Biomedical subjects

Noboru Machida

Publications and source records attributed to Noboru Machida.

At least 19 recordsLinked to original sources

PubMed2006

Cardiac involvement in Beagle-based canine X-linked muscular dystrophy in Japan (CXMDJ): electrocardiographic, echocardiographic, and morphologic studies.

BACKGROUND: Cardiac mortality in Duchenne muscular dystrophy (DMD) has recently become important, because risk of respiratory failure has been reduced due to widespread use of the respirator. The cardiac involvement is characterized by distinctive electrocardiographic abnormalities or dilated cardiomyopathy, but the pathogenesis has remained obscure. In research on DMD, Golden retriever-based muscular dystrophy (GRMD) has attracted much attention as an animal model because it resembles DMD, but GRMD is very difficult to maintain because of their severe phenotypes. We therefore established a line of dogs with Beagle-based canine X-linked muscular dystrophy in Japan (CXMDJ) and examined the cardiac involvement. METHODS: The cardiac phenotypes of eight CXMDJ and four normal male dogs 2 to 21 months of age were evaluated using electrocardiography, echocardiography, and histopathological examinations. RESULTS: Increases in the heart rate and decreases in PQ interval compared to a normal littermate were detected in two littermate CXMDJ dogs at 15 months of age or older. Distinct deep Q-waves and increase in Q/R ratios in leads II, III, and aVF were detected by 6-7 months of age in all CXMDJ dogs. In the echocardiogram, one of eight of CXMDJ dogs showed a hyperechoic lesion in the left ventricular posterior wall at 5 months of age, but the rest had not by 6-7 months of age. The left ventricular function in the echocardiogram indicated no abnormality in all CXMDJ dogs by 6-7 months of age. Histopathology revealed myocardial fibrosis, especially in the left ventricular posterobasal wall, in three of eight CXMDJ dogs by 21 months of age. CONCLUSION: Cardiac involvement in CXMDJ dogs is milder and has slower progression than that described in GRMD dogs. The distinct deep Q-waves have been ascribed to myocardial fibrosis in the posterobasal region of the left ventricle, but our data showed that they precede the lesion on echocardiogram and histopathology. These findings imply that studies of CXMDJ may reveal not only another causative mechanism of the deep Q-waves but also more information on the pathogenesis in the dystrophin-deficient heart.

Animals↗

PubMed2006

Mild hypertension in young Kurosawa and Kusanagi-hypercholesterolaemic (KHC) rabbits.

The coexistence of hypertension and hypercholesterolaemia from youth may increase the prevalence of and mortality from cardiovascular disease and stroke. We thus investigated haemodynamics of mild hypertension in young Kurosawa and Kusanagi-hypercholesterolaemic (KHC) rabbits aged 10-12 months old, as models of heritable hypercholesterolaemia. Pressure and flow waves were simultaneously recorded at the ascending aorta with a catheter-tip micromanometer and ultrasonic flow meter under pentobarbital anaesthesia, respectively. Systolic (119.3 +/- 6.5 and 138.4 +/- 7.4 mmHg (mean +/- SD) for control and KHC rabbit groups; p < 0.001), diastolic (95.7 +/- 6.1 and 109.8 +/- 5.2; p < 0.001), mean (105.8 +/- 6.5 and 122.5 +/- 4.9; p < 0.001) and pulse (23.7 +/- 2.5 and 28.6 +/- 4.0; p < 0.001) pressures as well as total peripheral vascular resistance (0.32 +/- 0.02 and 0.37 +/- 0.03 mmHg/ml/min; p < 0.001) were significantly greater in the KHC rabbit group than those in the age-matched control rabbit group, respectively, while there were no significant differences in the mean aortic flow, heart rate or stroke volume between the two rabbit groups. Aortic input impedance (p < 0.05) and reflection coefficient (p < 0.05) were significantly greater at lower frequency in the KHC rabbit group than in the control rabbit group, whereas there was no significant difference in the characteristic impedance between the two rabbit groups. Plasma angiotensin I (p < 0.01) and II (p < 0.01) levels and serum angiotensin converting enzyme activity (p < 0.05) were significantly greater in the KHC rabbit group than in the age-matched control rabbit group. Atheromatous plaque was in the early stage and composed mainly of abundant foam cells. Neither sclerotic lesions nor stenosis were observed in main peripheral arteries. The mild hypertension in young KHC rabbits was due partly to the increased activity of the renin-angiotensin system. These findings may be thought provoking in elucidating the mechanism and developing preventive and therapeutic strategies in young patients with coexistent hypertension and hypercholesterolaemia.

