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Biomedical subjects

R Nagai

Publications and source records attributed to R Nagai.

At least 199 records · Page 11Linked to original sources
PubMed2000

Overdrive suppression of antegrade conduction over the accessory pathway.

In a patient with Wolff-Parkinson-White syndrome whose accessory pathway was primarily capable of bidirectional conduction, antegrade conduction over the accessory pathway was transiently inhibited after rapid atrial or ventricular pacing or after spontaneous termination of atrioventricular reentrant tachycardia. Pacing rate and duration of tachycardia were related to the duration of the suppression of preexcitation, while the coupling interval of the first sinus beat to the last driven or tachycardia beat was irrelevant to the phenomenon. Thus, overdrive suppression of conduction may be the most likely mechanism of this phenomenon.

Adult↗
PubMed2000

Therapy with the nonpeptide endothelin receptor antagonist 97-139 in a murine model of congestive heart failure: reduction of cardiac mass and myofiber hypertrophy.

Endothelin-1 (ET-1) is a potent vasoconstrictor. This peptide exerts numerous effects on the heart, including regulation of cardiomyocyte growth during hypertrophy. The effects of the structurally novel, nonpeptide, ET-1-selective, competitive antagonist (ETA) 97-139 were investigated in mice with congestive heart failure (CHF) and myocardial hypertrophy. Morphological and microscopical analyses were conducted on day 56 after viral inoculation following 28 day treatment with 99-139. Eight week-old DBA2 mice were intraperitoneally inoculated with encephalomyocarditis virus at a dose of 500 pfu/mouse. The 30 mice were divided into two groups--an ETA treated group and an untreated group. Heart weight (HW) in the infected group was significantly (p < 0.05) increased compared to that in the uninfected group. HW and the HW/body weight (BW) ratio were significantly (p < 0.05) reduced in the ETA treated group compared with the untreated group (HW; 127.7 +/- 6.2 mg vs 144.3 +/- 4.2 mg, HW/BW; 4.9 +/- 0.9 x 10(-3) vs 5.4 +/- 0.5 x 10(-3)). Myofiber diameter in the ETA treated group was significantly reduced compared with the untreated group (12.1 +/- 1.5 microm vs 14.3 +/- 1.9 microm). These results suggest the ET-1 receptor antagonist 97-139 has an effect on the reduction of cardiac mass and myofiber hypertrophy, and that 97-139 may be a useful agent for CHF due to viral myocarditis.

Animals↗
PubMed2000

Nuclear hypersegmentation precedes the increase in blood eosinophils in acute eosinophilic pneumonia.

In this case of acute eosinophilic pneumonia (AEP), eosinophils with hypersegmented nuclei emerged in the blood before the increase of eosinophil count. An 18-year-old woman complaining of fever, cough and dyspnea was admitted because of diffuse ground-glass opacities in her chest roentgenogram. On admission, her blood cell count revealed a marked increase of neutrophils. Although the number of eosinophils was normal, some of them contained three- or four-lobed nuclei. She was diagnosed to have AEP through bronchoalveolar lavage and transbronchial lung biopsy. The combination with acute clinical course, pulmonary infiltration and the presence of hypersegmented eosinophils in blood may imply the diagnosis of AEP.

Acute Disease↗
PubMed2000

Insulin effect during embryogenesis determines fetal growth: a possible molecular link between birth weight and susceptibility to type 2 diabetes.

Low birth weight has been reported to be associated with impaired insulin secretion and insulin resistance. It has been proposed that this association results from fetal programming in response to the intrauterine environment (the thrifty phenotype hypothesis). To elucidate the relationship between birth weight and genetically determined defects in insulin secretion, we measured the birth weights of neonates derived from crosses of male pancreatic beta-cell type glucokinase knockout (Gck+/-) mice and female wild-type (WT) or Gck+/- mice. In 135 offspring, birth weights were lower in the presence of a fetal heterozygous mutation and higher in the presence of a maternal heterozygous mutation. Moreover, Gck-/- neonates had significantly smaller birth weights than WT or Gck+/- neonates (means +/- SE 1.49+/-0.03 [n = 30] vs. 1.63+/-0.03 [n = 30] or 1.63+/-0.02 [n = 50] g, respectively; P<0.01). Thus, Gck mutations in beta-cells may impair insulin response to glucose and alter intrauterine growth as well as glucose metabolism after birth. This study has confirmed the results of a previous report that human subjects carrying mutations in Gck had reduced birth weights and has provided direct evidence for a link between insulin and fetal growth. Moreover, birth weights were reduced in insulin receptor substrate-1 knockout mice despite normal insulin levels. Taken together, these results suggest that a genetically programmed insulin effect during embryogenesis determines fetal growth and provides a possible molecular link between birth weight and susceptibility to type 2 diabetes.

