Biomedical subjects
Publications and source records attributed to S Okuno.
We have searched for the lepton flavor violating decay tau(-)-->micro(-)eta using a data sample of 84.3 fb(-1) accumulated with the Belle detector at KEK. The eta meson was detected through the decay modes: eta-->gammagamma and pi(+)pi(-)pi(0). No signal candidates are found, and we obtain an upper limit for the branching fraction B(tau(-)-->micro(-)eta)<3.4 x 10(-7) at the 90% confidence level.
We report the first observation of the decay B+-->psi(3770)K+ where the psi(3770) is reconstructed in the D0(-)D(0) and D+D- decay channels. The obtained branching fraction is B(B+-->psi(3770)K+)=(0.48+/-0.11+/-0.07)x10(-3). We have measured the branching fraction for the decay B+-->D0(-)D0K+ to be (1.17+/-0.21+/-0.15)x10(-3) and set a 90% confidence level upper limit of 0.90 x 10(-3) for the decay B+-->D+D-K+. We also present the results of a search for possible decays to D(-)D and D0(-)D(0)pi(0) of the recently observed X(3872) particle. The analysis is based on 88 fb(-1) of data collected at the Upsilon(4S) resonance by the Belle detector at the KEKB asymmetric-energy e(+)e(-) collider.
We report the first observation of a b-->u type charmless baryonic B decay, B+-->pppi(+), as well as b-->s type B0-->ppK0 and B+-->ppK(*+) decays. The analysis is based on a 78 fb(-1) data sample recorded on the Upsilon(4S) resonance with the Belle detector at KEKB. We find B(B+-->pppi(+))=(3.06(+0.73)(-0.62)+/-0.37)x10(-6), B(B0-->ppK0)=(1.88(+0.77)(-0.60)+/-0.23)x10(-6), and B(B+-->ppK(*+))=(10.3(+3.6+1.3)(-2.8-1.7))x10(-6). We also update B(B+-->ppK+)=(5.66(+0.67)(-0.57)+/-0.62)x10(-6) and present an upper limit on B(B0-->ppK(*0)) at the 90% confidence level. A common feature of the observed decay modes is threshold peaking in baryon pair invariant mass.
We report the observation of the decay D0-->phigamma with a statistical significance of 5.4sigma in 78.1 fb(-1) of data collected by the Belle experiment at the KEKB e+e- collider. This is the first observation of a flavor-changing radiative decay of a charmed meson. The Cabibbo- and color-suppressed decays D0-->phipi(0), phieta are also observed for the first time. We measure branching fractions B(D0-->phigamma)=[2.60(+0.70)(-0.61)(stat)+0.15-0.17(syst)] x 10(-5), B(D0-->phipi(0))=[8.01+/-0.26(stat)+/-0.47(syst)] x 10(-4), and B(D0-->phieta)=[1.48+/-0.47(stat)+/-0.09(syst)] x 10(-4).
We report the measurement of an inclusive partial branching fraction for charmless semileptonic B decay and the extraction of /V(ub)/. Candidates for B-->X(u)lnu are identified with a novel X(u) reconstruction method based on neutrino reconstruction via missing 4-momentum and a technique called "simulated annealing." Based on 86.9 fb(-1) of data taken with the Belle detector, we obtain DeltaB(B-->X(u)lnu;M(X)<1.7 GeV/c2,q2>8.0 GeV2/c2)=[7.37+/-0.89(stat)+/-1.12(syst)+/-0.55(b-->c)+/-0.24(b-->u)]x10(-4) and determine |V(ub)|=[4.66+/-0.28(stat)+/-0.35(syst)+/-0.17(b-->c)+/-0.08(b-->u)+/-0.58(theory)]x10(-3).
The radiative decay B-->phi K gamma is observed for the first time. The branching fraction for the charged B--->phi K- gamma decay mode is measured to be B(B--->phi K- gamma)=(3.4+/-0.9+/-0.4)x10(-6). The photon energy distribution for the B--->phi K- gamma decay is presented. The signal for the neutral B(0)-->phi K(0)gamma decay mode is not statistically significant and an upper limit, B(B(0)-->phi K(0)gamma)<8.3x10(-6) at 90% C.L., is set. The analysis is based on a data set of 90 fb(-1) collected by the Belle experiment at the e(+)e(-) asymmetric collider KEKB.