Algorithms↗

PubMed2006

Comparison of right atrium incision and right ventricular outflow incision for surgical repair of membranous ventricular septal defect using cardiopulmonary bypass in dogs.

OBJECTIVE: To compare right atrium incision (RAI) and right ventricular outflow incisions (RVI) for surgical repair of membranous ventricular septal defect (VSD) facilitated by cardiopulmonary bypass (CPB). STUDY DESIGN: Retrospective study. ANIMALS: Dogs (n=10) with VSD. METHODS: Medical records of dogs that had VSD repair were reviewed. Membranous VSD without any malformation and abnormality was confirmed on several clinical examinations and by angiocardiography. RAI (5 dogs) and RVI (5 dogs) was used for VSD access and repair facilitated by CPB. Procedure comparison was by surgical duration, postoperative recovery period, and occurrence of postoperative arrhythmia. RESULTS: Duration of surgery was similar for RAI and RVI; however, postoperative recovery time was significantly reduced with RAI. Significant moderate operative damage occurred with right atrium incision. CONCLUSIONS: Right atrium incision was more effective than RVI for repair of membranous VSD using CPB. CLINICAL RELEVANCE: RAI should be considered in preference to RVI for repair of membranous VSD using CPB.

Animals↗

PubMed2005

Molecular pathological analysis on the mechanism of liver carcinogenesis in dicyclanil-treated mice.

To investigate the mechanism of hepatocarcinogenesis due to dicyclanil (DC), an insect growth regulator for sheep, histopathological and molecular biological analyses were performed in the liver of male ICR mice fed on a diet containing 1500 ppm of DC for 2 weeks (Experiment I; Exp. I). In gene expression analyses using a large-scale cDNA microarray and RT-PCR, fluctuations of expressions of metabolism-/oxidation-/reduction-related genes, such as CYP1A, aldehyde dehydrogenase family 1 subfamily A1 (Aldh1a1), and thioredoxin reductase 1 (Txnrd1), were predominantly observed in the liver of the DC-treated group. In Experiment II (Exp. II), small-scale and metabolism/oxidative stress-specific cDNA microarray, real-time RT-PCR, and measurement of NF-kappaB protein were performed in the mice liver using a two-stage hepatocarcinogenesis model, in which the male ICR mice were fed on a diet containing 1500 ppm of DC for 7 weeks after a single injection of dimethylnitrosamine (DMN). These mice were subjected to two-thirds partial hepatectomy (PH) at week 3. During histopathological examinations, a remarkable increase in gamma-glutamyltransferase-positive cells was observed in the DMN+DC+PH group. During the microarray and PCR analyses, the metabolism and oxidative stress-related genes, such as Cyp1a, P450 oxidoreductase (Por), and thioredoxin reductase 1 (Txnrd1); a few DNA damage/repair genes, such as 8-oxoguanine DNA-glycosylase 1 (Ogg1); and growth arrest and DNA-damage-inducible 45 alpha (Gadd45a), were fluctuated in this group, together with a slight increase in the concentration of activated NF-kappaB. These results suggest that DNA damages due to oxidative stress may be involved in the mechanism of DC-induced hepatocarcinogenesis in mice.

Animals↗

PubMed2004

Analysis of gene expression profiles of forestomach tumors in rasH2 mice initiated with N-ethyl-N-nitrosourea.