Animals↗
PubMed2000

Glycolaldehyde, a reactive intermediate for advanced glycation end products, plays an important role in the generation of an active ligand for the macrophage scavenger receptor.

Long-term incubation of proteins with glucose leads to the formation of advanced glycation end products (AGEs) that are recognized by AGE receptors. Glyoxal, glycolaldehyde (GA), and methylglyoxal are potential intermediates for the formation of AGE structures such as Nomega-(carboxymethyl)lysine (CML). We evaluated the contribution of these aldehydes to the formation of AGE structure(s), particularly the structure important for the receptor-mediated endocytic uptake of AGE proteins by macrophages. GA-modified bovine serum albumin (BSA), methylglyoxal-modified BSA (MG-BSA), and glyoxal-modified BSA (GO-BSA) were prepared, and their physicochemical, immunological, and biologic properties were compared with those of glucose-derived AGE-BSA. CML contents were high in GO-BSA and low in GA-modified BSA (GA-BSA) but did not exist in MG-BSA. The fluorescence patterns of GA-BSA and MG-BSA were similar to those of glucose-derived AGE-BSA but were weak in GO-BSA. Immunochemically, the antibody against non-CML structures of glucose-derived AGE-BSA reacted strongly with GA-BSA and weakly with GO-BSA but did not react with MG-BSA. The negative charge of these ligands increased to a similar extent. However, GA-BSA, but not MG-BSA or GO-BSA, underwent receptor-mediated endocytosis by the macrophage-derived cell line RAW 264.7, which was effectively inhibited by glucose-derived AGE-BSA, acetylated LDL, and oxidized LDL, which are well-known ligands for the macrophage type I and type II class A scavenger receptors (MSR-A). The endocytic uptake of GA-BSA by mouse peritoneal macrophages was also significant, but that by peritoneal macrophages from MSR-A-deficient mice was markedly reduced. Our results suggest that GA serves as an important intermediate for the generation of AGE structure(s) responsible for recognition by MSR-A.

Animals↗
PubMed2000

Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia.

To investigate the role of insulin receptor substrate (IRS)-2 in vivo, we generated IRS-2-deficient mice by gene targeting. Although homozygous IRS-2-deficient mice (IRS-2-/- mice) had a body weight similar to wild-type mice, they progressively developed type 2 diabetes at 10 weeks. IRS-2-/- mice showed insulin resistance and a defect in the insulin-stimulated signaling pathway in liver but not in skeletal muscle. Despite insulin resistance, the amount of beta-cells was reduced to 83% of that in wild-type mice, which was in marked contrast to the 85% increase in the amount of beta-cells in IRS-1-deficient mice (IRS-1-/- mice) to compensate for insulin resistance. Thus, IRS-2 plays a crucial role in the regulation of beta-cell mass. On the other hand, insulin secretion by the same number of cells in response to glucose measured ex vivo was significantly increased in IRS-2-/- mice compared with wild-type mice but was decreased in IRS-1-/- mice. These results suggest that IRS-1 and IRS-2 may play different roles in the regulation of beta-cell mass and the function of individual beta-cells.

Animals↗
PubMed2000

Epalrestat, an aldose reductase ihibitor, reduces the levels of Nepsilon-(carboxymethyl)lysine protein adducts and their precursors in erythrocytes from diabetic patients.

