presence or absence of collateral circulation to the infarct-related coronary artery in acute myocardial infarction (AMI) significantly impacts on infarct size and resulting left ventricular function. However, the determinants of collateral development have not been clarified. HYPOTHESIS: The purpose of this study was to elucidate the determinants of collateral development in humans. METHODS: The study group consisted of 248 patients (178 men, 70 women; mean age 63 years) undergoing coronary angiography within 12 h after the onset of a first AMI. All patients exhibited complete occlusion of the infarct-related artery. The extent of collateral circulation to the area perfused by the infarct-related artery was graded as none, or poorly or well developed, depending on the degree of opacification of the occluded coronary artery on the contralateral injection of contrast. RESULTS: Well-developed collateral circulation was observed in 92 of the 248 patients (37.1%). The prevalence of well-developed collaterals was 57% in patients with a history of angina pectoris prior to AMI, which was significantly (p < 0.0001) higher than the 26% in those without a history of angina. Multivariate stepwise logistic regression analysis was then applied to identify predictors of collateral development. Possible determinants of collateral development were long-standing preinfarction angina, severity of coronary artery disease, age, gender, and coronary risk factors (hypertension, diabetes, hypercholesterolemia, smoking). This analysis revealed that only the presence of a history of angina pectoris prior to AMI was a significant predictor of collateral development (p < 0.0001). CONCLUSIONS: A history of angina pectoris prior to AMI is a clinical marker for coronary stenoses. Since severe coronary stenoses can provide stimuli that lead to collateral development, it is reasonable that a history of angina would also be a clinical marker for collateral vessels.

Age Factors↗
PubMed1999

Serial circulating concentrations of C-reactive protein, interleukin (IL)-4, and IL-6 in patients with acute left heart decompensation.

BACKGROUND: Interleukin (IL)-6 has recently been shown to have negative inotropic effects, and several studies have reported increases in circulating concentrations of this cytokine in patients with depressed left ventricular ejection fraction and chronic left heart failure. However, most previous clinical studies have measured cytokines in compensated chronic heart failure. HYPOTHESIS: The purpose of this study was to examine the temporal evolution of circulating concentrations of C-reactive protein (CRP) and cytokines in patients with cardiomyopathy and acute cardiac decompensation, free of infection and unstable angina. METHODS: The time course of circulating concentrations of CRP, an anti-inflammatory cytokine interleukin (IL)-4, and a proinflammatory cytokine IL-6 were studied in eight patients with cardiomyopathy and acute cardiac decompensation in the absence of infection or unstable angina. Control samples were obtained from eight age-matched asymptomatic subjects. RESULTS: Increased circulating concentrations of CRP (2.6 +/- 0.8 mg/dl), IL-4 (164.6 + 36.5 pg/ml), and IL-6 (17.1 +/- 5.1 pg/ml) were found in all eight patients during acute cardiac decompensation; these values decreased significantly with the resolution of symptoms of cardiac decompensation (0.5 +/- 0.1 mg/dl, 77.8 +/- 23.6 pg/ml, 2.3 +/- 0.1 pg/ml, respectively, p < 0.05 for both). There was a significant correlation between peak CRP and peak IL-6 (p < 0.05). CONCLUSIONS: In patients with acute left heart decompensation in the absence of infection or coronary events, CRP, IL-4, and IL-6 increased and returned toward normal levels as the symptoms of heart failure resolved. Since the changes in concentrations of CRP, IL-4, and IL-6 in patients with heart failure are dynamic, the distinction between compensated and decompensated state is important when discussing the significance of acute reactive proteins or cytokines in the pathogenesis of heart failure.

Aged↗
PubMed1999

Apoptosis in congestive heart failure induced by viral myocarditis in mice.