To clarify the mechanisms underlying enhancement of carcinogenesis in transgenic mice carrying a human prototype c-Ha- ras gene (rasH2 mouse), animals received a single intraperitoneal injection of 120 mg/kg N-ethyl-N-nitrosourea (ENU) and at 20 weeks thereafter expression profiles in three induced forestomach squamous cell carcinomas were assessed using high-density oligonucleotide microarrays. In addition, the reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess mRNA expression of human c-Ha- ras gene and some molecules involved in the Ras-regulated mitogen-activated protein kinase (MAPK) pathway. Compared with normal forestomach tissue from control mice, 416 and 368 genes, respectively, were found to be commonly up- and down-regulated by 2-fold or more in the three tumors. Many genes involved in tumor invasion and metastasis such as transforming growth factor beta1 and matrix metalloproteinases were up-regulated, reflecting tumor progression. RT-PCR analysis confirmed up-regulation of transgene, mouse endogenous Ha- ras, N- ras, raf, Mekk2, c- fos, junB, c- myc and cyclin D1. These results suggest that activation of the Ras-MAPK cascade following up-regulation of both human and mouse endogenous ras genes is involved in the enhanced tumorigenesis of ENU-induced forestomach squamous cell carcinomas in rasH2 mice.

Animals↗

PubMed2004

Inhibitory effects of KAT-681, a liver-selective thyromimetic, on development of hepatocellular proliferative lesions in rats induced by 2-acetylaminofluorene and partial hepatectomy after diethylnitrosamine initiation.

To examine the potential inhibitory effects of a novel liver-selective thyromimetic, KAT-681 (KAT), on the development of hepatocellular proliferative lesions, male F344 rats were given a single intraperitoneal injection of 150 mg/kg diethylnitrosamine (DEN), followed by gavage administration of 7.5 mg/kg per day of 2-acetylaminofluorene (2-AAF) twice daily from weeks 2 to 4 with partial hepatectomy (PH) at week 3. From 5 weeks after the completion of 2-AAF administration, the rats were orally dosed with 0.04, 0.1, or 0.25 mg/kg per day KAT for 3 weeks, and subjected to morphometric analysis of the induced glutathione S-transferase placental form (GST-P)-positive lesions and hepatocellular adenomas (HCAs). Administration of KAT significantly and dose-dependently reduced the total area of GST-P-positive lesions (by 34-48%) and also their numbers (by 20-44%), their mean size not being significantly changed. No effects on the number of HCAs were apparent, although a reduction in their mean size was detected at a dose of 0.25 mg/kg per day KAT (by 34%). On biochemical analysis, serum activity of gamma-glutamyl transpeptidase, an enzyme related to hepatocarcinogenesis, was markedly reduced in rats given 0.25 mg/kg per day KAT (by 64%). The results of the present study thus suggest that KAT inhibits the development of altered hepatocellular foci and might be a promising chemopreventive agent for hepatocarcinogenesis.

2-Acetylaminofluorene↗

PubMed2004

Characteristic change in local pulse wave velocity in different segments of the atherosclerotic aorta in KHC rabbits.

BACKGROUND: Pulse wave velocity, conventionally determined between the carotid and femoral arteries, is a useful measure to estimate stiffness of the aorta. We investigated local pulse wave velocity (LPWV) in different segments in the aorta with relatively early-stage atherosclerosis in relation to the extent and severity of atherosclerotic lesions. METHODS: Pressure waves were recorded in eight aortic positions using two catheters with one or two micromanometers to determine LPWV in the ascending aorta, distal end of the aortic arch, proximal, middle, and distal thoracic aortas, and proximal, middle, and distal abdominal aortas in Kurosawa and Kusanagi-hypercholesterolemic (KHC) and normal rabbits aged 10 to 12 months. RESULTS: The LPWV in the KHC rabbit was greatest in the aortic arch, decreased almost to the normal level in the middle and distal thoracic aorta, increased in the proximal abdominal aorta, and showed almost identical change to that in the normal rabbit in the middle and distal abdominal aortic regions. There was significant difference in LPWV in the aortic arch, proximal thoracic, and proximal abdominal aortas between the two rabbit groups. The sclerotic lesion was prominent in the aortic arch, proximal thoracic aorta, and proximal abdominal aortas. The wall was severely thickened with abundant foam cells. The significant increase in LPWV would be mainly related to the increased wall thickness in these aortic regions. CONCLUSIONS: We can conclude that LPWV reflects well the distribution and severity of atherosclerotic lesion and the increased wall thickness in the local aortic region in which pulse waves were traveled.