OBJECTIVE: To clarify the role of the polyol pathway in the intracellular formation of advanced glycation end products in human tissues, we examined the effects of epalrestat, an aldose reductase inhibitor, on the level of Nepsilon-(carboxymethyl)lysine (CML) along with 3-deoxyglucosone (3-DG) and triosephosphates in erythrocytes from diabetic patients. Plasma thiobarbituric acid-reactive substances (TBARS) were also determined as indicators of oxidative stress. RESEARCH DESIGN AND METHODS: Blood samples were collected from 12 nondiabetic volunteers, 38 untreated type 2 diabetic patients, and 16 type 2 diabetic patients who had been treated with 150 mg epalrestat/day. Blood samples were also collected from 14 of the untreated type 2 diabetic patients before and after the administration of epalrestat for 2 months. The amount of erythrocyte CML was determined by a competitive enzyme-linked immunosorbent assay, and 3-DG was measured by high-performance liquid chromatography RESULTS: In diabetic patients not treated with epalrestat, the erythrocyte CML level was significantly elevated above levels seen in nondiabetic individuals (49.9 +/- 5.0 vs. 31.0 +/- 5.2 U/g protein, P < 0.05) and was significantly lower in patients receiving epalrestat (33.1 +/- 3.8 U/g protein, P < 0.05). Similar results were observed with 3-DG. The treatment of patients with epalrestat for 2 months significantly lowered the level of erythrocyte CML (46.2 +/- 5.6 at baseline vs. 34.4 +/- 5.0 U/g protein, P < 0.01) along with erythrocyte 3-DG (P < 0.05), triosephosphates (P < 0.05), fructose (P < 0.05), sorbitol (P < 0.05), and plasma TBARS (P < 0.05) without changes in plasma glucose and HbA(1c) levels. A positive correlation was evident between the erythrocyte CML and sorbitol (r = 0.49, P < 0.01) or fructose (r = 0.40, P < 0.05) levels in diabetic patients. CONCLUSIONS: The results indicate that epalrestat administration lowers CML and associated variables and that polyol metabolites are correlated with CML in the erythrocytes of diabetic patients. The observed results suggest that aldose reductase activity may play a substantial role in the intracellular formation of CML in the mediation of reactive intermediate metabolites and oxidative stress.

Aldehyde Reductase↗
PubMed2000

Possible involvement of altered RGD sequence in reduced adhesive and spreading activities of advanced glycation end product-modified fibronectin to vascular smooth muscle cells.

Although fibronectin (FN) modified by advanced glycation end products (AGEs) has been shown to contribute to the development of diabetic vascular complications through its reduced adhesive activity to vascular cells, little is known about changes in the cell binding domain of AGE-modified FN. Here we examined the mechanism of reduced adhesive and spreading activities of AGE-modified FN to vascular smooth muscle cells (SMCs), particularly the contribution of modification of Arg-Gly-Asp (RGD) sequence. Incubation with glucose caused not only the formation of N(epsilon) -carboxymethyllysine and pentosidine, but also polymerization of FN in a dose- and time-dependent manner. AGE-modified FN had significantly low adhesive and spreading activities to cultured SMCs. On the other hand, multimeric FN formed by disulfide bonds did not show any effect on either cell adhesion or spreading. The adhesive activity of type I collagen, one of the RGD sequence-containing proteins, to SMCs also decreased by AGE-modification. The inhibitory effect of AGE-modification on cell adhesion was significantly greater in type I collagen than in FN. Although the extent of AGE-modification of type I collagen was indistinguishable from that of FN, AGE-modification decreased the arginine content of type I collagen by 69.5% and of FN by 30.6%, compared with their non-glycated forms. The addition of RGD peptides caused a decrease in adhesion of SMCs to non-glycated FN, but not to AGE-modified FN. Modification of RGD sequence with glyoxal eliminated its inhibitory effect on cell adhesion. Our results suggest that a marked decrease in adhesive and spreading activities of AGE-modified FN to SMCs might largely be due to a modification of its RGD sequence by AGE, thus suggesting a potential link between AGE modification of FN and the pathogenesis of diabetic angiopathy.

Amino Acids↗
PubMed2000

Troglitazone, a PPARgamma ligand, inhibits osteopontin gene expression in human monocytes/macrophage THP-1 cells.

Peroxizome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear receptor family of transcription factors that regulate adipocyte differentiation. Recent studies indicate that liganded PPARgamma not only promotes differentiation but also inhibits the activation of macrophages. Osteopontin, a component of extracellular matrix, is synthesized by macrophages in atherosclerotic plaques. In this study, we examined whether PPARgamma ligand regulates osteopontin gene expression in THP-1 cells, a cell line derived from human monocytic leukemia cells which can differentiate to macrophage upon stimulation with phorbol ester PMA. Northern blot analysis showed that osteopontin expression is markedly induced in response to PMA. Troglitazone, a PPARgamma ligand, dramatically attenuated the PMA-induced osteopontin expression. Transient transfection assays of the human osteopontin promoter/luciferase construct which contains a 5'-flanking region between -1500 and +87 relative to the transcription start site demonstrate that either treatment with troglitazone or cotransfection of PPARgamma expression vector inhibits osteopontin promoter activity. These data indicate that troglitazone reduces osteopontin gene expression at transcriptional level through PPARgamma activation, and suggest the role of troglitazone in inhibiting the ability of macrophages to produce extracellular matrix, which is particularly relevant to atherosclerotic plaque formation.

