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Biomedical subjects

R Nagai

Publications and source records attributed to R Nagai.

At least 325 records · Page 18Linked to original sources
PubMed1998

Spatio-temporal changes of prolyl 4-hydroxylase in granulosa cells during ovulation in eCG-hCG-treated immature rat ovaries.

The immunolocalization of prolyl 4-hydroxylase (PHase), a key enzyme of collagen synthesis, and the effects of anti-progesterone RU486 on PHase during the ovulatory process in eCG-hCG-treated immature rat ovaries were studied to investigate the mechanisms of tissue repair in follicle walls after follicular rupture. Immunolocalization of PHase was studied using an anti-rat PHase subunit monoclonal antibody, and the amount of immunoreactive PHase was measured by enzymeimmunoassay. No obvious immunolocalization of PHase was observed in theca cells throughout the ovulatory process except just after follicular rupture. In contrast, in granulosa cells, PHase was first observed at 9 h after the hCG injection, and the staining intensity apparently increased from 9 to 15 h, especially around the apex of preovulatory follicles and the orifice of ruptured follicles. Consistent with these observations, PHase concentration in granulosa cells isolated from the ovaries significantly increased by 9 h (0.45 +/- 0.03 pg per cell), and reached a peak at 15 h (0.66 +/- 0.06 pg per cell) after the hCG injection. This peak was inhibited when 20 mg RU486 kg-1 was administered at 8 h (0.46 +/- 0.05 pg per cell), and the RU486-inhibited PHase concentration was recovered by the concomitant administration of 10 mg progesterone kg-1 (0.65 +/- 0.02 pg per cell). The results suggest that PHase expressed in granulosa cells may play an important role in the repair of ruptured follicle walls, via progesterone-dependent PHase production.

Analysis of Variance↗
PubMed1998

Pre-clinical Cushing's syndrome with body weight loss and normal circadian rhythm of blood pressure.

A 68-year-old woman was referred for evaluation of an incidentally discovered left adrenal mass. Her chief complaint was body weight loss. She showed no symptoms or signs suggestive of Cushing's syndrome. The circadian rhythm of blood pressure was also normal. Hormonal assessment revealed an abnormal diurnal variation in serum cortisol levels, suppressed baseline plasma adrenocorticotrophic hormone, and nonsuppression of serum and urinary cortisol with the dexamethasone suppression test. Adrenal scintigraphy with (131)I-6-beta-iodomethyl-norcholesterol showed uptake on the left adrenal and inhibition of the contralateral adrenal gland. She was diagnosed as pre-clinical Cushing's syndrome. Due to the lack of clinical symptoms and the risks of surgery, we emphasize the importance of careful assessment of the cortisol metabolism and scintigraphic scanning under dexamethasone suppression to avoid post-surgical Addisonian crisis.

Adrenal Gland Neoplasms↗
PubMed1998

Bilateral coronary ostial stenosis and aortic regurgitation due to syphilitic aortitis.

Coronary ostial stenosis in otherwise normal coronary vessels, is a rare complication of syphilitic aortitis, and most of the cases are found at autopsy. We report here a case in which bilateral coronary ostial stenosis and aortic regurgitation due to syphilitic aortitis was diagnosed; coronary artery bypass graft and aortic valve replacement were then performed. The macroscopic finding and the histopathological examination of the ascending aorta revealed the presence of syphilitic aortitis. It is important to note that syphilis is one of the causes of coronary ostial stenosis in young adults associated with aortic regurgitation.

Adult↗
PubMed1998

[Molecular genetics of cardiovascular diseases].

This review introduces recent progress in molecular genetics of cardiovascular diseases. Many genes and their mutations causing familial cardiovascular diseases have been discovered, including familial hypertrophic cardiomyopathy which is caused by mutated cardiac beta myosin heavy chain, light chains, troponin T, troponin I, or alpha-tropomyosin, and long QT syndrome by KvLQT1, HERG, minK or cardiac voltage-dependent Na channel mutation. The mutations in causative genes can affect clinical courses of diseases; amino acid substitutions of cardiac beta myosin heavy chain with charge changes seem to cause poorer prognosis of hypertrophic cardiomyopathy. Besides monogenic diseases, there are many cardiovascular diseases affected with genetic polymorphisms, such as hypertension, ischemic heart disease and atherosclerosis. Specific amino acid mutations or polymorphisms in the promoter region of the genes are known to become a risk factor of these diseases. Polymorphisms of genes encoding apolipoprotein E, angiotensin converting enzyme, angiotensinogen and endothelial NO synthase (ecNOS) have been well characterized as an important risk factor of cardiovascular diseases. We recently found a novel gene which seems to affect human aging phenotype and vascular endothelial function. It is important as a future study to clarify the regulatory mechanisms of the klotho gene in the cardiovascular system and the clinical significance of klotho gene polymorphisms.