It has recently been speculated that progressive deterioration of left ventricular function in chronic heart failure is due to the ongoing loss of viable cardiac myocytes. However, as there is little direct evidence of significant apoptosis contributing to the pathogenesis in cardiac myocytes in vivo, the significance of apoptosis in heart failure remains to be clarified. We investigated the role of apoptosis in heart failure induced by encephalomyocarditis virus myocarditis. DBA/2 mice were inoculated with the virus (day 0), then killed, and their hearts were extracted 3 to 28 days later. Internucleosomal DNA fragmentation, chromatin binding dye staining, and in situ terminal transferase deoxyuridine triphosphate (dUTP) end-labeling were used to detect apoptosis. Internucleosomal DNA fragmentation (DNA ladder) was clearly demonstrated on days 5 to 14 in the virus-infected hearts when myocardial necrosis and infiltration of mononuclear cells were prominent in the hearts. Apoptotic cells demonstrated morphological changes typical of apoptosis (condensation of chromatin and nuclear fragmentation). Both Fas antigen and Fas ligand immunoreactivity were detected in the infiltrating mononuclear cells. The in situ terminal transferase dUTP end-labeling method demonstrated condensed nuclei of infiltrating mononuclear cells on day 7. However, nuclei of cardiac myocytes surrounded by the cellular infiltration were absent. The main source of apoptotic cells in the heart in mice with viral myocarditis appeared to be the infiltrating mononuclear cells.

Animals↗
PubMed1999

On the mechanism of genistein-induced activation of protein kinase A-dependent Cl- conductance in cardiac myocytes.

Genistein, an inhibitor of protein tyrosine kinase (PTK), enhanced the activation of the cardiac isoform of the protein kinase A (PKA)-regulated cystic fibrosis transmembrane conductance regulator (CFTR) Cl- conductance in guinea-pig ventricular cells. We examined the mechanism(s) underlying this excitatory action of genistein by using patch-clamp techniques. The CFTR Cl- conductance, activated by isoproterenol (ISO, 10 nM; [Cl-] 153 mM extracellular, 21 mM intracellular; 36 degrees C), was enhanced by 20 microM genistein. Daidzein, a structural analogue of genistein with little inhibitory action on PTK, also enhanced CFTR Cl- currents. After maximal activation of the Cl- conductance by a cocktail of adenosine 3', 5'-cyclic monophosphate, 3-isobutyl-1-methylxanthine and okadaic acid or vanadate plus forskolin in the pipette, genistein was no longer stimulatory but was rather slightly inhibitory at 100 microM. Direct exposure of myocytes to higher concentrations of genistein (50-100 microM) elicited outwardly rectifying currents with a reversal potential of -47 mV in the absence of ISO. In the presence of 50 microM H-89, a PKA inhibitor, genistein had no effect. Vanadate in the pipette at a concentration (100 microM) inhibiting phosphotyrosine phosphatases alone did not prevent the action of genistein. In contrast, no conductance was activated by tyrphostins B42 or 51 or lavendustin A, other PTK inhibitors. Genistein's stimulation of cardiac CFTR Cl- conductance appears to be independent of the PTK pathway and to be due to its direct interaction with CFTR Cl- channels.

1-Methyl-3-isobutylxanthine↗
PubMed1999

Upregulated expression of cardiac endothelin-1 participates in myocardial cell growth in Bio14.6 Syrian cardiomyopathic hamsters.

OBJECTIVES: The purpose of this study is to investigate the role of endogenous endothelin-1 (ET-1) in myocardial growth in Bio 14.6 Syrian cardiomyopathic hamsters (Bio). BACKGROUND: While ET-1, as a growth-promoting peptide, has been implicated in the development of secondary cardiac hypertrophy, the role of endogenous ET-1 in cardiac growth in primary myocardial disease is unknown. METHODS: We measured left ventricular ET-1 levels by a specific sandwich enzyme-linked immunosorbent assay. Furthermore, we examined the chronic effect of T0201, an ET type A receptor-specific antagonist. RESULTS: The ET-1 levels in the left ventricles were 1.8-fold higher (p < 0.0005) at 20 weeks and 6.4-fold higher (p < 0.0001) at 35 weeks in the Bio compared to age-matched control F1B hamsters (F1B). The Bio ET-1 levels in the lungs exhibited an only 1.3-fold elevation at 35 weeks. Immunohistochemistry demonstrated the localization of ET-1 mainly in the cardiac myocytes. The treatment with T0201 significantly reduced the heart weight/body weight ratio in the Bio, but did not affect the heart weight/body weight ratio in the F1B. Histologically, T0201 reduced the myocyte diameter of Bio to a level similar with that of F1B. However, T0201 did not affect the extent of fibrosis in Bio or F1B. CONCLUSIONS: The ET-1 level in the heart of cardiomyopathic hamsters increases in stage-dependent and organ-specific manners. Though myocyte degeneration and subsequent replacement fibrosis do not require an ET-1 pathway, the accelerated synthesis of ET-1 in the heart may contribute to the pathological growth of remaining myocytes in this animal model.

