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Biomedical subjects

J Higaki

Publications and source records attributed to J Higaki.

At least 37 records · Page 2Linked to original sources
PubMed2001

A family with von Hippel-Lindau disease revealed by pheochromocytoma.

Von Hippel-Lindau (VHL) disease is an inherited neoplastic disease characterized by a predisposition to develop retinal angiomas, central nervous system hemangioblastomas, renal cell carcinomas, pancreatic cysts and pheochromocytomas. Recently, we encountered three members of the same family who each had both VHL disease and pheochromocytoma. As in all three patients we suspected pheochromocytoma, the diagnosis of VHL disease should be considered. The possible presence of VHL disease was initially investigated in all three patients based on the presence of pheochromocytoma. A mutational analysis of the VHL gene revealed the presence of a missense mutation, consisting of a G to A transversion, at nucleotide 713 in all three patients. This germline point mutation in the VHL gene is often detected in type 2 VHL disease with pheochromocytoma. Genetic analysis seems to be useful for early detection of VHL disease, even when the formal criteria for diagnosis of this disease are lacking.

Adrenal Gland Neoplasms↗
PubMed2001

Effects of antihypertensive drugs and gene variants in the renin-angiotensin system.

Many genes and environmental factors are involved in the pathogenesis of hypertension, but the exact cause of essential hypertension has not yet been clarified. Gene polymorphism of the renin-angiotensin system (RAS) is one of the candidates. In the current study, we examined whether there was a correlation between the gene polymorphisms in RAS and either the choice of antihypertensive drugs or their efficacy. Subjects with essential hypertension (n=299) were recruited from among the outpatients of Osaka University Hospital and provided their informed consent for genetic analysis. Physicians freely chose the antihypertensive drugs and adjusted its dose until the patient's blood pressure was well controlled. The efficacy of each antihypertensive drug was estimated using the following formula: ABP=BP 1 (before treatment) - BP 2 (after treatment)/BP 1 x 100 (%). Gene variants in RAS were determined using PCR or PCR-RFLP (restriction fragment of polymorphism). The gene polymorphisms of RAS were not associated with delta SBP or ADBP. However, the mean ASBP in subjects with a deletion homozygote of the angiotensin converting enzyme gene (ACE/DD) was significantly lower (p<0.05) than that in patients with an insertion I allele of the ACE gene. The gene polymorphisms of RAS did not significantly affect the choice of antihypertensive drugs. Even though gene polymorphism in the renin angiotensin system was not a major factor in the antihypertensive therapy, the determination of genotype might be of help in the management of essential hypertension.

Antihypertensive Agents↗
PubMed2001

[A case of severe systemic edema in an elderly hypertensive patient with systemic lupus erythematodes during long-term treatment with anti-hypertensive drugs].

A 71-year-old woman receiving both angiotensin II receptor antagonist and calcium antagonist suffered severe systemic edema. She had been treated for essential hypertension with amlodipine for 2 years and candesartan for 3 months, and systemic lupus erythematodes (SLE) with steroids. During treatment, severe systemic edema appeared, mainly on her face, arms, and legs. At first, we suspected drug-induced edema by candesartan, so it was halted, but the edema still continued. We then considered amlodipine to be the culprit, and finally, the severe systemic edema disappeared after cessation of amlodipine. To control her blood pressure, we recommended candesartan, but 3 months late she suffered severe systemic edema again, thus the causative we drugs of her edema were thought to be both amlodipine and candesartan. Edema is a common symptom in elderly patients and we frequently observe drug-induced edema. In this case, there was underlying acceleration of blood vessel permeability induced by SLE and steroids and moreover, vasodilatation by candesartan and/or amlodipine further accelerated blood vessel permeability, and thus might have caused severe edema. It is very difficult to determine the cause of edema, especially in elderly patients, but we should consider not only one but also two or more drugs as being involved in drug-induced edema.

Aged↗
PubMed2001

Hand-assisted laparoscopic splenectomy for idiopathic thrombocytopenic purpura during pregnancy.