Amino Acids↗
PubMed1998

[Three patients with insulin-treated diabetes and senile dementia of Alzheimer's type].

Senile dementia of Alzheimer's type (SDAT) is reported to be less frequent in patients with Diabetes Mellitus. However the, the number of elderly people in still increasing in Japan, an is the incidence of diabetes mellitus, especially in middle-aged and elderly people. Thus, we can expect to encounter more elderly people with diabetes and SDAT. We encountered three patients with diabetes who were treated with insulin and in whom SDAT developed. In all three, control of blood glucose levels gradually worsened, despite increases in the dose of injected insulin. It was later found that they did not inject insulin properly because of SDAT. They lived alone and their dementia was not diagnosed before their admission to the hospital. In its early phase, SDAT can be difficult to diagnose, especially in patients who live alone. SDAT should be considered when the control of blood glucose levels for no apparent reason in elderly patients with diabetes.

Aged↗
PubMed1998

Impaired expression of atrial natriuretic peptide in diabetic rats with myocardial infarction.

We evaluated the effects of myocardial infarction (MI) on the hemodynamics and the expression of atrial natriuretic peptide (ANP) mRNA in rats with streptozotocin-induced diabetes. Eight weeks after streptozotocin injection, the diabetic rats and age-matched nondiabetic controls underwent coronary artery ligation. One week later, the left ventricular end-diastolic pressure, systolic blood pressure, infarct size, and serum ANP levels did not differ significantly between the diabetic and nondiabetic rats. Compared with control animals without MI, the atrial ANP/beta-actin mRNA ratio in rats with MI was increased to 195% in diabetic animals and 213% in nondiabetic animals. In the left ventricle, however, the ANP/beta-actin mRNA ratio in diabetic animals with MI was increased to only 131% compared with control animals, whereas the corresponding increase in nondiabetic animals was 240% (p<0.05). Thus, the modulation of ANP mRNA expression after MI was impaired in the left ventricle, but not in the atria, of diabetic rats. A reduced myocardial expression of ANP could increase the morbidity and mortality associated with cardiovascular disorders in patients with diabetes.

Animals↗
PubMed1998

The somatostatin analog, octreotide, inhibits in vitro outgrowth of smooth muscle cells from canine coronary and carotid atherosclerotic plaque tissues.

Restenosis is caused by excessive neointima formation resulting from smooth muscle cell (SMC) proliferation and migration from the arterial media into the subendothelial space, stimulated by growth factors. A long-acting somatostatin analog, octreotide, activates protein tyrosine phosphatases and can inhibit the stimulatory effects of growth factors. In this study, we evaluated the effect of octreotide on SMC outgrowth from in vitro explants of both coronary and carotid arterial tissues in a canine endothelium-injury model. After 6 days of culture, SMC grew out of 33.3% and 58.3% of the explants from the injured canine carotid and coronary arterial tissues, respectively. In contrast, SMC outgrowth was not observed from any of the explants from normal canine carotid arterial tissue. Octreotide completely inhibited SMC outgrowth from injured canine carotid arterial tissue at a concentration of 10(-6) M. This agent also inhibited SMC outgrowth from injured canine coronary arterial tissue by 57% and 71% of the control value at concentrations of 10(-8) M and 10(-6) M, respectively. We conclude that our explant cell-culture model may prove to be valuable for assessing the effect of agents designed to reduce intimal proliferation, and that the use of the somatostatin analog octreotide in clinical settings may modify the high incidence of restenosis after coronary interventions by reducing SMC proliferation.

Animals↗
PubMed1998

[Evaluation of epidural blood patch in the treatment of two cases of spontaneous intracranial hypotension].

We evaluated the effect of epidural blood patch (EBP) in the treatment of two cases of spontaneous intracranial hypotension (SIH). Both case 1 (53-year old female) and case 2 (44-year old female) had severe postural headache and showed meningeal thickening by cranial MRI, and were diagnosed as SIH. Case 1: Although her intracranial pressure remained within normal ranges, an extradural leakage was shown in the middle thoracic region on isotope cisternography using indium-111 labeled DTPA. She underwent epidural blood patch with autologous blood at Th 6-7 level twice (10 ml and 15 ml, respectively) but without remarkable pain relief. Case 2: Her intracranial pressure was low (0 mmH2O on supine position), but, isotope cisternography using DTPA showed only the early appearance of isotope in the bladder but failed to disclose the site of the CSF leak. Epidural blood patch with 30 ml of autologous blood was performed at Th 12-L 1 level which only resulted in severe backache without clinical improvement. In conclusion, we could not find the effectiveness of EBP on the two cases of SIH, although there are many reports on its efficacy.