We report the first observation of the charmless hyperonic B decay, B0-->pLambda(pi)(-), using a 78 fb(-1) data sample recorded on the Upsilon(4S) resonance with the Belle detector at KEKB. The measured branching fraction is B(B0-->pLambda(pi)(-))=(3.97(+1.00)(-0.80)+/-0.56)x10(-6). Searches for B0-->pLambda(K)- and pSigma(0)pi(-) yield no significant signals and we set 90% confidence-level upper limits of B(B0-->pLambda(K)-)<8.2x10(-7) and B(B0-->pSigma(0)pi(-))<3.8x10(-6).
Transport system x(c)(-) is a member of plasma membrane heterodimeric amino-acid transporters and consists of two protein components, xCT and 4F2hc. This system mediates cystine entry coupled with the exodus of intracellular glutamate and regulates the intracellular glutathione (GSH) levels in most mammalian cultured cells. We studied the activity of system x(c)(-) and GSH content in human ovarian cancer cell line (A2780) and its cisplatin (CDDP)-resistant variant (A2780DDP). The rate of cystine uptake was approximately 4.5-fold higher in A2780DDP cells than in A2780 cells and the cystine uptake in A2780DDP cells was mediated by system x(c)(-). Intracellular GSH content was much higher in A2780DDP cells but it fell drastically in the presence of excess glutamate, which inhibited the cystine uptake competitively. xCT and 4F2hc mRNAs were definitely expressed in A2780DDP cells, but far less in A2780 cells. Expression of system x(c)(-) activity by transfection with cDNAs for xCT and 4F2hc made A2780 cells more resistant to CDDP. Similar results on the cystine uptake were obtained in human colonic cancer cell lines. These findings suggest that the system x(c)(-) plays an important role in maintaining the higher levels of GSH and consequently in CDDP resistance in cancer cell lines.
Although labile, assay of intact osteocalcin (iOC) is established as the standard assay for evaluating osteoblastic function. The present study examines the clinical usefulness of the newly developed immunoradiometric assay for osteocalcin (OC), which identifies the stable N-terminal midfragment of OC (N-MID OC assay), in hemodialysis (HD) patients. The performance of N-MID OC assay was compared to that of iOC assay in the sera obtained from 137 male HD patients, by comparing these assays with those of other bone metabolic markers and bone loss during a 1-year period before determination of serum markers. Serum N-MID OC values did not decrease significantly during 24 h incubation at room temperature, whereas serum iOC decreased significantly after 1 h incubation. Serum N-MID and iOC in the 137 male HD patients were 197.3 +/- 57.8 and 34.6 +/- 30.0 ng/ml, respectively, or 3.9 +/- 3.1 and 2.8 +/- 2.4 times above the respective reported normal upper limits. Serum N-MID OC correlated significantly in a positive manner with serum iOC (r = 0.934, P < 0.0001). Serum N-MID OC correlated no less significantly in a positive manner with serum levels of bone alkaline phosphatase, deoxypyridinoline, and intact parathyroid hormone compared to serum iOC. Of interest was the fact that serum N-MID OC, but not iOC, correlated significantly with both the amount and the rate of bone loss at the distal radius 1/3. In summary, the findings suggest that N-MID OC immunoreactivity is much more stable than iOC immunoreactivity and that N-MID OC assay may be less susceptible to the OC fragments reported to accumulate in uremic serum. It may, therefore, prove more reliable than iOC assay for evaluating bone turnover, and thus for reflecting bone loss, in HD patients.
AIM/HYPOTHESIS: Although derangements of calcium and phosphate control have been emphasized as important risk factors for vascular calcification in non-diabetic haemodialysis patients, similar risk factors for diabetic haemodialysis patients are not known. We compared factors affecting peripheral vascular calcification between haemodialysis patients with and without diabetes. METHODS: We examined 421 patients on maintenance haemodialysis. There were 89 patients with Type II (non-insulin-dependent) diabetes mellitus (53 men and 36 women, 62+/-10 years old) and 332 patients without diabetes (192 men and 140 women, 59+/-13 years old). Hand roentgenography was carried out, and visible vascular calcification of the hand arteries was evaluated. RESULTS: There were 42 diabetic patients and 45 non-diabetic patients with vascular calcification. The prevalence of vascular calcification in diabetic patients (47.1%) was higher than in non-diabetic patients (13.6%) ( p<0.001). In multivariate logistic regression, the main factors affecting vascular calcification in non-diabetic patients were advanced age, longer duration of haemodialysis, increased phosphate concentrations, male gender, and lower predialysis diastolic pressure. In diabetic patients, predictors for vascular calcification were higher values of HbA(1C) and longer duration of haemodialysis. In diabetic patients, a 1% increase in HbA(1C) increased the risk of calcification by 2.1-fold (95% CI 1.282-3.575, p=0.0029). CONCLUSION/INTERPRETATION: We have shown that poor glycaemic control, rather than calcium and phosphate concentrations, is a predictor of peripheral vascular calcification in diabetic patients on haemodialysis. This study emphasizes that glycaemic control remains critical even in diabetic patients with end-stage renal disease.