Animals↗
PubMed1999

Pimobendan inhibits the production of proinflammatory cytokines and gene expression of inducible nitric oxide synthase in a murine model of viral myocarditis.

OBJECTIVES: This study was designed to examine the effects of pimobendan in a murine model of viral myocarditis in relation to proinflammatory cytokine production and nitric oxide (NO) synthesis by inducible NO synthase (iNOS) in the heart. BACKGROUND: Pimobendan has been recently confirmed to improve both acute and chronic heart failure. Since the modulation of myocardial necrosis and contractile dysfunction by various proinflammatory cytokines may be partially mediated by the production of nitric oxide, the effects of pimobendan on the production ofproinflammatory cytokines and NO were investigated in an animal model of viral myocarditis involving heart failure. METHODS: DBA/2 mice were inoculated with the encephalomyocarditis virus. To observe its effect on survival up to 14 days, pimobendan (0.1 mg/kg or 1 mg/kg) or vehicles were given from the day of virus inoculation (day 0) orally once daily. The effects of pimobendan on histological changes, cytokine production, NO production and iNOS gene expression in the heart were studied in mice treated either with pimobendan, 1 mg/kg or with vehicles only, and sacrificed seven days after virus inoculation. RESULTS: The survival of mice improved in a dose-dependent fashion such that a significant difference (p < 0.02) was found between the higher-dose pimobendan group (20 of 30 [66.7%]) and the control group (11 of 30 [36.7%]). Histological scores for cellular infiltration (1.1+/-0.1 vs. 2.0+/-0.0, p < 0.001), intracardiac tumor necrosis factor (TNF)-alpha (18.2+/-1.8 vs. 35.8+/-4.2 pg/mg heart, p < 0.001) and interleukin (IL)-1beta (9.3 +/-1.2 vs. 26.6+/-7.1 pg/mg heart, p < 0.01) were significantly lower in the mice given pimobendan versus those of the control mice. Interleukin-6 levels (7.1+/-0.8 vs. 9.2+/-1.9 pg/mg heart) were also lower in the mice treated with pimobendan. Furthermore, intracardiac NO production was significantly (p < 0.001) less in the pimobendan group (0.165+/-0.004 nmol/mg heart) than in the control group (0.291+/-0.051 nmol/mg heart), and intracardiac iNOS gene expression in the mice given pimobendan was 74% lower than it was in the control animals (p < 0.01). CONCLUSIONS: These findings suggest that the beneficial effects of pimobendan in viral myocarditis are partially mediated by the inhibition of both proinflammatory cytokine production and NO synthesis by iNOS.

Animals↗
PubMed1999

Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and Caucasian patients.

Japanese investigators have provided a substantial contribution in the understanding of coronary vasomotor reactivity. On occasions, their findings have been at variance with those undertaken on caucasian patients, raising speculation that vasomotor differences between races may exist. In a comparative review of the published literature, we evaluated the vasoreactive differences among Japanese and caucasian patients with variant angina or myocardial infarction. In variant angina, Japanese patients appear to have diffusely hyperreactive coronary arteries compared with caucasian people, manifested by their segmental rather than focal spasm, hyperreactive nonspastic vessels and multivessel spasm. These differences may reflect the increased basal tone among Japanese variant angina patients and may relate to controversial differences in endothelial nitric oxide production or autonomic nervous system activity. Provocative vasomotor studies of Japanese patients with a recent myocardial infarction report a higher incidence of inducible spasm than caucasian studies, an observation recently supported by a controlled study. Furthermore, the hyperreactivity was diffuse, occurring in both non-infarct- and infarct-related vessels. These observations support the existence of racial coronary vasomotor reactivity differences but require confirmation in further prospectively conducted studies.

Adult↗
PubMed1999

Basic kinetics of 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) in canine myocardium.