Adult↗
PubMed1998

Detection of left ventricular enlargement by electrocariography.

Cardiomegaly is one of the commonest findings encountered in daily clinical practice, and its differential diagnosis is a common clinical problem. There are many electrocardiological (ECG) criteria known for left ventricular hypertrophy (LVH), but its limitations have also been suggested. We evaluated 102 patients fulfilling the ECG criteria of precordial and limb lead for LVH with echocardiographic findings as a gold standard. Among these 102 patients, the echocardiogram revealed 38 subjects with LVH, 26 subjects with left ventricular dilatation (LVD), 7 subjects with both findings, and 31 subjects with neither findings. Precordial criteria such as SV1+RV5 or RV6 > 30 mm, SV1 or SV2+RV5 > 35 mm, R+S > 40 mm, SV1 or SV2+RV5 or RV6 > 35 mm, SV2+RV4 or RV5 > 35 mm, high in sensitivity and low in specificity for LVD and LVH, are appropriate for screening LVD and LVH. Cornell limb lead criterion, SV3+RaVL > 28 mm (male), SV3+RaVL > 20 mm (female), high in sensitivity and specificity only for LVH, is the best elecrocardiographic criterion to evaluate LVH. Precordial and limb lead criteria such as R> 13 mm, RaVL > 12 mm, RaVF > 20 mm, onset of intrinsicoid deflection in V5 or V6> 0.05 sec, left axis deviation -30 degrees to -90 degrees, low in sensitivity, and high in specificity, are useful to rule out LVH and/or LVD. Our findings suggest LVD and LVH can be evaluated by ECG, but similar sensitivity and specificity for both LVH and LVD makes separation of LVH from LVD unattainable.

Electrocardiography↗
PubMed1998

Immunohistochemical distribution and subcellular localization of three distinct specific molecular structures of advanced glycation end products in human tissues.

Using three mouse anti-human monoclonal antibodies for advanced glycation end products (AGEs), 6D12, 1F6, and 2A2, we examined the immunohistochemical distribution and localization of AGEs in various organs and tissues obtained from nondiabetic autopsy or biopsy cases (men and women, 41 to 86 years of age). 6D12 recognizes Nepsilon-(carboxymethyl)lysine (CML), a nonfluorescent and non-cross-linked AGE structure, and 1F6 recognizes fluorolink, a fluorescent and cross-linked AGE structure. The epitope of 2A2 is unknown but is different from that of CML and fluorolink or other known AGE structures such as pyrraline, pentosidine, and crosslines. Immunohistochemistry with these monoclonal antibodies revealed the intra- and extracellular accumulation of AGEs in these organs and tissues. By double immunohistochemical staining with two of the three monoclonal antibodies in different combinations, positive reaction products for all three monoclonal antibodies were demonstrated in macrophages widely distributed in various organs and tissues; endothelial cells of endocardium, arteries, veins, and blood capillaries; mesenchymal cells; epithelial or parenchymal cells; blood cells; and extracellular matrix. This result indicates that these three different AGE-specific molecules are formed intracellularly and extracellularly. In some cell types, however, one or two of these specific molecules were not always found together, suggesting that the molecular structures of AGEs and their formation are heterogeneous. Immunoelectron microscopy demonstrated the localization of AGE-labeled immunogold particles in the nuclei, nuclear envelope, mitochondria, endoplasmic reticula, Golgi complexes, endocytic vesicles, lysosomal vacuoles or granules, secretory granules, cytosol, and cell membranes, as well as in the extracellular matrix. In addition, the double histochemical staining method for ceroid/lipofuscin and immunohistochemistry for AGEs demonstrated intralysosomal formation and accumulation of AGEs in ceroid/lipofuscin pigments. These results suggest that the extracellularly produced AGEs are taken up by receptors into the cells and accumulate in secondary lysosomes and that AGEs are formed intranuclearly and/or intracellularly, probably via different metabolic pathways.

Adult↗
PubMed1997

Mutation of the mouse klotho gene leads to a syndrome resembling ageing.

A new gene, termed klotho, has been identified that is involved in the suppression of several ageing phenotypes. A defect in klotho gene expression in the mouse results in a syndrome that resembles human ageing, including a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema. The gene encodes a membrane protein that shares sequence similarity with the beta-glucosidase enzymes. The klotho gene product may function as part of a signalling pathway that regulates ageing in vivo and morbidity in age-related diseases.

Aging↗
PubMed1997

Isolation of the embryonic form of smooth muscle myosin heavy chain (SMemb/NMHC-B) gene and characterization of its 5'-flanking region.