A successful case of a hand-assisted laparoscopic splenectomy with low-pressure pneumoperitoneum for autoimmune thrombocytopenic purpura in a patient at 23 weeks' gestation is reported. Preoperative splenic arterial embolization was performed on the same day as the operation using painless contour embolic material and super-absorbent polymer microspheres. The abdominal wall retraction method first was applied to avoid the effects of pneumoperitoneum on systemic hemodynamic alterations. However, a sufficient surgical view could not be obtained, as the intra-abdominal organs were elevated because of the enlarged uterus. A surgical view with 4 to 6-mm Hg pneumoperitoneum was available for the hand-assisted splenectomy. The postoperative course was uneventful, and the patient vaginally delivered a healthy infant. A hand-assisted laparoscopic splenectomy with low-pressure pneumoperitoneum after splenic arterial embolization would be feasible for patients with autoimmune thrombocytopenic purpura during a relatively advanced pregnancy.

Adult↗
PubMed2001

Symposium on the etiology of hypertension--summarizing studies in 20th century. 1. Hypertension and genes.

Under classical strategy, scientists have tried first to find a physiological phenomenon specific for essential hypertension, then to identify the protein underlying the physiological abnormality, and finally to clarify the causative gene which encoded the protein. On the other hand, under the reverse genetic approach, the correlation between hypertension and genetic abnormality is identified first, and then the pathogenesis is clarified-in reverse order. Therefore, it is not extraordinary for unexpected results to be obtained in the correlation between a gene and a disease, suggesting that this approach has a possibility to be a breakthrough in the chaos of hypertension research.

Angiotensinogen↗
PubMed2001

[Genetic polymorphisms of the renin-angiotensin system].

Essential hypertension is a multifactorial disease which is evoked by multiple environmental and genetic factors. Recent progress in molecular biology enables us a comprehensive understanding of the molecular pathogenesis of this disease. The genes of renin-angiotensin system such as renin, angiotensinogen, angiotensin-converting enzyme and angiotensin receptors genes are all reported as positive linkage to hypertension. Now ongoing progress of the human genome project will further accelerate the molecular studies on the rennin-angiotensin system and hypertension.

Angiotensinogen↗
PubMed2000

Nine polymorphisms of angiotensinogen gene in the susceptibility to essential hypertension.

Even if the importance of angiotensinogen (AGT) gene has been known in gene targeting animals and humans genetic studies, its precise mechanism and the interaction among AGT gene variants, plasma AGT concentration and risk for hypertension remain uncertain. We examined whether AGT gene variants predispose to hypertension via an increase of plasma AGT concentration. Plasma AGT concentration was estimated from plasma angiotensin I which was cleaved by an excess amount of human renin and measured by RIA. Using 9 AGT gene variants which included new polymorphisms (G-152A and T+31C), we examined the association with hypertension and with plasma concentration by a case-control study. Haplotype analysis revealed that G-6A, T+31C and M235T polymorphisms were in absolute linkage disequilibrium and were associated with hypertension but not with plasma AGT level. On the other hand, -1074t;T235 haplotype was associated with an increase of AGT level but not with hypertension. In the haplotype analysis, only H3 haplotype frequency, which contained G-6, T+31 and M235 alleles, was significantly increased in normotensive subjects, suggesting that this haplotype is associated with a hypotensive effect. According to combined haplotype analysis of diallele and microsatellite markers, it remains a possibility that M235T, T+31C, G-6A, A-20C and G-1074T polymorphisms may play an important role in increased risk for essential hypertension. Our results suggest that the positive association between AGT polymorphism and hypertension is not simply explained by an increase of plasma AGT concentration.

Alleles↗
PubMed2000

Ribozyme oligonucleotides against transforming growth factor-beta inhibited neointimal formation after vascular injury in rat model: potential application of ribozyme strategy to treat cardiovascular disease.