BMIPP is a radioiodinated fatty acid analogue used for myocardial single photon emission CT (SPECT) imaging based on high cardiac fatty acid metabolism. In normal dogs, 74% of the injected BMIPP was instantly extracted and was then retained in 65.3%. The washout of the retained radioactivity was low, and most of the washout was alpha- and beta-oxidation metabolites. ATP concentration plays an important role in the myocardial uptake and retention of BMIPP. The ATP-dependent BMIPP uptake at the TG pool was strongly regulated by etomoxir with modifying mitochondrial beta-oxidation and subsequent ATP production. Thus, myocardial viability was reflected on the BMIPP uptake in acute ischemia. In spite of insignificant changes in early extraction and retention. BMIPP back diffusion (r = -0.92) and full-oxidation metabolite (r = 0.78) were correlated with the severity of ischemia. Mismatched region of BMIPP with flow (Tl-201) showed decreased metabolic enzymes such as citrate synthase and 3-hydroxyacyl-CoA dehydrogenase. These data suggest that BMIPP would be feasible for detecting cellular energy state from lipid metabolism.

Animals↗
PubMed1999

Synthesis of glycosylated human interleukin-1alpha, neoglyco IL-1alpha, coupled with N-acetylneuraminic acid.

In order to develop glycosylated cytokine, recombinant human IL-1alpha was chemically modified with N-acetylneuraminic acid (NANA). NANA with C9 spacer, 8-(hydrazinocarbonyl)octyl 5-acetamido-3, 5-dideoxy-D-glycero-alpha-D-galacto-2-nonulo-pyranosidonic acid potassium salt (6), was synthesized by glycosylation of C9 spacer, 8-[2-N-(benzyloxycarbonyl)hydrazinocarbonyl]octanol, with methylthio glycoside derivatives of NANA in the presence of molecular sieves 3A and methyl (methylthio)sulfonium trifrate in propionitrile, followed by separation of a and beta anomers with a column chromatography and deprotection. Compound 6 was coupled to IL-1alpha by the acyl azide method. The glycosylated IL-1 was purified by anion-exchange chromatography, and NANA coupled to IL-1 was confirmed by oxidation with NaIO4. Based on the molecular weight average number of carbohydrate molecules introduced per molecule of IL-1alpha was estimated to be 2.9.

Chromatography, High Pressure Liquid↗
PubMed1999

Genetic polymorphisms at the tumour necrosis factor loci (TNFA and TNFB) in cardiac sarcoidosis.

Many studies have previously confirmed high TNFalpha (tumor necrosis factor-alpha) production in sarcoidosis, and have shown that TNFalpha plays an important role in granuloma formation. We investigated TNFA and TNFB (lymphotoxin-alpha) gene polymorphisms in 26 cardiac sarcoidosis patients of Japanese origin. These studies revealed a significant increase in the more uncommon TNFA2 allele in the patient group, suggesting that the TNFA gene controls the genetic susceptibility to cardiac sarcoidosis.

Asian People↗
PubMed1999

Up-regulation of glomerular extracellular matrix and transforming growth factor-beta expression in RF/J mice.