Base Sequence↗
PubMed2000

Advanced glycation end products in diabetic corneas.

PURPOSE: Corneal complications are often associated with diabetes mellitus and can be vision threatening. Corneas in diabetic patients are exposed to increased glucose concentration despite cornea's avascular property, and this condition may contribute to the accumulation of advanced glycation end products (AGEs). The focus of this study was to examine the role of AGEs in the pathogenesis of diabetic keratopathy. METHODS: An anti-AGE monoclonal antibody (6D12), which recognizes a N(epsilon)-carboxymethyl lysine (CML)-protein adduct as an epitope, was prepared. Immunohistochemical localization of CML was examined in human age-matched diabetic and nondiabetic corneas (8 of each). In vitro, type I collagen-, type IV collagen-, or laminin-coated 96-well plates were glycated by glucose-phosphate. In some experiments, aminoguanidine was present in the incubation mixture. The amounts of CML-protein adducts in the extracellular matrix (ECM) were determined by enzyme-linked immunosorbent assay using 6D12. SV40-immortalized human corneal epithelial cells were seeded onto modified or unmodified ECM in 96-well plates and allowed to attach for 3 hours. Attached cells were fixed, and the areas of attached cells in each condition were measured. Attached cells without fixation were removed, and cell number was counted. RESULTS: In all of the 8 diabetic corneas, CML immunoreactivity was observed in the epithelial basement membrane, whereas CML immunoreactivity was not found in the corresponding area in 7 of 8 nondiabetic corneas. In vitro, nonenzymatic glycation of laminin on the culture dish attenuated adhesion and spreading of corneal epithelial cells. The presence of amninoguanidine in the incubation mixture during glycation inhibited CML formation and promoted the adhesion and spreading of corneal epithelial cells in a dose-dependent manner. CONCLUSIONS: The accumulation of AGEs on the basement membrane, particularly on laminin, may play a causative role in the corneal epithelial disorders of diabetic patients.

Aged↗
PubMed2000

[Genetic diagnosis and cardiovascular diseases].

Many of cardiovascular diseases are multifactorial and both environmental and genetic factors are associated with their onset and/or progression. Recently, the development of genetic analysis has enabled us to understand genetic backgrounds regulating the susceptibility to the specific environmental factors. These progress may bring us new strategies for diagnosis and/or prevention of diseases. In this review, we mainly discuss the current knowledge of these genetic analysis and perspectives in cardiovascular diseases. We also present briefly genetic mutations in cardiomyopathy, long QT syndrome, congenital cardiovascular diseases and so on. Additionally, we describe considerable problems about the interpretation and notification of the results of genetic diagnosis.

Blood Coagulation Factors↗
PubMed2000

Coronary microangiopathy in type 2 diabetic patients: relation to glycemic control, sex, and microvascular angina rather than to coronary artery disease.

UNLABELLED: Coronary microangiopathy is a major complication in diabetics. However, the presence of independent factors in association with coronary microangiopathy in patients with non-insulin-dependent diabetes mellitus (NIDDM) or the difference in coronary microangiopathy between diabetics with coronary artery disease (CAD) and those with microvascular angina is unclear. METHODS: Nineteen patients with NIDDM and microvascular angina, 18 patients with NIDDM and CAD, and 17 age-matched control subjects were studied. Myocardial segments that were perfused by angiographically normal coronary arteries were studied. The baseline myocardial blood flow (MBF) and the MBF during dipyridamole administration were measured using PET and 13N-ammonia, after which the myocardial flow reserve (MFR) was calculated to assess coronary microangiopathy. RESULTS: The baseline MBF was comparable among NIDDM patients with microvascular angina, NIDDM patients with CAD, and control subjects. However, the MBF during dipyridamole administration was significantly lower in NIDDM patients with microvascular angina (126 +/- 42.7 mL/min/100 g) than that in either NIDDM patients with CAD (210 +/- 70.1 mL/min/100 g; P < 0.01) or control subjects (293 +/- 159 mL/min/100 g; P < 0.01), as was the MFR (NIDDM with microvascular angina, 1.90 +/- 0.73; NIDDM with CAD, 2.59 +/- 0.81 [P < 0.01]; control subjects, 3.69 +/- 1.09 [P < 0.01]). Multivariate stepwise regression analysis showed that, among the factors considered, glycemic control was independently related to the MFR (r = 0.838; P < 0.05). CONCLUSION: Glycemic control appears to be essential for coronary microangiopathy in NIDDM.

