Biomedical subjects

Y Komatsu

Publications and source records attributed to Y Komatsu.

At least 19 recordsLinked to original sources

PubMed2006

Phase I/II study of docetaxel and S-1 in patients with advanced gastric cancer.

The aims of this phase I/II study of docetaxel and S-1 were to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and recommended dose (RD) in the phase I part and to explore the tumour response, survival and safety in the phase II part. Patients with histologically- or cytologically confirmed unresectable or recurrent gastric cancer were eligible. Treatment consisted of intravenous docetaxel on day 1 (starting dose 50 mg m(-2)) and oral S-1 at a fixed dose of 40 mg m(-2) twice daily on days 1-14, every 4 weeks up to six cycles. Nine patients took part in the phase I portion of the study. The MTD of docetaxel was determined to be 50 mg m(-2), with the DLTs of grade 3 infection associated with grade 3 neutropenia and grade 4 neutropenia during S-1 administration. The RD of docetaxel was 40 mg m(-2) in combination with S-1 40 mg m(-2) b.i.d. The efficacy and safety of this regimen was therefore assessed in 46 patients with at least one measurable lesion. The overall response rate and estimated median overall survival were 46% (95% CI, 31-61%) and 14.0 months (8.3-17.3 months), respectively. The most common grade 3/4 toxicity was neutropenia (67% of patients), which was predictable and manageable. This regimen showed promising activity with moderate toxicities in advanced gastric cancer.

Adenocarcinoma↗

PubMed2006

Regulation of SV40 large T-antigen stability by reversible acetylation.

Reversible acetylation on protein lysine residues has been shown to regulate the function of both nuclear proteins such as histones and p53 and cytoplasmic proteins such as alpha-tubulin. To identify novel acetylated proteins, we purified several proteins by the affinity to an anti-acetylated-lysine antibody from cells treated with trichostatin A (TSA). Among the proteins identified, here we report acetylation of the SV40 large T antigen (T-Ag). The acetylation site was determined to be lysine-697, which is located adjacent to the C-terminal Cdc4 phospho-degron (CPD). Overexpression of the CBP acetyltransferase acetylated T-Ag, whereas HDAC1, HDAC3 and SIRT1 bound and deacetylated T-Ag. The acetylation and deacetylation occurred independently of p53, a binding partner of T-Ag, but the acetylation was enhanced in the presence of p53. T-Ag in the cells treated with TSA and NA or the acetylation mimic mutant (K697Q) became unstable in COS-7 cells, suggesting that acetylation regulates stability of T-Ag. Indeed, NIH3T3 cells stably expressing K697Q showed decreased anchorage-independent growth compared with those expressing wild type or the K697R mutant. These results demonstrate that acetylation destabilizes T-Ag and regulates the transforming activity of T-Ag in NIH3T3 cells.

Acetylation↗

PubMed2006

Negative correlation between bone mineral density and TSH receptor antibodies in male patients with untreated Graves' disease.

INTRODUCTION: Although it has been established that hyperthyroidism leads to reduced bone mineral density (BMD), with accelerated bone turnover promoting bone resorption in female patients, there is a dearth of data for male patients with hyperthyroidism. This study evaluated BMD and bone metabolism in male patients with Graves' disease. METHODS: The study included 56 Japanese male patients with newly diagnosed Graves' disease and 34 normal Japanese male control subjects of similar age and body mass index. We used dual energy x-ray absorptiometry to measure BMD at sites with different cortical/cancellous bone ratios (lumbar spine, femoral neck, and distal radius). RESULTS: At the lumbar spine and the distal radius, BMD and T-scores were significantly lower for patients than for controls. At the femoral neck, on the other hand, the same values were relatively, but not significantly, lower in patients than in controls. However, Z-scores at all three sites were significantly lower for patients than for controls. The Z -score at the distal radius of patients was significantly lower than that at their lumbar spine and femoral neck. In addition, Z-score at the distal radius correlated negatively with age, free thyroxine, thyroid stimulating hormone receptor antibodies, thyroid stimulating antibody, and urinary N-terminal telopeptide of type I collagen normalized by creatinine. CONCLUSIONS: These results indicate a high prevalence of cortical bone loss in male patients with Graves' disease, especially elderly patients. We conclude that BMD measurement is crucial in all Graves' disease patients regardless of their gender and that the radial BMD as well as BMD at the lumbar spine and femoral neck should be monitored to effectively prevent bone loss and subsequent fracture.