AIM: Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes in the Otsuka Long Evans Tokushima Fatty (OLETF) rat strain. To evaluate possible metabolic and pathological improvements generated by correction of the Dmo1 genetic pathway, we produced congenic lines, in which both OLETF Dmo1 alleles are replaced by the F344-derived genome. METHODS: Congenic animals were produced by introgressing F344-derived Dmo1 alleles into the OLETF rat. Congenic animals of the fourth generation (BC4) were intercrossed to obtain F1 animals (BC4:F1). Animals of the next generation, BC4:F2, were used for this study. We used 23 BC4:F2 males harbouring homozygous replacement of the OLETF Dmo1 region with the F344-derived genome. Seven animals with OLETF-derived Dmo1 alleles were used as controls. RESULTS: Dmo1-F344/F344 congenic rats showed significant decreases in body weight, abdominal fat weight, serum triacylglycerols, total cholesterol, food consumption and blood glucose after glucose loading (13%, 39%, 45%, 27%, 18% and 27% respectively; p < 0.05) compared with Dmo1-OLETF/OLETF animals. Furthermore, histopathological analysis of the kidney showed that mesangial sclerosis, hyalin deposits and deposition of PAS-positive substance were significantly lower in Dmo1-F344/F344 animals (p < 0.05). CONCLUSION: Improvements in metabolic parameters and histopathological scores show that correction of the Dmo1 genetic pathway in the diabetic and mildly obese OLETF rat strain produces wide-ranging therapeutic effects. Thus, this pathway might represent a new drug target also applicable to humans.
T-0128 is a novel camptothecin (CPT) analogue (T-2513: 7-ethyl-10-aminopropyloxy-CPT)-carboxymethyl (CM) dextran conjugate via a Gly-Gly-Gly linker, with a molecular weight (MW) of 130 kDa. Our previous studies demonstrated that T-0128 has strong antitumor activity against human tumor xenografts that are highly refractory to CPT analogues attributable to the passive tumor targeting of released T-2513. This study examines the effects of carrier, dose, and tumor on T-0128 pharmacokinetics. To study carrier effect, tumor-bearing rats received one i.v. injection of fluorescein isothiocyanate (FITC)-labeled CM dextran with a different degree of substitution (DS) of the carboxymethylated groups and a different MW. Results showed that CM dextran from Dextran T-110 (MW 110 kDa) with a DS value of 0.4 is an appropriate drug carrier for T-0128 regarding plasma half-life and passive tumor targeting. To study dose and tumor effects, non-tumor- and tumor-bearing rats were treated with T-0128 doses ranging from 1 to 25 mg/kg (based on the amount of T-2513 bound to CM dextran). Dose-dependent pharmacokinetics of T-0128 were observed in both kinds of rats. The presence of tumor reduced the plasma half-life and systemic exposure of T-0128. The saturation of hepatic and splenic tissue uptake clearances (CLups), and a large contribution of the tumor CLup to the total body clearance explain these results. Overall, our data provide a rationale for the selection of the carrier for T-0128 and a need for pharmacokinetic studies to evaluate the influences of tumor on the drug disposition.
We analyzed the relationship between resistance to nadifloxacin, a fluoroquinolone antimicrobial agent, and mutations in the quinolone resistance-determining regions (QRDRs) of the A subunit of DNA gyrase and topoisomerase IV, in 24 clinical isolates of Staphylococcus aureus. Seven known mutations were found in the QRDRs. The minimum inhibitory concentration (MIC) of nadifloxacin increased in a manner that was dependent on mutations in the A subunit of DNA gyrase, and did not appear to be related to mutations in the A subunit of topoisomerase IV. The type 9 mutant, which included four mutations, was highly resistant to ofloxacin, norfloxacin and sparfloxacin, but only moderately resistant to nadifloxacin (MIC, 12.5 microg/ml). One of the norfloxacin-resistant strains that expressed high levels of norA was not resistant to nadifloxacin. To the best of our knowledge, this is the first report describing a fluoroquinolone antimicrobial agent whose primary target is suggested to be DNA gyrase in S. aureus.