Adult↗
PubMed2000

Homocysteine as a risk factor for restenosis after coronary angioplasty.

We examined the relationship between plasma homocysteine levels and restenosis after PTCA (Percutaneous transluminal coronary angioplasty) to investigate whether plasma homocysteine levels can be a predictor of restenosis after PTCA. One hundred and twelve male patients who have undergone a successful elective PTCA were consecutively enrolled and plasma homocysteine levels were measured at the time of follow-up angiography. Plasma homocysteine levels in patients with restenosis were significantly higher than those in patients without restenosis (15.0 +/- 3.9 vs. 13 +/- 2.9 micromol/L; P = 0.011). The difference was augmented when diabetic patients were selectively studied. The comparison between restenosis group and non-restenosis group indicated the threshold effect of hyperhomocysteinemia. These results suggest that plasma homocysteine is a potential risk factor of restenosis after PTCA, and therapeutic strategy targeted against hyperhomocysteinemia may be beneficial for preventing restenosis.

Aged↗
PubMed2000

[Prediction of cardiac sympathetic nerve activity and cardiac functional outcome after treatment in patients with dilated cardiomyopathy: examination using dobutamine gated blood pool scintigraphy].

OBJECTIVES: This study evaluated whether dobutamine gated blood pool scintigraphy can predict improvement of cardiac sympathetic nerve activity and cardiac function. METHODS: Sixteen patients(10 men and 6 women, mean age 59 +/- 13 years) with dilated cardiomyopathy underwent dobutamine gated blood pool scintigraphy to measure left ventricular ejection fraction (LVEF) using tracer at 0, 5, 10 and 15 micrograms/kg/min before treatment. Patients were divided into good responders (LVEF increase > or = 15%) 8 patients(GR Group) and poor responders(LVEF increase < 15%) 8 patients (PR Group) after treatment with beta-blocker or amiodarone with a background treatment of digitalis, diuretics and angiotensin converting enzyme inhibitor. I-123 metaiodobenzylguanidine(MIBG) imaging to evaluate cardiac sympathetic nerve activity and echocardiography were performed before and at one year after treatment. MIBG imaging was obtained 4 hours after tracer injection, and the heart/mediastinum count ratio(H/M ratio) calculated from the anterior planar image and the total defect score(TDS) from the single photon emission computed tomography image. LVEF and left ventricular endo-diastolic dimension (LVDd) were measured by echocardiography and New York Heart Association(NYHA) functional class was evaluated. RESULTS: The GR Group showed TDS decreased from 28 +/- 6 to 17 +/- 12(p < 0.05), H/M ratio increased from 1.79 +/- 0.26 to 2.07 +/- 0.32(p < 0.05), LVEF increased from 29 +/- 8% to 48 +/- 10%(p < 0.01), and LVDd decreased from 65 +/- 4 mm to 58 +/- 5 mm(p < 0.05). In contrast, the PR Group showed no significant changes in TDS, H/M ratio, LVEF and LVDd. NYHA functional class improved in both groups. The improvement was better in the GR Group than in the PR Group. CONCLUSIONS: Dobutamine gated blood pool scintigraphy is useful to predict the improvement of the cardiac sympathetic nerve activity and cardiac function, and symptoms after treatment in patients with dilated cardiomyopathy.

3-Iodobenzylguanidine↗
PubMed2000

Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia.

Abetalipoproteinemia (ABL) is an inherited disease characterized by the virtual absence of apolipoprotein B (apoB)-containing lipoproteins from plasma. Only limited numbers of families have been screened for mutations in the microsomal triglyceride transfer protein (MTP) gene. To clarify the genetic basis of clinical diversity of ABL, mutations of the MTP gene have been screened in 4 unrelated patients with ABL. Three novel mutations have been identified: a frameshift mutation caused by a single adenine deletion at position 1389 of the cDNA, and a missense mutation, Asn780Tyr, each in homozygous forms; and a splice site mutation, 2218-2A-->G, in a compound heterozygous form. The frameshift and splice site mutations are predicted to encode truncated forms of MTP. When transiently expressed in Cos-1 cells, the Asn780Tyr mutant MTP bound protein disulfide isomerase (PDI) but displayed negligible MTP activity. It is of interest that the patient having the Asn780Tyr mutation, a 27-year-old male, has none of the manifestations characteristic of classic ABL even though his plasma apoB and vitamin E were virtually undetectable. These results indicated that defects of the MTP gene are the proximal cause of ABL.

Abetalipoproteinemia↗