Animals↗

PubMed2004

Beta-blocker improves survival, left ventricular function, and myocardial remodeling in hypertensive rats with diastolic heart failure.

BACKGROUND: Chronic beta-blocker therapy improves survival and left ventricular (LV) systolic function in patients with congestive heart failure. However, its efficacy in diastolic heart failure (DHF) with preserved normal LV systolic function remains uncertain. METHODS: Dahl salt-sensitive hypertensive rats fed a high-salt diet from 7 weeks of age were randomized to groups that were either not treated (DHF; n = 20) or treated with metoprolol (MP) from 7 weeks of age (DHF+7wkMP; n = 22) or from 17 weeks of age (DHF+17wkMP; n = 8). Both LV function and remodeling were evaluated by serial echocardiography, followed by hemodynamic and pathologic studies. RESULTS: Hypertension and pressure-overload LV hypertrophy were established by 17 weeks of age in DHF rats. At about 20 weeks of age DHF rats experienced overt heart failure, which was accompanied not by a decrease in LV fractional shortening but by diastolic filling abnormalities. The LV concentric hypertrophy was strikingly attenuated in DHF+7wkMP rats but not in DHF+17wkMP rats. However, LV myocardial fibrosis and the further progression of diastolic dysfunction were prevented in both MP-treated groups. Survival at 21 weeks of age was significantly improved in DHF+7wkMP (86%) and DHF+17wkMP (75%) rats compared with DHF rats (25%). CONCLUSIONS: In this study, MP prevented not only the development of LV hypertrophy but also the progression of diastolic dysfunction, and improved survival in rats with DHF. The preventive effect of MP on myocardial fibrosis is suggested as one of the mechanisms contributing to halt the progression of diastolic dysfunction, a finding that may lead to clinical benefits in regard to DHF caused by hypertension.

Adrenergic beta-Antagonists↗

PubMed2004

Change in the static rheological properties of the aorta in Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits with progress of atherosclerosis.

The rheological properties of the arterial wall have intimate connections with the fine structure of the wall. Alteration in fine structure due to cardiovascular disease, such as atherosclerosis, could affect the rheological characteristics of the wall. The present study was designed to investigate changes in the static rheological properties of the aorta in Kurosawa and Kusanagi-Hypercholesterolemic (KHC) rabbits aged 10-12, 22-24 and 34-36 months in relation to histological alteration of the wall due to progression of atherosclerosis with age. Circumferential wall strips were excised from the ascending, proximal descending thoracic and proximal abdominal aortas and their stress/strain relationship was recorded. Tensile force of the wall showed a slight but insignificant decrease in the KHC rabbit group aged 10-12 months compared to that in the age-matched control group in the proximal thoracic aorta and increased significantly with ageing in the KHC rabbits in these aortic regions mainly at medium and high strain ranges. Wall stress was significantly smaller in the 10-12 months old KHC rabbit group than in the age-matched control group in the proximal thoracic and proximal abdominal aortas and increased significantly with ageing in the KHC rabbit groups chiefly at medium and high strain ranges. Incremental elastic modulus determined at 50% stretching of the initial length of the wall strip was also significantly lower in the KHC rabbit group aged 10-12 months in comparison to that in the age-matched control group and increased significantly with ageing in the KHC rabbit group. The intima thickened severely with abundant foam cells in the KHC rabbits aged 10-12 months. With increasing age, collagen and elastin fibres showed signs of gradual proliferation among the foam cells. The aortic wall in KHC rabbits was viscoelastic in the relatively early stage of atherosclerosis due to abundant foam cells, and thereafter increased in stiffness gradually with fibrous proliferation and calcification. We can conclude that the static rheological properties of the atherosclerotic aortic wall changed in association with alteration in the microstructure of the wall with progression of atherosclerosis.

Animals↗

PubMed2004

Surgical correction of subvalvular aortic stenosis using cardiopulmonary bypass in a dog.

