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Biomedical subjects

Hiroyuki Kobayashi

Publications and source records attributed to Hiroyuki Kobayashi.

At least 55 records · Page 3Linked to original sources
PubMed2005

Acute treatment with morphine augments the expression of serine racemase and D-amino acid oxidase mRNAs in rat brain.

To obtain further insight into the interactions between the N-methyl-D-aspartate receptor and opioid receptor systems, we have investigated the effects of the acute treatment of morphine on the expression of serine racemase and D-amino acid oxidase mRNAs in several brain areas of rats. The morphine administration produced a dose-dependent and transient elevation in the levels of serine racemase and D-amino acid oxidase mRNAs in all the brain areas. The present results are the first to suggest an interaction between the expression of the mRNAs for the D-serine-related enzymes and the opioid receptor activation.

Analgesics, Opioid↗
PubMed2005

Intercellular adhesion molecule (ICAM-1) response after major neonatal surgery.

Surgical stress induces systemic endocrine-metabolic responses that influence the function of endothelial cells (EC) to cause various systemic reactions. Intercellular adhesion molecule (ICAM)-1 is an adhesion molecule that plays an important role in inflammation, and increased expression of ICAM-1 on EC is a reflection of EC activation. In this study, we investigated the ICAM-1 response to surgical stress in neonates undergoing major surgery. Fifteen neonates (mean age at surgery: 3.5 +/- 1.2 days) were divided into two groups according to indications for surgery: Group I: Congenital diaphragmatic hernia without persistent pulmonary hypertension (n = 5); Group II: Gastrointestinal surgery [n = 10: duodenal atresia (n = 3), intestinal atresia (n = 6), and esophageal atresia (n = 1)]. Serum samples were obtained preoperatively, immediately after completion of surgery (time zero), and 24, 48, 72, 96, and 120 h after surgery to measure ICAM-1 levels using an enzyme-linked immunosorbent assay, C-reactive protein (CRP), and white blood cell count (WBC). Postoperative recovery was uneventful in all cases. ICAM-1 levels in both groups increased significantly within 24 h of surgery (Group I: P = 0.0038, Group II: P = 0.0320). In Group I, ICAM-1 peaked 72 h postoperatively while in Group II it continued to rise until 96 h postoperatively. The difference between peak levels reached was not significant. CRP was first detected 24 h postoperatively in both groups and continued to increase until 48 h postoperatively. Again, the difference between peak levels reached was not significant. No significant changes in WBC were observed in either group. We found that ICAM-1 increases in response to surgical stress in neonates, although there was no significant difference in levels. However, surgical stress as represented by serum ICAM-1 would appear to last longer with intestinal surgery than with non-intestinal surgery. Further research is required to establish the usefulness of ICAM-1 as an easily detectable substance associated with endothelial damage that reflects the host's response to major surgical stress.

Biomarkers↗
PubMed2005

Close association of Chlamydia pneumoniae IgA seropositivity by ELISA with the presence of coronary artery stenosis in haemodialysis patients.

BACKGROUND: Traditional risk factors of cardiovascular disease do not fully explain the accelerated atherosclerosis present in patients with end-stage renal disease (ESRD). The goal of this study was to identify the association of clinical and laboratory factors including seropositivity for Chlamydia pneumoniae determined by a specific enzyme-linked immunosorbent assay (ELISA) with the presence of coronary artery disease identified by coronary angiography in ESRD patients. METHODS: We prospectively enrolled 161 consecutive ESRD patients undergoing haemodialysis for >6 months (106 men, 55 women; mean age 63.1+/-10.2 years; mean dialysis duration 91.3+/-90.1 months). All patients underwent coronary angiography within 1 week after blood sampling. The associations of coronary artery disease with clinical parameters including C. pneumoniae IgA and IgG seropositivity were analysed using multiple logistic regression models. RESULTS: Coronary stenosis >50% was found in 102 of 161 haemodialysis patients (63.4%). Of the 102 patients, 75.5% were asymptomatic. Seropositivity for C. pneumoniae IgA was found in patients with coronary stenosis (77 out of 102, 75.5%) more frequently (P<0.001) than in patients without coronary stenosis (10 out of 59, 16.9%). Seropositivity for C. pneumoniae IgA but not IgG was strongly associated with the presence of coronary stenosis in multiple logistic regression analysis (odds ratio, 18.440; 95% confidence interval, 7.500-45.337), independently of the Framingham coronary risk factors, factors peculiar to ESRD or serum C-reactive protein levels. CONCLUSIONS: C. pneumoniae IgA seropositivity determined by ELISA is an independent laboratory factor indicating the presence of coronary artery stenosis in ESRD patients undergoing maintenance haemodialysis.

