Biomedical subjects

T Ogihara

Publications and source records attributed to T Ogihara.

At least 271 records · Page 15Linked to original sources

PubMed1998

Effectiveness of omeprazole-amoxicillin-clarithromycin (OAC) therapy for Helicobacter pylori infection in a Japanese population.

BACKGROUND: Omeprazole or lansoprazole, amoxicillin, clarithromycin (PPI/AC) therapy has been reported to provide a high cure rate of H. pylori infection with few adverse effects. Effectiveness of H. pylori therapy may vary among different geographic regions and patient populations. However, there are few reports in Japan as to its effectiveness. We have, therefore, studied the effectiveness of H. pylori therapy in a large group of Japanese patients. METHODS: For this study, 366 H. pylori-positive patients with peptic ulcer disease or non-ulcer dyspepsia (263 men and 103 women, mean age 48.5 years) were assigned to 6 groups, each receiving a different PPI/AC regimen. Group 1 received omeprazole (OPZ) 20 mg, amoxicillin (AMOX) 1500 mg, and clarithromycin (CAM) 400 mg; Group 2 OPZ 40 mg, AMOX 1500 mg, and CAM 400; and Group 3 OPZ 20 mg, AMOX 2000 mg, and CAM 600 mg daily for 14 days. The group treated with lansoprazole (LPZ) 30 mg, AMOX 1500 mg and CAM 400 mg was used for 14 days in Group 1L. OPZ 20 mg, AMOX 750 mg, and CAM 200 mg were given to Group 4 for 28 days and OPZ 20 mg, AMOX 1500 mg, CAM 400 mg was administered to Group 5 for 7 days. Cure of infection was assessed by 13C urea breath test one month after completion of therapy. RESULTS: Cure rates calculated by excluding the patients who showed borderline value of 13C urea breath test (delta 13C value between 5 and 10% in Groups 1, 1L, 2, 3, 4, and 5 were 82.7% (95% CI; 74-90), 88.9% (76-96), 84.9% (72-93), 81.3% (67-91), 84.6% (72-93), and 85.1% (72-94) on an intention-to-treat basis, and 88% (80-94), 95.2% (84-99), 95.6% (85-99), 90.7% (78-97), 95.7% (85-99) and 88.9% (76-96) on a per-protocol basis, respectively. Adverse effects that affected compliance were observed in 10 of 237 patients on 14-day regiments, one of 47 on a 28-day regimen and one of 46 on a 7-day regimen. CONCLUSION: Two weeks PPI/AC therapy is highly effective for cure of H. pylori infection in the Japanese population. The low dose one month regimen and the one week OAC regimen were also effective in our patient population.

Adult↗

PubMed1998

[13C]-urea breath test for assessment of cure of Helicobacter pylori infection at 1 month after treatment.

Although the [13C]-urea breath test has been reported to provide high specificity and sensitivity, its reliability in determination of cure, including when and how the assessment of cure is made, is not fully established. Here we evaluate the reliability of judgment of cure after 1 month of therapy using the [13C]-urea breath test, including the appropriate time to assess its cure. Our subjects were 199 H. pylori-infected patients (144 men and 55 women; 50.5+/-0.76 years) who underwent cure therapy, took the breath test at 1 month, and underwent both the breath test and invasive tests using endoscopy at 6 months after completion of therapy. Accuracy of the breath test in judgment of cure at 1 month was investigated by comparing the results at 1 month with those at 6 months when cut-off value of the breath test was set at 5 per thousand. Chronologic alterations of the delta13C value were also analyzed in cured patients who underwent the breath test at 1, 3, and 6 months. In 167 (94.9%) of 176 patients whose breath test values were less than 5 per thousand, cure was reconfirmed at 6 months. In 14 (60.9%) of 23 patients whose values were greater than 5 per thousand, cure was demonstrated at 6 months. The mean delta13C values of 33 cured patients who took the breath test at 1 month and repeated the breath test at 3 and 6 months for any reasons were 4.14+/-0.74 per thousand, 2.02+/-0.23 per thousand, and 1.72+/-0.19 per thousand, respectively, and the value at 3 months was significantly smaller than that at 1 month. The reliability of assessment of cure by only the breath test at 1 month was sufficiently high (94.9%) once the patients were judged to be cured. However, because the breath test at 1 month yielded a high false-positive rate and the breath test values at 3 and 6 months were similar, evaluation of cure of H. pylori infection by the [13C]-urea breath test should preferably be done at 3 months after treatment to minimize false-positive results, or the concept of a borderline group should be established for patients with positive but relatively high delta13C values (5-10 per thousand) who repeated the breath test 3 months after treatment.