BACKGROUND: RF/J mice were first reported as a murine model of spontaneous glomerulosclerosis by Gude and Lupton in 1960, but the precise histologic characteristics and immunopathological background of this mouse have not been investigated further. METHODS: Measurements of serum levels of immunoglobulins, anti-single strand DNA (anti-ss-DNA) antibody, complement (C3), and circulating immune complex (IC) were performed. Analyses of glomerular histological and immunopathological lesions in association with the detection of mRNA expression of collagen IV, TGF-beta, matrix protein turnover related enzymes, matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2) and platelet-derived growth factor (PDGF) were also performed in young (10-week-old) and elderly (60-week-old) RF/J mice with age-matched BALB/C mice as the controls. RESULTS: High levels of serum IgA and IgG from as early as 20 weeks of age were noted in the RF/J mice. Serum anti-ss-DNA antibody of aged RF/J mice increased up to 23% of that of aged MRL-lpr/lpr mice, and serum C3 concentration significantly decreased with age, reaching lower levels than that of BALB/c mice. IgA-IC levels were significantly high compared to BALB/C mice both in the early and late stages of life, whereas IgG-IC levels were high only in mice younger than 20 weeks. Semiquantitative and quantitative analyzes of renal histopathological findings revealed significantly marked and age-related mesangial matrix expansion in RF/J mice, with increasing frequency of global glomerular sclerosis and tubulointerstitial damage. On the other hand, although precise measurements of glomerular cell numbers also showed an apparent augmentation in both young and old RF/J mice compared to BALB/C mice, glomerular cellularity decreased with age in RF/J mice. Immunohistochemical study revealed massive immunoglobulin deposition from a young age in association with significantly higher accumulation of matrix proteins, such as types I and IV collagen and laminin from the early stage of life. In addition, in these glomeruli, transforming growth factor-beta1 (TGF-beta1) was highly expressed both in young and old mice. The mRNA expression of MMP-2 was up-regulated only in the early stage of life. Although PDGF mRNA of RF/J mice was significantly up-regulated in the early stage of life, the differences between the mice disappeared in the late stage of life. CONCLUSIONS: These findings suggest that in RF/J mice, an immunopathological background inducing high serum immunoglobulin and IC levels from the early stage of life is closely related to mesangioproliferative glomerular lesions mediated by PDGF, and that development of massive extracellular matrix accumulation in glomeruli was induced by up-regulated expression of TGF-beta with inappropriate regulation of protein turnover-related enzyme production.

Age Factors↗
PubMed1999

Direct inhibitory effects of simvastatin on matrix accumulation in cultured murine mesangial cells.

BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been demonstrated to suppress glomerular injuries in various renal diseases. These agents inhibit in vitro proliferation of several cell types, including mesangial cells. This effect indicates the ability to ameliorate mesangioproliferative lesions, independent of the improvement of hypercholesterolemia. On the other hand, it is not clear whether HMG-CoA reductase inhibitors directly regulate extracellular matrix (ECM) accumulation from mesangial cells. METHODS: In this study, to examine the in vitro effects of simvastatin, an HMG-CoA reductase inhibitor, on mRNA expressions of matrix proteins, growth factors, and matrix turnover proteins, we incubated cultured murine mesangial cells stimulated by fetal calf serum (FCS) with or without simvastatin for 24 hours, and Northern analysis was performed. RESULTS: Simvastatin showed a slightly suppressive effect on mRNA expression of type IV collagen and fibronectin and a slightly up-regulative effect on that of type I collagen, whereas mRNA expression of type III collagen was markedly up-regulated. mRNA expression of platelet-derived growth factor (PDGF)-B chain and PDGF receptor beta-subunit was suppressed, whereas that of transforming growth factor-beta (TGF-beta) was not affected by simvastatin. Concerning matrix turnover proteins, simvastatin markedly reduced mRNA expression of plsminogen activator inhibitor-1 (PAI-1) without affecting the expression of tissue-type plasminogen activator (tPA). CONCLUSION: These results suggest type-specific modulation of matrix protein production independent of TGF-beta and the suppressive effects of autocrine PDGF by administration of HMG-CoA reductase inhibitors in mesangial cells. Moreover, the beneficial effects of these agents on matrix protein accumulation may be through promoting ECM degradation derived from PAI-1 suppression.

Animals↗
PubMed1999

Human interleukin-1 receptor antagonist: large-scale expression in Bacillus brevis 47-5Q.

Interleukin-1 receptor antagonist (IL-1RA) has been used as a tool to study the biologic activity of IL-1 and as a possible therapeutic substance for inflammatory disease. To perform in vivo study, however, large quantities of IL-1RA are required. Bacillus brevis strains secrete large amounts of protein but little protease into the medium. Using B. brevis 47-5Q, we developed a large-scale expression system of human IL-1RA (HuIL-1RA). The bacteria secreted HuIL-1RA into the culture medium at very high levels, approximately 200 mg/L. The protein was isolated in one-step purification with monoclonal antibody (mAb) against HuIL-1RA. The IL-1RA molecule was determined to be functionally active by the inhibiting assay of HuIL-1-induced cell proliferation in a mouse T cell line, D10N4M.

Animals↗
PubMed1999

Does circulating erythropoietin reflect progression of IgA nephropathy? Comparison with urinary N-acetyl-beta-D-glucosaminidase.