BACKGROUND: Because the mechanisms of atherosclerosis or restenosis after angioplasty have been postulated to involve an increase in transforming growth factor (TGF)-beta, a selective decrease in TGF-beta may have therapeutic value. Thus, we used the ribozyme strategy to actively cleave the targeted gene to selectively inhibit TGF-beta expression. METHODS AND RESULTS: We constructed ribozyme oligonucleotides (ONs) targeted to the sequence of the TGF-beta gene that shows 100% homology among the human, rat, and mouse species. The specificity of ribozyme against TGF-beta gene was confirmed by selective inhibition of TGF-beta mRNA in cultured vascular smooth muscle cells as well as balloon-injured blood vessels in vivo. Importantly, the marked decrease in TGF-beta resulted in significant inhibition of neointimal formation after vascular injury in a rat carotid artery model (P:<0.01), whereas DNA-based control ONs and mismatched ribozyme ONs did not have any inhibitory effect on neointimal formation. Inhibition of neointimal formation was accompanied by (1) a reduction in collagen synthesis and mRNA expression of collagen I and III and (2) a significant decrease in DNA synthesis as assessed by proliferating cell nuclear antigen staining. Moreover, we modified ribozyme ONs containing phosphorothioate DNA and RNA targeted to the TGF-beta gene. Of importance, modified ribozyme ONs showed a further reduction in TGF-beta expression. CONCLUSIONS: Overall, this study provides the first evidence that selective blockade of TGF-beta resulted in inhibition of neointimal formation, accompanied by a reduction in collagen synthesis and DNA synthesis in a rat model. We anticipate that modification of ribozyme ON pharmacokinetics will facilitate the potential clinical utility of the ribozyme strategy.

Animals↗
PubMed2000

Quantitative ultrasonic tissue characterization can identify high-risk atherosclerotic alteration in human carotid arteries.

BACKGROUND: Recently, ultrasonic tissue characterization of the composition of plaques has been performed in a quantitative fashion on the basis of integrated backscatter (IBS) analysis, but most of those studies have used high-frequency ultrasound to obtain microscopic images. METHODS AND RESULTS: We performed B-mode measurement and IBS signal analysis with acoustic densitometry with a 7.5-MHz linear-array transducer in freshly excised human aortas (n=58) (normal, atheromatous, and fibrous tissue) obtained at autopsy. Atheromatous and fibrous tissue had a similar intima-media thickness (IMT), but the IBS value in atheromatous specimens was lower than that in fibrous specimens. We further applied this method to human carotid ultrasonography. The subjects were young (80 regions), middle aged with 1 or no coronary risk factors (low risk) (120 regions), middle aged with >/=2 coronary risk factors (high risk) (240 regions), or elderly (80 regions) or were patients with myocardial infarction (MI) with multivessel disease (90 regions). The IMT was similar in middle-aged, elderly, and MI subjects. In contrast, the IBS value was significantly higher in elderly subjects and lower in high-risk middle-aged and MI subjects compared with that in low-risk middle-aged subjects. The percent of regions diagnosed as atheromatous (IBS less than mean minus 2-SD value of IBS in young subjects) was 11% in low-risk middle-aged subjects, 29% in high-risk middle-aged subjects, and 63% in the MI group. CONCLUSIONS: In conjunction with conventional B-mode imaging, IBS analysis with carotid ultrasonography appeared to provide prognostic information to identify a high-risk group with systemic atherosclerosis, which could lead to coronary heart disease in individuals with early-stage disease.

Adult↗
PubMed2000

Potential contribution of a novel antifibrotic factor, hepatocyte growth factor, to prevention of myocardial fibrosis by angiotensin II blockade in cardiomyopathic hamsters.

BACKGROUND: Because hepatocyte growth factor (HGF) prevented and/or regressed fibrosis in liver and pulmonary injury models, HGF may play an important role in the pathogenesis of fibrotic cardiovascular disease. Because angiotensin (Ang) II significantly decreased local HGF production, we performed (1) in vitro experiments using fibroblasts and (2) administration of an ACE inhibitor (temocapril) and an Ang II type 1 receptor antagonist (CS-866) to cardiomyopathic hamsters. METHODS AND RESULTS: In human fibroblasts, HGF significantly increased the production of matrix metalloprotease-1 (MMP-1) and urokinase plasminogen activator, whereas HGF also significantly attenuated the reduction of MMP-1 activity induced by Ang II. In contrast, HGF significantly decreased transforming growth factor (TGF)-beta mRNA stimulated by Ang II, whereas HGF also decreased basal TGF-beta protein level without affecting growth. Similarly, in rat cardiac fibroblasts, HGF inhibited the expression and production of TGF-beta, whereas HGF upregulated its specific receptor, c-met. Conversely, in vivo experiments revealed that administration of temocapril and CS-866 to cardiomyopathic hamsters resulted in a significant decrease in fibrotic area and increase in cardiac HGF concentration and mRNA (P<0.01), whereas cardiac concentration and mRNA of HGF were significantly decreased in cardiomyopathic hamsters. In contrast, mRNA expression of collagen III was markedly decreased by treatment with temocapril and CS-866. CONCLUSIONS: Here, we demonstrated that Ang II blockade prevented myocardial fibrosis in the cardiomyopathic hamster, accompanied by a significant increase in cardiac HGF. Overall, increase in local HGF expression may participate in the prevention of myocardial injury by Ang II blockade through its antifibrotic action.