Breath Tests↗

PubMed1998

Transcription factor decoy for nuclear factor-kappaB inhibits tumor necrosis factor-alpha-induced expression of interleukin-6 and intracellular adhesion molecule-1 in endothelial cells.

BACKGROUND: Several cytokines and adhesion molecules released from endothelium play an important role in inflammation, immune responses, and probably atherogenesis. OBJECTIVE: To determine whether the transcription factor nuclear factor-kappaB mediated expression of these genes involved in the inflammatory response of endothelial cells to tumor necrosis factor-alpha, by using transcription factor decoy oligodeoxynucleotides. DESIGN AND METHODS: We first transfected fluorescein isothiocyanate (FITC)-labeled double-stranded oligodeoxynucleotides into endothelial cells by a cationic liposome-mediated method of gene transfer. We then confirmed that the decoy oligodeoxynucleotides could block binding of nuclear factor-kappaB to its specific cis element effectively. In addition, we transfected the reporter gene chloramphenicol acetyltransferase driven by three repeated nuclear factor-kappaB binding sequences in the promoter and enhancer region. RESULTS: FITC-labeled oligodeoxynucleotides were detected in the nuclei of approximately 70% of the total cells. Tumor necrosis factor--stimulated expression of chloramphenicol acetyltransferase was partially inhibited by transfection of nuclear factor-kappaB decoy oligodeoxynucleotides, but not by transfection of scrambled oligodeoxynucleotides. Also nuclear factor-kappaB decoy oligodeoxynucleotides but not scrambled oligodeoxynucleotides inhibited tumor necrosis factor-induced expression of interleukin-6 and intracellular adhesion molecule-1 both at the messenger RNA and at protein level (assessed by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay). CONCLUSION: Our results demonstrate that nuclear factor-kappaB decoy oligodeoxynucleotides transfected by cationic liposome method inhibited tumor necrosis factor--induced expression of interleukin-6 and intracellular adhesion molecule-1 in endothelial cells.

Animals↗

PubMed1998

Hepatocyte growth factor as a potential index of complication in diabetes mellitus.