BACKGROUND: Recent reports describe that erythropoietin (Epo) is produced by peritubular interstitial fibroblast-like cells in response to a hypoxic stimulus. We studied serum Epo levels as a possible marker of tubulointerstitial damage in the progression of IgA nephropathy (IgAN), in comparison with urinary (u-) levels of N-acetyl-beta-D-glucosaminidase (NAG), which is mainly derived from proximal tubular cells and is used as a marker of tubular damage. METHODS: Thirty-eight patients with IgA nephropathy (IgAN) with relatively preserved renal function (serum creatinine: sCr, 0.5-2.2 mg/dl) were examined. The severity of glomerulosclerosis and interstitial fibrosis of the renal biopsy tissue was expressed by semiquantitative grading scores. Clinical parameters including serum creatinine (sCr), blood pressures, and 24-h proteinuria levels were obtained at the renal biopsy. Epo was measured by a radioimmunoassay (RIA) of sera obtained in the morning and u-NAG was measured by colorimetric method of 24-h urine samples. RESULTS: The mean Epo level of the patients (17.7+/-6.3 mU/ml) was not different from the control level (19.3+/-3.7 mU/ml). There were no significant correlations between Epo levels and red blood cell (RBC) counts, haematocrit (Hct), or haemoglobin (Hb) levels. The mean u-NAG level of the patients (6.7+/-6.2 U/gCr) was significantly higher than the control level (1.9+/-0.5 U/gCr). There was an inverse quantitative correlation between Epo and u-NAG levels in the patients (P<0.02). The u-NAG levels showed quantitative positive correlations with sCr (P<0.001), u-proteins (P<0.001), systolic (SBP) (P<0.001), and diastolic blood pressures (DBP) (P<0.05). Conversely, Epo levels were inversely correlated with sCr, SBP and DBP (each P<0.05). The patients with higher u-proteins (>2.0 g/day) showed significantly decreased Epo levels (P<0.05) than those with lower u-proteins (<2.0 g/day). The both scores of glomerulosclerosis and interstitial fibrosis were positively correlated with the u-NAG levels (each P<0.001), but were not correlated with the Epo levels. CONCLUSIONS: The significant correlation between u-NAG and serum Epo levels suggests that tubular damage and interstitial cell dysfunction are associated each other in the progression of IgAN. Serum Epo levels bearing inverse correlations with sCr, blood pressure levels and heavy proteinuria seem to reflect clinical severity of IgAN, whereas u-NAG can be more useful progression marker of IgAN bearing correlations with both clinical and histological findings.

Acetylglucosaminidase↗
PubMed1999

Characterization of a novel missense mutation in the pore of HERG in a patient with long QT syndrome.

INTRODUCTION: A new strategy to elucidate the molecular mechanisms underlying the long QT syndrome (LQTS) is now available with genetic mutational analyses and characterization of ion channel mutations. METHODS AND RESULTS: In a 26-year-old woman with LQTS, we identified a novel missense mutation in the pore of HERG by using polymerase chain reaction/single-strand conformation polymorphism (PCR/SSCP) and sequencing of her genomic DNA. The mutation resulted in an amino acid substitution of a positively charged lysine for a highly conserved uncharged asparagine at codon 629 (N629K). Whole cell, patch clamp studies were conducted in COS7 cells by transfecting with wild-type (WT) and/or the mutant N629K HERG. The WT HERG produced an I(Kr)-like, E-4031-sensitive conductance with an inward rectification. In contrast, the cells transfected with the N629K HERG did not display any time-dependent current. Cotransfection of WT and N629K HERG (at a ratio of 1:1) produced a significantly smaller conductance when compared with WT HERG (WT 59.9 +/- 7.3 pA/pF [n = 22] vs WT+N629K 5.5 +/- 2.3 pA/pF [n = 11]; P < 0.01), but did not alter K+ ion selectivity and tail current-voltage dependence. Because aprindine hydrochloride was effective in preventing ventricular tachycardias, we also tested the effect of the drug on WT HERG (I(Kr)) and KvLQT1/KCNE1 (I(Ks)) currents expressed in COS7. CONCLUSION: Functional analyses of a novel missense mutation in the pore of HERG suggest that the mutation causes marked reduction of I(Kr) via a dominant negative effect.

Adult↗