Angiotensin II↗
PubMed2000

Hypoxia-induced endothelial apoptosis through nuclear factor-kappaB (NF-kappaB)-mediated bcl-2 suppression: in vivo evidence of the importance of NF-kappaB in endothelial cell regulation.

The transcription factor nuclear factor-kappaB (NF-kappaB) plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes involved in endothelial activation. Although recent reports have documented the contribution of NF-kappaB to apoptosis, it is still controversial. Especially, the role of NF-kappaB in endothelial apoptosis is largely unknown. Hypoxia significantly induced human aortic endothelial cell death and apoptosis in a time-dependent manner (P<0.01), accompanied by NF-kappaB activation. Decrease in total cell number and increase in apoptotic cells induced by hypoxia were significantly attenuated by NF-kappaB decoy, but not by scrambled decoy, oligodeoxynucleotides (ODNs) (P<0.01). Increase in DNA fragmentation induced by hypoxia was also significantly inhibited by NF-kappaB decoy ODNs as compared with scrambled decoy ODNs (P<0.01). Moreover, transfection of NF-kappaB decoy ODNs resulted in a significant decrease in caspase-3-like activity, which is a common pathway for apoptosis, compared with scrambled decoy ODNs. Importantly, transfection of NF-kappaB decoy ODNs significantly increased protein of bcl-2, an inhibitor of apoptosis, and did not alter bax, a promoter of apoptosis, thereby resulting in a significant increase in the ratio of bcl-2 to bax (P<0.01). bcl-2 mRNA was also decreased by hypoxia, whereas transfection of NF-kappaB decoy ODNs significantly attenuated decrease in bcl-2 mRNA. These results demonstrate that activation of NF-kappaB by hypoxia induced endothelial apoptosis in a bcl-2-dependent manner. The importance of NF-kappaB in endothelial apoptosis was confirmed by the observation that pyrrolidine dithiocarbamate, a potent NF-kappaB inhibitor, prevented endothelial apoptosis, caspase 3-like activity, and bcl-2 downregulation induced by hypoxia. To test this hypothesis in vivo, we transfected NF-kappaB decoy ODNs into rat intact carotid artery after reperfusion injury. Reperfusion injury was associated with a significant increase in endothelial apoptosis at 24 hours, whereas NF-kappaB decoy ODN treatment markedly decreased terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive endothelial cells at 24 hours after reperfusion (P<0.01). Here, using synthetic double-stranded DNA with high affinity for NF-kappaB as a decoy approach, we demonstrated that activation of NF-kappaB by hypoxia caused aortic endothelial cell death and apoptosis through the suppression of bcl-2. NF-kappaB-mediated endothelial apoptosis induced by hypoxia may be involved in the pathogenesis of endothelial dysfunction observed in cardiovascular ischemic diseases.

Animals↗
PubMed2000

Deletion allele of angiotensin-converting enzyme gene increases risk of essential hypertension in Japanese men : the Suita Study.

BACKGROUND: The Framingham Study recently revealed that the homozygous deletion polymorphism of the angiotensin-converting enzyme gene (ACE DD) is associated with increased risk for essential hypertension in a male-specific manner. However, this association has not been confirmed in races other than whites. METHODS AND RESULTS: Using a large number of Japanese subjects (n=5014) that were randomly selected from the general population (the Suita Study), we examined the association between ACE DD and hypertension. The frequency of DD (17.1%) in hypertensive men was significantly higher (P<0.0015) than that (11.8%) in other mildly hypertensive or normotensive men, and the estimated odds prevalence for hypertension (DD vs II) was 1.75 (95% CI 1.21 to 2.53). In contrast, no significant association was confirmed in women (OR 1.17, 95% CI 0.79 to 1.72). CONCLUSIONS: Despite the lower frequency of the DD genotype in Japanese than in whites, the ACE gene polymorphism was associated with increased risk for hypertension, suggesting that this polymorphism is a mild but certain genetic risk factor for essential hypertension in men.