To examine the molecular mechanisms that regulate the expression of the SMemb/NMHC-B gene, a nonmuscle myosin heavy chain isoform predominantly expressed in fetal aorta, we have isolated and characterized the 5'-flanking region of the rabbit SMemb/NMHC-B gene. Transient transfection experiments demonstrated that 105 base pairs of 5'-flanking sequence was necessary to direct high level transcription in C2/2 cells, vascular smooth muscle cells derived from rabbit aorta. An essential cis-regulatory element was localized between -100 and -91 base pairs from the transcription start site based on the results that replacement mutagenesis within this region significantly reduced promoter activity. Sequence of this region is completely conserved between mouse and rabbit and fits no known DNA binding consensus. Gel mobility shift assays revealed that a specific DNA-protein complex was formed at this site with nuclear extracts from C2/2 cells, which can be competed by H-2Kb CCAAT box but not by Hsp70 CCAAT box or other CCAAT-containing sequences. We conclude that expression of the SMemb/NMHC-B gene is regulated through an interaction between a sequence element located at -100 and a distinct member of CCAAT-binding proteins.

3T3 Cells↗
PubMed1997

Stretch-induced hypertrophic growth of cardiocytes and processing of brain-type natriuretic peptide are controlled by proprotein-processing endoprotease furin.

When hypertrophic growth is induced in neonatal rat cardiocytes by stretching, the cardiocytes express high levels of brain-type natriuretic peptide (BNP) and the proprotein-processing enzyme furin. A BNP precursor, gammaBNP, possesses a furin-cleavable Arg-X-X-Arg motif, which is cleaved when gammaBNP is processed to form BNP-45. The Arg-X-X-Arg motif is found in many precursors of growth factors and growth-related proteins. To determine if furin converts gammaBNP to BNP-45 as well as other unidentified growth-promoting protein precursors to their active form that may induce hypertrophic growth in cardiocytes, we used two protease inhibitor systems, synthetic peptidyl chloromethyl ketones (CMK) (dec-Arg-Val-Lys-Arg-CMK and dec-Phe-Ala-Lys-Arg-CMK; where dec is decanoyl) and vaccinia vector-integrated native and variant alpha1-antitrypsins. The furin-specific inhibitors, dec-Arg-Val-Lys-Arg-CMK and variant alpha1-antitrypsin with the inhibitory determinant Arg-X-X-Arg, suppressed the stretch-induced hypertrophic growth of cardiocytes as well as the processing of gammaBNP to BNP-45. The other serine protease inhibitors and variant alpha1-antitrypsin against elastase, or thrombin, however, neither suppressed the hypertrophic growth nor prevented the processing of gammaBNP to BNP-45. Thus, we suggest that furin catalyzes the conversion of gammaBNP to BNP-45 as well as growth-promoting proproteins to their active form, which might induce hypertrophic growth in cardiocytes.

Animals↗
PubMed1997

Redifferentiation of smooth muscle cells after coronary angioplasty determined via myosin heavy chain expression.

BACKGROUND: The pathophysiology of phenotypic modulation of smooth muscle cells (SMCs) involved in restenosis after angioplasty is not well understood. Smooth muscle myosin heavy chain (SM MHC) isoforms (SM1 and SM2) are specific markers for SMC differentiation. In particular, SM2 is useful as a marker of mature SMCs. SMemb is a nonmuscle myosin heavy chain (NM MHC) whose expression is upregulated in immature or activated SMC. METHODS AND RESULTS: To determine SMC phenotypes in neointimal tissues after percutaneous transluminal coronary angioplasty (PTCA), we performed immunohistochemistry on human coronary arteries with antibodies against alpha-SM actin, SM1, SM2, and SMemb. Tissues were obtained from six autopsied patients and from atherectomy specimens from 16 patients who had undergone PTCA. Medial SMCs were positive for alpha-actin, SM1, and SM2. Expression of SM1 and SM2 in the neointima varied with the time after intervention, whereas alpha-actin was constitutively expressed in all cases studied. Neointimal cells at 16 and 20 days after PTCA contained alpha-actin but little or no SM1 or SM2, indicating that these cells modulated their phenotype to the immature state. Neointimal SMCs recovered SM MHC expression, first SM1 and then SM2, by 6 months after PTCA. Increased expression of SMemb was found in the neointima but without apparent relationship to the time after PTCA. CONCLUSIONS: Neointimal SMCs show features of an undifferentiated state, indicated by altered expression of SM MHC, and undergo redifferentiation in a time-dependent manner. The expression of SM MHC isoforms provides insight into the biology of healing after angioplasty and furnishes useful tools for the understanding of the roles of differentiation and phenotypic modulation of SMCs in human vascular lesions.

Aged↗