OBJECTIVE: Diabetes mellitus (DM), characterized by the premature development of microvascular and macrovascular disease, shows a loss of vasodilatory properties of resistance vessels. However, the mechanisms of endothelial dysfunction in diabetes have not yet been clarified. Hepatocyte growth factor (HGF) in vascular cells was down-regulated by high glucose levels, potentially accelerating the endothelial dysfunction in DM. In this study, the serum HGF level was measured to investigate further the role of HGF in DM. METHODS: Tissue and circulating HGF levels were measured in the KKAy mouse, a rodent model of non-insulin-dependent diabetes mellitus (NIDDM), and lean C57 BL control mice. Then, serum HGF concentrations were measured in NIDDM patients without liver, kidney or lung damage. For the study of serum HGF concentration, 30 normotensive and age-matched 58 DM patients were studied. The 58 DM patients were divided into 26 patients without hypertension and 32 patients with hypertension [22 patients without hypertensive complications (WHO I) and 10 patients with hypertensive complications (WHO II + III)]. RESULTS: The serum HGF concentration in KKAy mice was significantly lower than that in control mice (P < 0.01), at 14 weeks of age when they exhibit features of diabetes. Similarly, tissue HGF concentrations in the heart and kidney were decreased significantly in KKAy mice compared with control C57 BL mice (P< 0.05). The serum HGF concentration showed a significant negative correlation with hemoglobin (Hb) A(Ic) concentration (P< 0.01, r= -0.41). Since the serum HGF concentration is a potential index of the severity of hypertension, the serum levels of HGF in DM patients without and with hypertension were examined. The serum HGF concentration in DM patients without hypertension was significantly lower than that in normal subjects (P< 0.05), whereas that in DM patients with hypertension was significantly higher than that in normal subjects (P < 0.01). Moreover, the serum HGF concentration in DM patients with hypertensive complications was further higher than that in others (P < 0.01). CONCLUSION: The present data showed that serum, cardiac and renal HGF concentrations in KKAy mice were significantly decreased compared with control mice. Therefore, a decrease in local HGF may be a trigger of endothelial dysfunction in DM. Clinical data also demonstrated a significant negative correlation between serum HGF and HbA(Ic) concentrations in diabetic patients without complications. In contrast, the serum concentration of HGF was significantly elevated depending on the severity of hypertension. These results suggest that HGF may be a new index of complications such as hypertension in DM.

Animals↗

PubMed1998

Expression of parathyroid hormone/parathyroid hormone-related protein receptor in vascular endothelial cells.

The parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor has been reported to be expressed in many tissues, including vascular smooth-muscle cells (VSMCs), but it has not been identified in vascular endothelial cells. To determine whether vascular endothelial cells can express the PTH/PTHrP receptor, its gene expression was examined in simian virus 40-transformed rat lung vascular endothelial cells (TRLECs) by the reverse-transcription polymerase chain reaction (RT-PCR). Results in TRLEC, with rat VSMCs and kidney as controls, showed identical 741-bp products. Furthermore, incubation with PTHrP[1-34] reduced the thrombin-stimulated endothelin-1 (ET-1) expression in TRLECs. Our results demonstrate that vascular endothelial cells can express the PTH/PTHrP receptor and therefore are also a target tissue for PTHrP.

Animals↗

PubMed1998

Endothelin-1 enhances nitric oxide-induced cell death in cultured vascular smooth-muscle cells.

Increased expression of endothelin-1 (ET-1) immunoreactivity is demonstrated in the active atherosclerotic plaque. Here we show that both ETA and ETB receptors are expressed in rat vascular smooth-muscle cells (VSMCs). ET-1 binding to ETB receptors enhances nitric oxide-induced cell death in VSMCs. These findings suggest that ET-1 may participate in the mechanism of cell death (apoptosis) in the plaque through activation of ETB-mediated pathways and that a selective ETB receptor antagonist could be useful in preventing acute plaque alterations, such as plaque rupture.

Amino Acid Sequence↗

PubMed1998

Association between angiotensin II receptor gene polymorphism and serum angiotensin converting enzyme (SACE) activity in patients with sarcoidosis.

BACKGROUND: Serum angiotensin converting enzyme (SACE) is considered to reflect disease activity in sarcoidosis. SACE activity is increased in many patients with active sarcoid lesions. The mechanism for the increased SACE activity in this disease has not been clarified. ACE insertion/deletion (I/D) gene polymorphism has been reported to have an association with SACE levels in sarcoidosis, but no evidence of an association between angiotensin II receptor gene polymorphism and SACE in this disease has been found. A study of the association of angiotensin II receptor gene polymorphisms with sarcoidosis was therefore undertaken. METHODS: ACE (I/D), angiotensin II type 1 receptor (AGTR1), and angiotensin II type 2 receptor (AGTR2) gene polymorphisms were investigated by polymerase chain reaction (PCR) and SACE levels were measured in three groups of patients: those with sarcoidosis or tuberculosis and normal controls. RESULTS: There was no difference in allele frequency of AGTR1 and AGTR2 polymorphism among the three groups. Neither AGTR1 nor AGTR2 polymorphisms were associated with sarcoidosis. SACE activity was higher in patients with sarcoidosis with the AGTR1 A/C genotype than in others. However, this tendency was not detected in patients with tuberculosis. CONCLUSIONS: The AGTR1 allele C is associated with high activity of SACE in patients with sarcoidosis. It is another predisposing factor for high levels of SACE in patients with sarcoidosis and is considered to be an independent factor from the ACE D allele for high levels of SACE in sarcoidosis. This fact could be one of the explanations for the increased SACE activity in sarcoidosis.