A three-month-old male Golden Retriever had symptoms including exercise intolerance, dyspnea and syncope and was diagnosed with subvalvular aortic stenosis. Cardiac catheterization revealed a left ventricular-aortic systolic pressure gradient of 90 mm Hg. Surgical correction of the condition was achieved using cardiopulmonary bypass. The subvalvular fibrous lesion was resected through an aortotomy. The stenosis was dilated from 8.5 mm to 12.0 mm in diameter. Postoperatively the dog was asymptomatic. Seven months after surgery, the pressure gradient decreased to 44 mm Hg. However, after another three months, the dog died suddenly without any premonitory signs. Postmortem examination revealed that pathologic changes caused by increased left ventricular pressure overload were not severe.

Animals↗

PubMed2003

Acquired mitral stenosis in a cat with hypertrophic cardiomyopathy.

A seven-year-old castrated male domestic shorthair cat was diagnosed with hypertrophic cardiomyopathy (HCM) and suspected mitral stenosis (MS) based on electrocardiography, thoracic radiographs and echocardiographic findings. Post-mortem examination of the heart revealed morphological features consistent with HCM. In addition, there was marked fibrous deposition on the surfaces of the chordae tendineae extending to both mitral valve leaflets, which caused total chordal fusion into pillars of fibrous tissue and fusion of the commissures. The present case indicates that acquired MS can occur in association with HCM in the cat.

Animals↗

PubMed2003

Ebstein's anomaly in a beagle dog.

An intact male beagle dog aged 1 year was referred because of shortness of breath, exercise intolerance and cardiac murmur. Based on the results from electrocardiography, thoracic radiography and echocardiography, the dog was diagnosed as Ebstein's anomaly. Although the orally administered digoxin, vasodilators and diuretics partially improved congestive signs, the dog became to be refractory and died 20 months after the diagnosis. Necropsy confirmed malformation and apical displacement of the basal attachment of tricuspid valve leaflets.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2003

Hypertrophic cardiomyopathy in an aged dog.

A 14-year-old female Yorkshire terrier was presented with the complaint of cardiac murmur and convulsive seizure. Thickened mitral valve, left atrial enlargement, excess motions of the left ventricular (LV) free wall and the ventricular septum, and tricuspid, mitral and aortic valve regurgitations were recognized on echocardiography. Follow-up echocardiography revealed the progression of concentric LV hypertrophy and LV outflow obstruction. Clinical symptoms associated with cardiac failure did not develop during the observation period. The pathological examination of the heart revealed that the dog had the morphological hallmarks of hypertrophic cardiomyopathy: massive ventricular hypertrophy, disorganization of cardiac muscle cells, interstitial myocardial fibrosis, and abnormal intramural coronary arteries.

Aging↗

PubMed2003

Absence of in vivo genotoxicity and liver initiation activity of dicyclanil.

In order to clarify the in vivo genotoxicity of dicyclanil with the potential of hepatocarcinogenicity, the stomach, colon, liver, kidney, urinary bladder, lung, brain and bone marrow of male ddY mice given a single oral administration of 100 and 200 mg/kg body weight of dicyclanil were evaluated in an alkaline single-cell gel electrophoresis (comet) assay. In addition, to investigate its possible initiation activity, partially hepatectomized male F344 rats given a single oral administration of 75 mg/kg body weight of dicyclanil were examined by a short-term liver initiation assay. Three and 24 hr after administration, cell migration, as a marker of DNA damage in comet assay, was not observed in any of the tissues of dicyclanil-treated mice. There were no significant differences in the number and area of glutathione S-transferase placental form (GST-P) positive foci, as a marker of hepatocellular preneoplastic lesions in rats, between treated and control groups. These results indicate that dicyclanil has neither in vivo genotoxicity nor initiation activity, and suggest that the hepatocarcinogenicity in mice induced by dicyclanil is attributable to a non-genotoxic mechanism.

Administration, Oral↗

PubMed2002

Hypertrophic cardiomyopathy in a mixed breed cat family.

A spayed female mixed cat (case 1) and its female offspring, the result of a pairing between case 1 and its male sibling, were diagnosed with hypertrophic cardiomyopathy (HCM). A pedigree survey revealed that the prevalence of HCM was at least 12.5% in the family, which was considered to be significantly higher than that in a hospital-based population (approximately 1.6%). Thus, this finding seems to support the suspected occurrence of familial HCM in this group of related cats.

Animals↗

PubMed2002

Postnatal changes in the rheological properties of the aorta in Sprague-Dawley rats.