Adult↗

PubMed2006

High-rate pulmonary involvement in autoimmune pancreatitis.

Autoimmune pancreatitis (AIP) has extrapancreatic complications such as Sjögren's syndrome, retroperitoneal fibrosis and sclerosing cholangitis. We studied 30 patients with AIP. Of these, we identified pulmonary involvement in four patients during follow up. Among them, two patients had respiratory failure. They showed good response to steroid therapy, but a higher dose of prednisolone was necessary to maintain remission than that required in biliary involvement. Elevation of immunoglobulin G(4) and Krebs von den Lungen-6 levels were characteristic of pulmonary involvement. They may be useful for early detection of pulmonary complication.

Aged↗

PubMed2006

Gene expression profiling of primate neocortex: molecular neuroanatomy of cortical areas.

One hundred years have passed since Brodmann's mapping of the mammalian neocortex. Solely on the basis of morphological observations, he envisaged the conservation and differentiation of cortical areal structures across various species. We now know that neurochemical, connectional and functional heterogeneity of the neocortex accompanies the morphological divergence observed in such cytoarchitectonic studies. Nevertheless, we are yet far from fully understanding the biological significance of this cortical heterogeneity. In this article, we review our past works on the gene expression profiling of the postnatal primate cortical areas, by quantitative real-time polymerase chain reaction (PCR), DNA array, differential display PCR and in situ hybridization analyses. These studies revealed both the overall homogeneity of gene expression across different cortical areas and the presence of a small number of genes that show markedly area-specific expression patterns. In situ hybridization showed that, among such genes, occ1 and retinol-binding protein (RBP) mRNAs are selectively expressed in the neuronal populations that seem to be involved in distinct neural processing such as sensory reception (for occ1) and associative function (for RBP). Such a molecular neuroanatomical approach has the promise to provide an important link between structure and function of the cerebral cortex.

Animals↗

PubMed2005

Interleukin-6 (IL-6)--373 A9T11 allele is associated with reduced susceptibility to chronic periodontitis in Japanese subjects and decreased serum IL-6 level.

We investigated whether interleukin-6 (IL-6) gene polymorphisms could be associated with chronic periodontitis (CP) and serum IL-6 level. One hundred and twelve CP and 77 non-CP Japanese subjects were analyzed for IL-6 -597 (G/A), -572 (C/G), -373 (A(n)T(m)), -190 (C/T), and -174 (G/C) polymorphisms. We could only detect -572 and -373 polymorphisms and found that the frequency and carriage rate of the -373 A9T11 allele were significantly higher in non-CP subjects. Enzyme-linked immunosorbent assay confirmed that the -572 and -373 G[A9T11] haplotypes were associated with lower serum IL-6 level. These findings suggest that IL-6 -373 A9T11 allele could be associated with reduced susceptibility to CP among Japanese subjects and decreased serum IL-6 level.

Alleles↗

PubMed2005

Extrahepatic biliary obstruction after percutaneous tumour ablation for hepatocellular carcinoma: aetiology and successful treatment with endoscopic papillary balloon dilatation.