Analysis of Variance↗

PubMed1998

Oxidation products of uric acid and ascorbic acid in preterm infants with chronic lung disease.

Allantoin, the oxidation product of uric acid (UA), can be used as an in vivo marker of free radical generation. The aims of the present study were to evaluate the allantoin changes in plasma and bronchoalveolar lavage fluid (BALF) as well as to examine plasma levels of ascorbic acid (AA) and its oxidation product, dehydroascorbic acid (DHAA), in infants with or without chronic lung disease (CLD) during the first week of life. The study population was 20 infants of 24-30 weeks gestation, comprising 10 who subsequently developed CLD and 10 without CLD. In the CLD infants, the plasma allantoin/UA ratio showed a significant increase after day 1 and continued to increase gradually to reach a peak on day 6 (6.5 +/- 4.1% for CLD and 2.1 +/- 0.9% for non-CLD infants). The allantoin/UA ratio in BALF was also higher in CLD infants and the difference reached significance on days 4-6 (41.2 +/- 15.8% for CLD and 11.7 +/- 9.9% for non-CLD infants). In contrast to allantoin, the plasma DHAA/AA ratio did not differ between the 2 groups throughout the study period. Our findings that the allantoin/UA ratios were significantly higher in CLD than non-CLD infants not only in plasma but also in BALF, and that the intergroup differences of this ratio in both plasma and BALF was more prominent in the latter half of the first week of life further confirm our previous speculation that oxygen radicals are involved in the development of neonatal CLD.

Allantoin↗

PubMed1998

Requiring higher doses of erythropoietin suggests pregnancy in hemodialysis patients.

BACKGROUND/AIMS: Pregnancy in hemodialysis (HD) patients tends to be diagnosed late because of its infrequency and the lack of validity of urine pregnancy tests, and because these patients tend to have menstrual irregularities. The outcome is influenced by pregnancy-related anemia. We investigated the characteristics of pregnancy-related anemia and whether it is a useful diagnostic clue to pregnancy in HD patients. METHODS: We retrospectively investigated six pregnancies of 5 HD patients (mean age 30 years), including 4 patients treated with recombinant human erythropoietin (rHuEpo) and a transfusion-dependent patient with two pregnancies in the pre-rHuEpo era. RESULTS: The mean duration of HD was 6 years, the mean duration of the patients' marriages at the time of pregnancy was 6 years, and the mean gestational age at diagnosis was 11 weeks and 4 days. The progression of anemia (an 8% decrease in the hematocrit) was detected by 8 weeks of gestation in all patients. The prepregnancy hematocrit was stable in 5 pregnancies, facilitating the detection of changes, but during one of the pregnancies of the transfusion-dependent patient the hematocrit was low and was influenced by the transfusions. The amount of rHuEpo required to attain a target hematocrit of 30% increased gradually or rapidly until delivery. CONCLUSIONS: The progression of anemia or hyporesponsiveness to rHuEpo was a useful early diagnostic clue to pregnancy in HD patients. However, the prepregnancy hematocrit should be stabilized with rHuEpo, so that decreases can be easily detected. The precise mechanisms of hyporesponsiveness to rHuEpo, which progressed during pregnancy and subsided after delivery, remain to be clarified.

Adult↗

PubMed1998

Inhibition of growth of human vascular smooth muscle cells by overexpression of p21 gene through induction of apoptosis.