Aged↗
PubMed2005

Caveolae-independent activation of protein kinase A in rat neonatal myocytes.

Cardiomyocytes express both beta(1)- and beta(2)-adrenergic receptors, and these receptors play a differential role in chronotropic and inotropic effects of the heart. Caveolae are known as an important regulator of G-protein-coupled receptor signaling. In the present report, we examined whether caveolae have a role in beta-adrenergic receptor-stimulated cAMP production and protein kinase A activation in neonatal myocytes. Isoproterenol-stimulated cAMP production was mediated by beta(1)- and beta(2)-subtypes, which depends on the receptor number of each subtype. However, protein kinase A activation was exclusively mediated by the beta(1)-subtype. Disruption of caveolae by methyl-beta-cyclodextrin treatment did not affect the relative contribution of subtypes to isoproterenol-stimulated cAMP production. beta(1)-Subtype-mediated protein kinase A activation was also not affected by the disruption of caveolae. These results suggest that beta(1)-adrenergic receptor-mediated protein kinase A activation is compartmentalized and independent of caveolae.

Adrenergic beta-Agonists↗
PubMed2005

Safety and pharmacokinetic study of RPI.4610 (ANGIOZYME), an anti-VEGFR-1 ribozyme, in combination with carboplatin and paclitaxel in patients with advanced solid tumors.

PURPOSE: RPI.4610 (ANGIOZYME) is a chemically stabilized ribozyme targeting vascular endothelial growth factor receptor 1. The purpose of this study was to evaluate the safety and pharmacokinetics of RPI.4610 in combination with carboplatin and paclitaxel in patients with advanced solid tumors. METHODS: The study used a sequential treatment design evaluating a single dose level for all three drugs: paclitaxel 175 mg m-2 and carboplatin AUC=6 on day 1 of a 21-day cycle, and RPI.4610 100 mg m-2 day-1 beginning on day 8 and continuing daily thereafter. Pharmacokinetic samples were drawn on day 1 of courses 1 (chemotherapy alone) and 2 (chemotherapy+RPI.4610), and on day 8 of course 1 (RPI.4610 alone). Ratios were generated by comparing the pharmacokinetic parameters for the combination of carboplatin with paclitaxel when administered alone or together with RPI.4610. RESULTS: Twelve patients were enrolled in this trial and received two to six courses of treatment each. The most common grade 3-4 toxicities were neutropenia (three patients), thrombocytopenia (three patients), pain (three patients), anemia (two patients) and fatigue (two patients). The ratio of the mean maximum plasma concentration (Cmax) for carboplatin when administered with paclitaxel alone versus when administered with paclitaxel and RPI.4610 was 1.07 (90% confidence interval, 0.77-1.37). Similarly, the ratio of the mean AUC0-last for carboplatin was 1.04 (0.73-1.35). For paclitaxel the ratio of the mean Cmax when administered with carboplatin alone versus with carboplatin and RPI.4610 was 1.17 (1.03-1.31), and the ratio of the mean AUC0-last was 1.17 (1.04-1.30). Objective tumor responses were observed and included one patient with a complete response (bladder cancer) and one patient with a partial response (esophageal cancer). CONCLUSIONS: These results indicate that RPI.4610, carboplatin, and paclitaxel can be administered safely in combination without substantial pharmacokinetic interactions.

Adult↗
PubMed2005

Galpha12/13-mediated production of reactive oxygen species is critical for angiotensin receptor-induced NFAT activation in cardiac fibroblasts.