BACKGROUND AND AIMS: Percutaneous tumour ablation (PTA), such as ethanol injection and radiofrequency ablation, is now recognised as a primary treatment for hepatocellular carcinoma (HCC). Although PTA is a relatively safe procedure, it can cause biliary obstruction as a rare complication. As patients with cirrhosis undergoing surgery or endoscopic retrograde cholangiopancreatography/sphincterotomy have a high mortality rate from bleeding, we adopted the use of endoscopic papillary balloon dilatation (EPBD) in these patients and now report the results. We retrospectively analysed the incidence of biliary obstruction after PTA and the efficacy of treatment with EPBD. PATIENTS AND METHODS: A total of 1043 patients with HCC were treated by PTA, of whom 538 were treated with transarterial embolisation with up to eight years of follow up. RESULTS: There were 17 (1.6%) cases of hilar obstruction due to tumour progression and 35 (3.4%) cases of extrahepatic obstruction. Apart from the expected causes of biliary obstruction (haemobilia n = 11, gallstones n = 11, and three miscellaneous causes), we found that 10 patients had obstruction due to biliary casts. This is the first description of biliary casts after percutaneous tumour ablation therapy. Extrahepatic biliary obstruction by procedure related haemobilia occurred within three days of PTA while other causes occurred between 0 and 17 (average 4.9) months. Biliary casts occurred more frequently after ethanol injection than after radiofrequency ablation. EPBD successfully dissipated biliary obstruction in 33 of 35 cases, while two died due to hepatic failure despite successful drainage. CONCLUSIONS: Extrahepatic biliary obstruction is an uncommon complication after PTA for HCC, and can be safely and effectively treated with EPBD, despite impaired liver function.

Adult↗

PubMed2005

Treatment of a Gilbert's syndrome patient with irinotecan, leucovorin and 5-fluorouracil.

The patient was an elderly male who had radical surgery for sigmoid cancer in 2001. Owing to metastasis of his cancer to the left supraclavicular lymph nodes in 2002, the patient was admitted to our hospital for systemic chemotherapy. We started treatment with irinotecan, leucovorin, 5-fluorouracil (IFL). After administering 100 mg/m2 of irinotecan, 250 mg/m2 leucovorin and 600 mg/m2 5-fluorouracil to the patient on day 1, grade 3 leukopenia developed rapidly and grade 4 thrombocytopenia was observed on day 5. We excluded irinotecan from the medication and continued the administration of 5-fluorouracil and leucovorin, but his tumors had not been reduced sufficiently. Based on some examination results, we assumed that the patient had Gilbert's syndrome and that the severe side effects that occurred were due to prolongation of SN38 metabolism. We again administered irinotecan but at reduced dose (25 mg/m2). Four courses of this modified IFL were administered safely and the response was favorable.

Aged↗

PubMed2004

Decreased bone mineral density at the distal radius, but not at the lumbar spine or the femoral neck, in Japanese type 2 diabetic patients.

The purpose of this study is to assess the association between type 2 diabetes and bone mineral density. This study included 145 Japanese patients (64 men and 81 women) with type 2 diabetes and 95 non-diabetic control subjects (41 men and 54 women) of similar age. We measured bone mineral density (BMD) at the sites with different cortical/cancellous bone ratio (lumbar spine, femoral neck, and distal radius) using dual-energy X-ray absorptiometry. BMD and Z score at the distal radius were significantly lower in type 2 diabetic patients than those in control subjects, and in type 2 diabetic patients, the Z score at the distal radius was lower than that at their own lumbar spine and femoral neck. In type 2 diabetic patients, negative correlation between BMD and the mean HbA1c during the previous 2 years was found significantly at the distal radius in both genders and at the femoral neck in women. These results indicate the selective cortical bone loss in type 2 diabetes and suggest the importance of also determining BMD at the radius and keeping good metabolic control to prevent bone loss in type 2 diabetic patients.

Absorptiometry, Photon↗

PubMed2004

Polymorphisms in the IL-6 receptor (IL-6R) gene: strong evidence that serum levels of soluble IL-6R are genetically influenced.

We have investigated the association of the recently identified IL6R polymorphisms with the serum levels of soluble IL-6 receptor (sIL-6R). sIL-6R is generated by shedding of the membrane-bound receptor (IL-6Ralpha) or alternative mRNA splicing. In total, 115 healthy volunteers were genotyped, with 70 of them analyzed for sIL-6R levels. Using the PCR/RFLP methods, two important polymorphic sites were selected for genotyping: the 48892A/C (D358A) in exon 9 and the -183G/A in the promoter region. In exon 9, C allele carriers had higher sIL-6R level (P<0.0001) showing that this sequence variation, which corresponds to the proteolytic cleavage site of IL-6Ralpha, strongly influences the serum sIL-6R levels. In the promoter region, G allele carriers had lower sIL-6R levels (P<0.0082) compared with the A allele carriers. This could be attributed to the linkage disequilibrium (D'=0.54, chi2=51.3, P<0.0001) between the -183G/A and the 48892A/C gene polymorphisms.