The senescent cell-derived inhibitor (sdi)-1 protein (p21 product) has been identified as a downstream mediator of the tumor suppressor p53 in the regulation of cell cycle progression through a G1 phase checkpoint. Given the importance of cell cycle inhibition for the treatment of restenosis, in this study we focused on the function of p21 gene in inhibiting proliferation of vascular smooth muscle cells (VSMC). To test the hypothesis, we transfected human p21 gene into human aortic VSMC using hemagglutinating virus of Japan-liposome-mediated transfer. Initially, we examined the successful transfection of human p21 gene into VSMC. p21 protein was increased in VSMC transfected with p21 vector as compared with control vector. Accompanied by increased p21 protein, transfection of p21 vector resulted in a significant decrease in number of VSMC induced by 2% serum (P<.01). Although p21 has been reported to play an important role in the regulation of apoptosis in some cells, apoptosis mediated by p21 is still controversial. Therefore, we hypothesized that overexpression of p21 mediates apoptosis in human VSMC, in addition to the blockade of cell cycle progression. First, we assessed the concordance between morphologic analysis and apoptosis as determined by nuclear staining with Hoechst 33342. Cells transfected with p21 gene exhibited the characteristic features of cell shrinkage, membrane blebbing, and rounding that are typical of apoptotic death. Of greater interest, a significant increase in apoptotic cells was observed in VSMC transfected with p21 vector as compared with control vector (P<.01). These results were confirmed by the measurement of DNA fragmentation. Consistent with nuclear staining, DNA fragmentation in VSMC transfected with human p21 gene was significantly increased as compared with that in VSMC transfected with control vector (P<.05). To study the molecular mechanisms of apoptosis mediated by overexpression of p21 gene, the protein levels of bax, a promoter of apoptosis, and bcl-2, an inhibitor of apoptosis, were also measured by Western blotting. Overexpression of p21 gene significantly increased protein of bax (P<.05), whereas transfection of p21 gene did not alter bcl-2 protein. Importantly, the ratio of bax to bcl-2 was significantly increased in VSMC transfected with human p21 vector as compared with control vector (P<.05). Overall, these results demonstrated that inhibition of VSMC growth by overexpression of human p21 gene was accompanied by induction of apoptosis through an inappropriate increase in bax protein. These results suggest that regulation of cell cycle by p21 may be closely linked to programmed cell death/apoptosis in human VSMC.

Aorta↗

PubMed1998

Familial hypertension, insulin, sympathetic activity, and blood pressure elevation.

This study evaluated the effects of a positive family history of hypertension (FH+) on the contributions of sympathetic nervous system (SNS) activity and insulin to blood pressure elevation (BPE). The study design was longitudinal and evaluated BP, body mass index (BMI), and fasting plasma insulin and norepinephrine (NE) levels for 10 years in 557 young, nonobese Japanese men who were normotensive at entry. FH+ was defined as hypertension in first-degree relatives as verified by historical records or direct determination. BPE was defined as a > or = 10% rise in systolic and diastolic BP over entry levels during the 10-year period. In the total group FH+ was noted in 16%, and BPE occurred in 18% of normotensive subjects. When evaluated by FH, the prevalence of BPE was 33% in FH+ compared with 16% in FH- (P<0.05). BP levels were greater both at entry and at year 10 in the FH+ group. The absolute increment in plasma NE over 10 years was greater in the BPE group than in those without BPE (P<0.01). Of note, the rise in plasma NE levels in BPE individuals was identical in FH+ and FH- subjects. Plasma insulin increments were also greater in normotensive subjects with BPE than in normotensive subjects without BPE. However, compared with NE, development of hyperinsulinemia was more pronounced in the FH+ subjects. The results indicate that SNS hyperactivity may be a less genetically determined predictor of hypertension than is hyperinsulinemia. Because SNS changes in this initially normotensive population appeared more closely related to the development of hypertension than to hyperinsulinemia, environmental rather than genetic factors may be the main determinant of early BPE in nonobese normotensive subjects.