We examined regional and intracellular distribution of Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaM-KK beta), which activated Ca(2+)/calmodulin-dependent protein kinase I and IV (CaM-K I and IV) immunohistochemically in the central nervous system of the rat by light and electron microscopy. Although most neurons in the brain and spinal cord exhibited the immunoreactivity, no labeled neurons were observed in the globus pallidus or entopeduncular nucleus, and only a small number of neurons showed weak immunoreactivity in the substantia nigra pars reticulata. In general, the immunoreactivity was observed both in the cytoplasm and cellular nucleus, although the immunoreactivity was not found in the cellular nucleus in some large neurons such as in the mesencephalic trigeminal nucleus, lateral vestibular nucleus or gigant cellular reticular formation. As to motoneurons of the cranial nerve nuclei and the anterior horn of the spinal cord, they revealed the immunoreactivity both in the cytoplasm and nucleus. The reaction product appeared as fine granules in the cytoplasm and nucleus under light microscopy. Electron microscopic observations confirmed that the reaction product was localized mainly on the Golgi apparatus or on the nuclear chromatin. Immunolabeling for antibody against CaM-KK beta was discussed with the distribution of CaM-K I, IV and another CaM-KK, CaM-KK alpha, in the central nervous system.
Whole-genome scans have identified Dmo1 as a major quantitative trait locus (QTL) for obesity and dyslipidaemia in the Otsuka Long Evans Tokushima Fatty (OLETF) rat. We have produced congenic rats for the Dmo1 locus, using marker-assisted speed congenic protocols, enforced by selective removal of other QTL regions (QTL-marker-assisted counterselection), to efficiently transfer chromosomal segments from non-diabetic Fischer 344 (F344) rats into the OLETF background. In the third generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis. We conclude that single-allele correction of an impaired genetic pathway can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.
An Otsuka Long-Evans Tokushima Fatty (OLETF) strain of rat spontaneously developed hyperglycemia, hyperinsulinemia, insulin resistance and mild obesity, which had been studied as animal model for type II diabetes mellitus (T2DM). Recently, we observed that this strain coincidentally developed atypical hyperplasia of the choledocho-pancreatic ductal epithelium with a complete incidence. In an effort to locate genes responsible for this hyperplasia, we prepared 288 backcross progeny from a mating between OLETF rats and BN rats (which do not develop hyperplasia), and performed a genome-wide scan using 207 polymorphic genetic markers. We observed a prominent association of hyperplasia with a region involving a marker locus D14Mit4 (P = 0.00020, Fisher's exact test) and Cckar (the cholecystokinin-A receptor gene; P = 0.00025, Fisher's exact test) which is known to be disrupted in an OLETF strain. Our findings indicated that epithelial hyperplasia of the choledocho-pancreatic duct is associated with a region on rat chromosome 14 around the Cckar gene in an additive fashion with another two susceptible loci, each on chromosome 9 and 7. This implied the possibility that Cckar deficiency could result in a predisposition towards pancreatic duct hyperplasia.
We present two cases of transient abnormal myelopoiesis associated with trisomy 21 that had hypoechoic hepatomegaly during the late fetal period. Fetal chromosomal abnormality and fetal myeloproliferative disorder should be suspected in such cases.
Diabetic bone disease is characterized by low bone turnover resulting from impaired secretion of parathyroid hormone (PTH). However, it was suggested that the difference in duration of hemodialysis (HD) therapy and age of patients between HD patients with and without diabetes mellitus (DM) may be responsible for a significant reduction in serum intact PTH (iPTH) level in HD patients with DM. The present study showed that although such major factors affecting PTH secretion as age, sex, HD duration, and serum calcium, phosphate, and magnesium levels did not differ significantly between HD patients with and without DM, serum iPTH levels were still significantly lower in HD patients with than without DM. Among biochemical markers for bone metabolism, serum levels of intact osteocalcin (iOC) and deoxypyridinoline (DPD) were significantly lower in HD patients with than without DM, whereas serum bone-specific alkaline phosphatase, pyridinoline, and beta-crosslaps did not differ significantly between the two groups of patients. In summary, our findings indicate that PTH secretion may be significantly impaired in HD patients with DM compared with those without DM, and serum iOC and DPD are bone markers sensitive enough to detect low bone turnover in HD patients with DM.