Adult↗

PubMed2004

A prospective randomised study of "covered" versus "uncovered" diamond stents for the management of distal malignant biliary obstruction.

BACKGROUND AND AIM: Covered self-expandable metal stents (EMS) were recently developed to overcome tumour ingrowth in conventional EMS. However, supporting evidence for the efficacy of covered EMS is lacking. PATIENTS AND METHODS: We enrolled 112 patients with unresectable distal biliary malignancies. They were randomly assigned to polyurethane covered (n = 57) or original diamond stent (n = 55). RESULTS: Stent occlusion occurred in eight patients (14%) after a mean of 304 days in the covered group, and in 21 patients (38%) after a mean of 166 days in the uncovered group. The incidence of covered EMS occlusion was significantly lower than that of uncovered EMS (p = 0.0032). The cumulative stent patency of covered stents was significantly higher than that of uncovered stents (p = 0.0066). No tumour ingrowth occurred in the covered group while it was observed in 15 patients in the uncovered group. In subgroup analysis, the cumulative patency of the covered EMS was significantly higher in pancreatic cancer (p = 0.0363) and metastatic lymph nodes (p = 0.0354). There was no significant difference in survival between the two groups. Acute cholecystitis was observed in two of the covered group and in none of the uncovered group. Mild pancreatitis occurred in five of the covered group and in one of the uncovered group. CONCLUSIONS: Covered diamond stents successfully prevented tumour ingrowth and were significantly superior to uncovered stents for the treatment of patients with distal malignant biliary obstruction. However, careful attention must be paid to complications specific to covered self-expandable metal stents, such as acute cholecystitis and pancreatitis.

Acute Disease↗

PubMed2003

Yeast pheromone signaling pathway as a bioassay to assess the effect of chemicals on mammalian peptide hormones.

The intercellular pheromone signal transduction pathways involved in sexual reproduction in the yeast Saccharomyces cerevisiae constitute an extracellular network system involving cell surface receptors. The system is analogous to the signaling pathway of mammalian peptide hormones. The yeast mating pheromone alpha factor is homologous to mammalian gonadoliberins such as luteinizing hormone-releasing hormone (LHRH). In this study, we used the yeast pheromone signaling pathway as a model system to evaluate the effect of industrial chemicals on mammalian peptide hormones. Haploid a- and alpha-cell types conjugate, using mating pheromones, to form diploid cells. However, in a cells treated with certain chemicals used in pesticides, fungicides, and industrial products (i.e., TPN (CAS No. 1897-45-6), thiuram (CAS No. 137-26-8), captan (CAS No. 133-06-2), oxine-copper (CAS No. 10380-28-6), zineb (CAS No. 12122-67-7), and ziram (CAS No. 137-30-4)) the induction of shmoo formation was suppressed even when commercial alpha-factor was added. The FUS1-lacZ gene, which is transcriptionally regulated by a pheromone, was transferred into yeast and the effects of TPN, captan, zineb, and ziram, under sublethal conditions, were investigated: beta-Galactosidase levels declined to levels similar to that of untreated control cells when in the absence of the alpha-factor. Furthermore, these chemicals influenced conjugation to alpha-cells, and mating efficiency declined as chemical concentration increased. Analysis of the yeast pheromone signaling pathway helps to establish chemical toxicity assay models for mammalian peptide signal transduction pathways.

Animals↗

PubMed2003

Awakenings from persistent vegetative state: report of three cases with parkinsonism and brain stem lesions on MRI.