Adult↗

PubMed1998

Conditioned medium from HepG2 cells transfected with human apolipoprotein(a) gene stimulates growth of human vascular smooth muscle cells: effects of overexpression of human apolipoprotein(a) gene.

Lipoprotein(a) [Lp(a)] is well known to stimulate growth of vascular smooth muscle cells (VSMCs), resulting in atherosclerosis. Its mechanism is postulated to be decreased in active transforming growth factor (TGF)-beta. However, the exact mechanisms and cellular processing from apolipoprotein(a) [apo(a)] to Lp(a) have not yet been clarified because no cultured cells producing apo(a) are available. Therefore, it is necessary to establish apo(a)-producing cells to study the role of apo(a). We evaluated the effects of overexpression of human apo(a) gene on human aortic VSMC growth. First, we tested whether transfection of apo(a) gene into human hepatoma cells, HepG2 cells, producing human apoB resulted in the formation of Lp(a). Transfection of apo(a) gene into HepG2 cells resulted in detectable levels of Lp(a) in the medium, as assessed by ELISA and Western blot, whereas no Lp(a) was detected in the medium of HepG2 cells transfected with control vector and untransfected HepG2 cells. Expression of apo(a) mRNA was also confirmed by reverse transcription-polymerase chain reaction. In contrast, Western blotting showed a single band detected by specific anti-apo(a) antibody, but not anti-apoB antibody, in the medium of apo(a)-transfected VSMCs. These results demonstrate that Lp(a) can be formed from apo(a) on HepG2 cells, whereas transfection of apo(a) gene into VSMCs resulted in the production of apo(a) alone but not Lp(a). Next, we examined the biological effects of overexpression of apo(a) gene on growth of VSMCs and endothelial cells. Incubation of cultured medium of HepG2 cells transfected with apo(a) gene with human VSMCs or endothelial cells resulted in a significant increase in cell number compared with the conditioned medium of HepG2 cells transfected with control vector. In contrast, transfection of apo(a) gene directly into VSMCs caused no significant effect on VSMC growth. Therefore, we measured TGF-beta concentration in the conditioned medium of VSMCs. However, using ELISA, only latent but not active TGF-beta was detected in the medium of VSMCs. Moreover, addition of neutralizing anti-TGF-beta antibody did not alter VSMC growth. These results suggest that Lp(a) could stimulate growth of VSMCs via the independent mechanisms from the inhibition of TGF-beta activation. Overall, these data demonstrate that overexpression of apo(a) gene in cells producing apoB results in formation of Lp(a), resulting in a mitogenic action on human endothelial cells and VSMCs. These results provide new information to understand the mechanisms of the mitogenic action of Lp(a) and suggest the role of Lp(a) in the pathogenesis of atherosclerosis.

Apolipoproteins↗

PubMed1998

Negative regulation of local hepatocyte growth factor expression by angiotensin II and transforming growth factor-beta in blood vessels: potential role of HGF in cardiovascular disease.