Age Factors↗
PubMed2000

Transfection of antisense p53 tumor suppressor gene oligodeoxynucleotides into rat carotid artery results in abnormal growth of vascular smooth muscle cells.

BACKGROUND: Although loss of activity of an antioncogene, the p53 tumor suppressor gene product, has been postulated in the pathogenesis of human restenosis, little is known about the role of p53 in the regulation of vascular smooth muscle cell (VSMC) growth. In this study, to clarify the role of p53 in the pathogenesis of restenosis, we examined transfection of antisense p53 oligodeoxynucleotides (ODN) into VSMC in vitro and rat carotid artery in vivo. METHODS AND RESULTS: The specificity of antisense p53 ODN was confirmed by a significant decrease in p53 protein. Transfection of antisense p53 ODN into VSMC resulted in a significant increase in DNA synthesis and cell number as compared with sense and scrambled ODN (P<0.01). Importantly, transfection of antisense p53 ODN into rat intact carotid artery resulted in a significant increase in the ratio of neointima to medial area at 2 and 4 weeks after transfection, accompanied by a significant decrease in p53 protein (P<0.01). Moreover, cotransfection of wild-type p53 plasmid completely abolished neointimal formation induced by antisense p53 ODN. The sustained effect of a single antisense ODN administration was confirmed by the kinetics of ODN in the vessel wall with the use of FITC-labeled ODN. CONCLUSIONS: Overall, the present study demonstrated that loss of p53 by antisense p53 ODN resulted in an abnormal VSMC growth in vitro and in vivo. These results demonstrated the potential contribution of p53 to the pathogenesis of restenosis.

Animals↗
PubMed2000

Ileal perforation due to a Richter hernia at the drain insertion site following an operation for idiopathic rectal perforation: report of a case.

A case of a Richter hernia at the insertion site of the drainage tube following open abdominal surgery is reported. A 54-year-old man underwent an emergency operation for an idiopathic rectal perforation. A partial resection of the rectum and drainage using four 10-mm (outer diameter) drainage tubes with round cross sections was performed. Despite an uneventful early postoperative course, an emergency reoperation was required for peritonitis due to a bowel perforation 14 days after removing the drain inserted into the rectosacral space. A laparotomy revealed an incarcerated Richter hernia with ileal perforation through the 10-mm drainage site. The postoperative course after a partial resection of the ileum and drainage with Penrose drains was uneventful. This is the first report of a Richter hernia through the insertion site of a drainage tube in abdominal surgery. The possible occurrence of a Richter hernia in cases with postoperative drainage using large-size round drainage tubes should thus be considered in such patients.

Drainage↗
PubMed2000

Human G-protein beta3 subunit variant is associated with serum potassium and total cholesterol levels but not with blood pressure.

The activity of a sodium-proton exchanger is enhanced in the patients with essential hypertension and regulated via G-protein, which is a signal transducer between receptors and intracellular effectors. A recent study has revealed that a novel variant (C825T) in exon 10 of the gene encoding the beta3 subunit of heterotrimetric G proteins (GNB3) is a genetic factor predisposing to hypertension in Caucasians. We examined the association between GNB3/ C825T and blood pressure, lipids, electrolytes, and other parameters in a Japanese population. Subjects (n = 352) were selected from the Ohasama Study, the population of which is regarded as from a rural community in Japan. To obtain precise clinical measurements, 24-h ambulatory blood pressure monitoring (ABPM), brain magnetic resonance imaging (MRI), and carotid ultrasonography (CUS) were conducted in this population. In addition, we recruited 762 subjects from outpatients at the Osaka University Medical School to carry out the association study between hypertension and GNB3. The GNB3 genotype distribution did not differ significantly between normotensives and hypertensives in either of the two studies. The T825 allele of GNB3 was not associated with the presence of hypertension, blood pressure level, the number of brain lacunae or carotid wall thickness. However, the serum potassium and total cholesterol levels were significantly higher in subjects with the T allele (P < .005). The T825 allele of GNB3 is associated with increased serum potassium and total cholesterol levels but not with blood pressure in a Japanese population.

Adult↗