Three patients with a persistent vegetative state after severe head injury are reported. They recovered from a prolonged disturbance of consciousness after the administration of levodopa. These patients all had parkinsonian features. On magnetic resonance imaging, the distribution of lesions implied a diffuse axonal injury involving the substantia nigra or ventral tegmental area. The existence of patients whose dopaminergic systems may have been selectively damaged by a severe head injury should be recognised because such individuals may respond to levodopa treatment.

Adolescent↗

PubMed2002

Mosapride, a 5HT-4 receptor agonist, improves insulin sensitivity and glycaemic control in patients with Type II diabetes mellitus.

AIMS/HYPOTHESIS: We investigated the potential role of mosapride, a 5HT-4 receptor agonist, in glycaemic control in Type II (non-insulin-dependent) diabetic mellitus patients without autonomic neuropathy. METHODS: Thirty-four inpatients with Type II diabetes mellitus were randomly assigned to receive either mosapride (5 mg orally three times a day, n=17) or a placebo ( n=17) for 1 week (first study). Changes in blood glucose and insulin were determined basally as well as after intravenous glucose loading. Insulin sensitivity was evaluated during hyperinsulinaemic-normoglycaemic-clamp studies and by measuring the number of and the autophosphorylation of insulin receptors on the erythrocytes of patients ( n=9). Sixty-nine outpatients with Type II diabetes were similarly treated with mosapride or a placebo for 8 weeks (second study). Finally, tissue- specific expression of 5HT-4 receptors was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Mosapride lowered fasting blood glucose and fructosamine concentrations ( p<0.05) (first study). It significantly increased the number of (Mosapride 3323+/-518 vs 4481+/-786 [ p<0.05], Control 4227+/-761 vs 3275+/-554 per 300 microl erythrocytes) and the tyrosine autophosphorylation (Mosapride 3178+/-444 vs 4043+/-651 [ p<0.05], Control 3721+/-729 vs 3013+/-511 insulin receptor unit) of insulin receptors, as well as glucose utilisation (Mosapride 4.92+/-0.53 vs 5.88+/-0.72 [ p<0.05], Control 4.74+/-0.65 vs 4.70+/-0.31 mg/kg x min). Mosapride treatment for 8 weeks significantly reduced fasting glucose (9.91+/-0.34 vs 8.51+/-0.34 mmol/l, p<0.05), insulin (53.2+/-4.62 vs 40.8+/-5.52 pmol/l, p<0.05) and HbA(1c) (8.61+/-0.20 vs 7.67+/-0.19%, p<0.01) concentrations (second study). The RT-PCR analysis demonstrated specific expression of 5HT-4 receptors in the muscle, but not in the liver or fat tissues. CONCLUSIONS/INTERPRETATION: Mosapride could improve insulin action at muscle and glycaemic control in Type II diabetic patients.

Base Sequence↗

PubMed2002

Classification of abomasal displacement in cows according to histopathology of the liver and clinical chemistry.

Histopathological features of livers and blood chemical values in cows with abomasal displacement were investigated. Liver biopsy samples were collected during redressment operations in 92 cows with abomasal displacement, and the samples were stained with haematoxylin and eosin or periodic acid Schiff (PAS). Blood was collected for chemical tests. Livers were histopathologically divided into the following four types: normal histology cases (21%), fatty degeneration cases (36%), cloudy swelling cases (19%) and fatty degeneration cases with cloudy swelling (24%). The number of PAS-positive samples was significantly higher in the normal histology group and significantly lower in the severe fatty degeneration group and severe cloudy swelling group. Cows with fatty degeneration had significantly higher levels of serum 3-hydroxybutyric acid, non-esterified fatty acid and aspartate aminotransferase than did those with cloudy swelling or normal histology. The results indicate that the morbid conditions of cows with abomasal displacement can be classified into four types.

3-Hydroxybutyric Acid↗

PubMed2002

The relationship between consumption of antimicrobial agents and the prevalence of primary Helicobacter pylori resistance.