Because hepatocyte growth factor (HGF) is a member of the endothelium-specific growth factors, we hypothesized that HGF may play a role in cardiovascular disease. Therefore we first examined the role of local HGF production in endothelial cell (EC) growth. Addition of anti-HGF antibody to EC resulted in a significant decrease in EC number. Moreover, coculture of vascular smooth muscle cells (VSMC) with EC resulted in an increase in EC number that was completely inhibited by anti-HGF antibody, suggesting that HGF secreted from EC and VSMC regulates EC growth in an autocrine-paracrine manner. Interestingly, transforming growth factor (TGF)-ss significantly decreased HGF secretion from EC, whereas interleukin 6 stimulated immunoreactive HGF secretion. In human VSMC, TGF-ss and angiotensin II suppressed local HGF production in a dose-dependent manner. Interestingly, anti-TGF-beta antibody resulted in significant but not complete inhibition of the decrease in local HGF production. To further study the regulation of local HGF production, we used a coculture system. Coculture of VSMC with EC resulted in a significant decrease in local HGF secretion. The decrease in local HGF production by coculture was significantly attenuated by anti-TGF-beta antibody, suggesting that inhibition of local HGF production in the coculture system was due to TGF-beta activation. Moreover, a further decrease in local HGF production in the coculture system by angiotensin II was also observed. Finally, we studied the role of angiotensin II in the regulation of the local HGF system in vivo by using a balloon injury rat model. Of importance, local HGF production was significantly decreased in balloon-injured arteries compared with intact vessels, accompanied by a reduction of HGF mRNA. An angiotensin-converting enzyme inhibitor (cilazapril) or an angiotensin II type 1 receptor antagonist (E-4177) significantly stimulated local vascular HGF production associated with the inhibition of neointimal formation after balloon injury compared with vehicle. In contrast, hydralazine did not alter local HGF production or neointimal formation despite decreasing blood pressure to a similar level as that in rats treated with cilazapril or E-4177. Overall, local HGF secretion from vascular cells was negatively regulated by TGF-beta and angiotensin II. The present study also demonstrated that blockade of angiotensin II significantly inhibited neointimal formation, accompanied by a significant increase in local vascular HGF production in vivo in the balloon injury model. Given the strong mitogenic activity of HGF on endothelial cells, increased local HGF production by blockade of angiotensin II may enhance reendothelialization after balloon injury. Downregulation of the local vascular HGF system by TGF-beta and vascular angiotensin may play an important role in the pathogenesis of cardiovascular diseases.

Angiotensin II↗

PubMed1998

Meta-analysis of the association of Trp64Arg polymorphism of beta 3-adrenergic receptor gene with body mass index.

A possible pathogenic polymorphism in the beta 3-adrenergic receptor gene (Trp64Arg) has been reported to be associated with increased body weight, clinical features of insulin resistance, and early development of type 2 diabetes mellitus in several populations. However, such findings have not been consistent among studies, making the hypothesis that this genetic marker is associated with clinical features controversial. To assess the effect of the genotypes on body mass index (BMI), we performed a meta-analysis of the data from the literature using an extension of ANOVA for continuous measures. In a total of 48 subgroups containing subjects with (n = 2447) and without (n = 6789) the Trp64Arg variant, the summary weighted mean difference in BMI was 0.30 (95% confidence interval, 0.13-0.47) kg/m2, indicating that variant carriers exhibited higher BMI (on the average, 0.30 kg/m2 higher) than normal homozygous subjects. In this case, there was no significant evidence against homogeneity of the effect (P = 0.36). This is the first meta-analysis assessing quantitative phenotypes in relation to a genetic polymorphism, and the results support the hypothesis that the Trp64Arg polymorphism is associated with BMI across diverse population groups, suggesting that the beta 3-adrenergic receptor gene locus plays a role in genetic predisposition to increased body weight in a universal manner.

Analysis of Variance↗

PubMed1998

Analysis of a variable number of tandem repeats in a heart disease gene by capillary electrophoresis with laser-induced fluorescence detector.

Capillary electrophoresis with laser-induced fluorescence detector (CE-LIF) was successfully applied to the analysis of the variable number of tandem repeats (VNTR) in a human apolipoprotein B gene (APOB). Apolipoprotein B VNTR alleles containing more than 35 repeat units are a significant risk factor for heart disease. Thus, we developed a method for accurately determining the number of repeat units (16 bp) in the VNTR using capillary electrophoresis. The CE-LIF technique gave excellent resolution of APOB alleles differing by 2 or 4 repeat units over the range 600 to 1000 bp. The recommended conditions for the analysis of APOB VNTR loci by CE-LIF are as follows: effective length of capillary (100 microns i.d., 360 microns o.d.), 50 cm; running buffer, 50 mM Tris-borate 0.5% methylcellulose and 0.1 microM fluorescent dye YO-PRO-1; electric field, 150 V/cm.