Postnatal changes in the rheological properties of the aortic wall were investigated in relation to morphological development of the wall in Sprague-Dawley (SD) rats at 3, 8 and 20 weeks old. The mechanical tensile characteristics of the longitudinal wall strip excised from the proximal thoracic aorta were assessed with stress-strain and stress-relaxation tests. Wall tension in the low and medium strain ranges was significantly lower in 3-week-old rats than in 8-week-old rats and in 8-week-old rats than in 20-week-old rats. Wall stress was significantly lower in 3-week-old rats than in 8- and 20-week-old rats mainly in the medium strain range, but was significantly greater in 3-week-old rats than in 8- and 20-week-old rats in the high strain range. The value of incremental elastic modulus at 3 weeks old was significantly smaller than that at 8 and 20 weeks old at a strain of 0.25 and significantly larger than that at 8 and 20 weeks old at a strain of 0.50. The value of relaxation strength at 5 min after the stretching was significantly greater at 3 weeks old than that at 8 and 20 weeks old. The wall was viscoelastic in the low and medium strain ranges at 3 weeks though large wall stress was generated in the high strain range. Histological investigation revealed that the smooth muscle layer, fine elastin fiber connecting thick elastin fibers and wall thickness were thin at 3 weeks old in comparison with those at 8 and 20 weeks old, though there was no significant difference in number of nuclei of the smooth muscle cells among the three age groups. Changes in the tensile characteristics of the wall reflected well those of the microstructure of the wall with growth. The rheological properties and microstructure of the aortic wall were close to maturation at 8 weeks in SD rats.

Aging↗

PubMedDate not supplied

Possible mechanisms underlying the testicular toxicity of oxfendazole in rats.

To clarify the mechanisms underlying the testicular toxicity of oxfendazole (OX), adult Wistar rats were orally administered a dose of 100 mg/kg/day for 3, 7, or 14 days. Assays of sex-related hormones showed a significant decrease in only the estradiol serum level at days 3 and 7, as compared with the control group. Histopathologically, marked degeneration of meiotic spermatocytes was observed in stage XIV-I seminiferous tubules from day 3 onwards, and these spermatocytes gave positive results on terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL). Abnormalities of spermiogenesis such as megakaryospermatids and binucleated spermatids were also observed in the testes of OX-treated rats. Under the electron microscope, lipid accumulation and dilatation of the endoplasmic reticulum were frequently found in the cytoplasm of the Sertoli cells on day 3. These results strongly suggest that OX induces both apoptosis of meiotic spermatocytes, most probably due to disruption of the microtubules, and degeneration of the Sertoli cells, characterized by distended endoplasmic reticulum and prominent cytosolic lipid accumulation.

Administration, Oral↗

PubMedDate not supplied

Carcinogenic susceptibility to N-bis(2-hydroxypropyl)nitrosamine (DHPN) in rasH2 mice.

To evaluate the susceptibility of rasH2 mice to N-bis(2-hydroxypropyl)nitrosamine (DHPN), a potent carcinogen targeting the lung, liver, thyroid, and kidney, male, 6-week old, rasH2 mice and wild-type littermates (non-Tg mice) were given DHPN in drinking water at 0, 20 or 200 ppm, and 0 or 200 ppm, respectively, for 26 weeks. The experiment using rasH2 mice given 200 ppm DHPN and non-Tg mice given 200 and 0 ppm DHPN was completed at 20 weeks, since mortality in these groups was remarkably increased due to hemangiosarcomas of the liver. Histologically, tumors developed in the lung and liver in both rasH2 and non-Tg mice treated with DHPN. In addition, proliferative lesions were observed in the forestomach, urethra, and excretory duct of salivary glands in rasH2 mice given 200 ppm DHPN. RT-PCR analysis showed no marked difference in expression of mRNAs for the transgene and the endogenous mouse ras gene between the whole lung tissue containing a neoplasm and normal lung tissue. Our results suggest that rasH2 mice are highly susceptible to DHPN, the target organs including the forestomach, salivary gland and urethra, which have not been found to develop tumors in previous long-term carcinogenicity studies of DHPN in rats and mice.

Administration, Oral↗