BACKGROUND: Primary and acquired resistance to the antimicrobial agents is a primary reason for the failure of Helicobacter pylori eradication therapies. We assessed the primary antibiotic resistance rates of H. pylori to three different antibiotics and its relationship due to the annual antibiotic consumption in Japan during the period prior to approval of anti-H. pylori therapy in Japan. MATERIALS AND METHODS: Antibiotic susceptibility was tested using the agar dilution method for clarithromycin, amoxicillin and metronidazole. Isolates were considered resistant when the MIC value was > 8 mg/l for metronidazole, > 1 mg/l for clarithromycin and < 0.5 mg/l for amoxicillin. RESULTS: Helicobacter pylori isolates were obtained from 593 Japanese patients from 1995 to 2000. Primary resistance of H. pylori to clarithromycin, metronidazole and amoxicillin was found in 11%, 9% and 0.3% strains, respectively. The proportion with clarithromycin resistance significantly increased from 7% in 1997-98 to 15.2% in 1999-2000 (p =.003). During the same period the metronidazole resistance rate also increased from 6.6% in 1997-98 to 12% in 1999-2000 (p =.02). The prevalence of clarithromycin and metronidazole was related to the annual consumption of these antimicrobial agents. CONCLUSION: Resistance rates for both clarithromycin and metronidazole appear to reflect the annual consumption of these agents. The high rate of clarithromycin resistance in Japan suggests that the effectiveness of clarithromycin-based therapies may be compromised in the near future.

Anti-Bacterial Agents↗

PubMed2001

Changes in cortical noradrenergic axon terminals of locus coeruleus neurons in aged F344 rats.

The noradrenergic innervations and noradrenaline contents of the frontal cortex in two age groups (9 and 25 months) of male F344 rats have been quantified by electrophysiological and biochemical methods. In the electrophysiological study, the percentage of locus coeruleus (LC) neurons activated antidromically from the frontal cortex decreased with age. In contrast, the percentage of LC neurons showing multiple antidromic latencies, which suggests axonal branching of individual LC neurons, increased markedly between 9 and 25 months in the frontal cortex. In the biochemical study, we found no significant difference in noradrenaline levels in the cortical terminal fields of LC neurons during aging. These results suggest that LC neurons give rise to axonal branches to retain noradrenaline levels in their target fields in the aged brain. Our findings show that LC neurons preserve a strong capability for remodeling their axon terminals even in the aged brain.

Aging↗

PubMed2001

Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity.

Cyclic hydroxamic-acid-containing peptide 1 (CHAP1), designed as a hybrid of trichostatin A and trapoxin, is a lead compound for the development of potent inhibitors of histone deacetylase (HDAC). In this study, we synthesized a series of CHAP derivatives and evaluated their biological activities by monitoring the potency of their inhibition of HDAC activity, their ability to augment the expression of MHC class-I molecules in B16/BL6 cells, and their effect on cell proliferation. A structure-activity relationship study using these three assay systems revealed several requirements of their structure for the strong inhibition of HDAC not only in the cell-free situation, but also in cells. When the structures of CHAP derivatives are represented as cyclo(-Asu(NHOH)-AA(2)-AA(3)-Pro or Pip-)(n), where Asu(NHOH) and Pip are zeta-hydroxamide-alpha-aminosuberic acid and pipecolic acid, respectively, (a) the tetrapeptide structure (n = 1) was better than the octapeptide one (n = 2); (b) AA(2) and AA(3) should be hydrophobic; and (c) the combination of amino acid chirality should be LDLD for the strongest inhibition of HDAC in cells (LDLD > LLLD, LDLL > LLDL). cyclo(-L-Asu(NHOH)-D-Tyr(Me)-L-Ile-D-Pro-) or CHAP31 was selected as one of the strongest CHAPs, and its biological activity was characterized further. CHAP31 was much more stable in the presence of cultured cells (t(1/2) > 3000 h) than trichostatin A (t(1/2) = 14.7 h) or trapoxin A (t(1/2) = 2.10 h). CHAP31 exhibited antitumor activity in C57BL x DBA/2 F(1) (BD2F(1)) mice bearing B16/BL6 tumor cells. Furthermore, CHAP31 inhibited the growth in four of five human tumor lines implanted into nude mice. These results suggest CHAP31 to be promising as a novel therapeutic agent for cancer treatment.

Animals↗