Alleles↗

PubMed1998

Exogenous ouabain is accumulated in the adrenals and mimics the kinetics of endogenous digitalis-like factor in rats.

Ouabain has been isolated as an endogenous pathogenetic factor in salt-induced hypertension and has been shown to be rich in the adrenals. In this study, organ accumulation of orally administered [3H]ouabain was examined in rats. Exogenous [3H]ouabain was accumulated in high levels in the adrenals, especially in the zona intermedia, and was not metabolized in the rat. Accumulated [3H]ouabain mimicked the movement of "endogenous" digitalis-like factor, since 1) the plasma [3H]ouabain level decreased in bilaterally adrenalectomized rats, 2) the plasma [3H]ouabain level increased accompanied by a decrease in [3H]ouabain content in the adrenals in reduced renal mass hypertensive rats, and 3) [3H]ouabain levels in plasma and in the adrenals increased in spontaneously hypertensive rats, as compared with those in respective control animals. Moreover, the rat diet contained a relatively high amount of ouabain-like immunoreactivity (OLI), and the ratio of the [3H]ouabain content to OLI in each organ was comparable to that of the daily intake of dietary [3H]ouabain to OLI. Furthermore, high 3H-radioactivities were also observed in the adrenals of rats that ingested [3H]digoxin and [3H]digitoxin. These data suggest that exogenous ouabain, related cardiotonic glycosides of plant origin, or both accumulate in the adrenals and, at least in part, act as "endogenous" digitalis-like factor(s).

Adrenal Cortex↗

PubMed1998

Oligonucleotide-based gene therapy for cardiovascular disease.

Gene therapy is emerging as a potential strategy for the treatment of cardiovascular disease such as restenosis after angioplasty, vascular bypass graft occlusion, transplant coronary vasculopathy, homozygous familial hypercholesterolemia and cystic fibrosis, for which no known effective therapy exists. Gene therapy requires efficient in vivo gene transfer technology. During the past decade, many gene transfer methods including viral transfer techniques have been developed, and some are being applied clinically in human gene therapy studies. Molecular biology and pathophysiology of the cardiovascular system have started to emerge, and the time is ripe for the introduction of gene therapy to the management of cardiovascular disorders. In this review, we have focused on the future potential of oligonucleotide-based gene therapy for the treatment of cardiovascular disease.

Cardiovascular Diseases↗

PubMed1998

Altered expression levels and impaired steps in the pathway to phosphatidylinositol 3-kinase activation via insulin receptor substrates 1 and 2 in Zucker fatty rats.

To elucidate the mechanism of obesity-related insulin resistance, we investigated the impaired steps in the processes of phosphatidylinositol (PI) 3-kinase activation through binding with insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) in liver and muscle of Zucker fatty rats. The expressions of IRS-1 and IRS-2 were shown to be downregulated in both liver and muscle in fatty rats (hepatic IRS-1, 83%; hepatic IRS-2, 45%; muscle IRS-1, 60%; muscle IRS-2, 78%), resulting in decreased tyrosine phosphorylation in response to insulin stimulation. Despite the decrease in the tyrosine phosphorylation levels of hepatic IRS-1 and IRS-2 being mild to moderate, associated PI 3-kinase activities were dramatically decreased in fatty rats (IRS-1, 14%; IRS-2, 10%), which may suggest alteration in the sites of phosphorylated tyrosine residues of hepatic IRS-1 and IRS-2. In addition, we demonstrated that the expressions of p85alpha and p55alpha regulatory subunits of PI 3-kinase were reduced (p85alpha, 67%; p55alpha, 54%), and that the p50alpha regulatory subunit was markedly upregulated (176%) in the livers of fatty rats without apparent alterations in expressions of the catalytic subunits p110alpha and p110beta. These alterations may reflect the obesity-related insulin resistance commonly observed in human NIDDM.

Albumins↗