Angiotensin II (Ang II) activates multiple signaling pathways leading to hyperplasia of cardiac fibroblasts. Reactive oxygen species (ROS) produced by Ang II stimulation are assumed to play pivotal roles in this process. Here, we show that ROS mediate Ang II-induced activation of nuclear factor of activated T cells (NFAT) in rat cardiac fibroblasts. Ang II-induced NFAT activation was suppressed by diphenyleneiodonium (an NADPH oxidase inhibitor), dominant negative (DN)-Rac, DN-p47(phox), and an inhibitor of Galpha(12/13) (Galpha(12/13)-specific regulator of G protein signaling domain of p115RhoGEF, p115-regulator of G protein signaling (RGS)). Stimulation of Ang II receptor increased the intracellular ROS level in a Rac- and p47(phox)-dependent manner. Because p115-RGS suppressed Ang II-induced Rac activation, Ang II receptor-coupled Galpha(12/13) mediated NFAT activation through ROS production by Rac activation. Ang II-induced nuclear translocation of the green fluorescent protein (GFP)-tagged amino-terminal region of NFAT4 (GFP-NFAT4) was suppressed by p115-RGS or BAPTA but not by diphenyleneiodonium. The expression of constitutively active (CA)-Galpha(12/13), CA-G translocation alpha(13), or CA-Rac increased the nuclear of GFP-NFAT4. These results suggest that NFAT activity is regulated by both Ca(2+)-dependent and ROS-dependent pathways. Furthermore, activation of c-Jun NH(2)-terminal kinase (JNK) induced by Ang II stimulation is required for NFAT activation because Ang II-induced NFAT activation was inhibited by SP600125, a selective JNK inhibitor. These results indicate that Ang II stimulates the nuclear translocation and activation of NFAT by integrated pathways including the activation of Galpha(12/13), Rac, NADPH oxidase, and JNK and that Galpha(12/13)-mediated ROS production is essential for NFAT transcriptional activation.

Active Transport, Cell Nucleus↗
PubMed2005

G alpha 12/13- and reactive oxygen species-dependent activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase by angiotensin receptor stimulation in rat neonatal cardiomyocytes.

In the present study, we examined signal transduction mechanism of reactive oxygen species (ROS) production and the role of ROS in angiotensin II-induced activation of mitogen-activated protein kinases (MAPKs) in rat neonatal cardiomyocytes. Among three MAPKs, c-Jun NH(2)-terminal kinase (JNK) and p38 MAPK required ROS production for activation, as an NADPH oxidase inhibitor, diphenyleneiodonium, inhibited the activation. The angiotensin II-induced activation of JNK and p38 MAPK was also inhibited by the expression of the Galpha(12/13)-specific regulator of G protein signaling (RGS) domain, a specific inhibitor of Galpha(12/13), but not by an RGS domain specific for Galpha(q). Constitutively active Galpha(12)- or Galpha(13)-induced activation of JNK and p38 MAPK, but not extracellular signal-regulated kinase (ERK), was inhibited by diphenyleneiodonium. Angiotensin II receptor stimulation rapidly activated Galpha(13), which was completely inhibited by the Galpha(12/13)-specific RGS domain. Furthermore, the Galpha(12/13)-specific but not the Galpha(q)-specific RGS domain inhibited angiotensin II-induced ROS production. Dominant negative Rac inhibited angiotensin II-stimulated ROS production, JNK activation, and p38 MAPK activation but did not affect ERK activation. Rac activation was mediated by Rho and Rho kinase, because Rac activation was inhibited by C3 toxin and a Rho kinase inhibitor, Y27632. Furthermore, angiotensin II-induced Rho activation was inhibited by Galpha(12/13)-specific RGS domain but not dominant negative Rac. An inhibitor of epidermal growth factor receptor kinase AG1478 did not affect angiotensin II-induced JNK activation cascade. These results suggest that Galpha(12/13)-mediated ROS production through Rho and Rac is essential for JNK and p38 MAPK activation.

Angiotensin Receptor Antagonists↗
PubMed2005

Long-term outcome of bladder augmentation using living-related partial bladder transplantation in rats.

Long-term histopathologic changes after bladder augmentation (BA) in rats using living-related partial bladder transplantation (LPBTx) or conventional ileocystoplasty (ICP) were compared. In this study, BA (n = 37), LPBTx (n = 18), and ICP (n = 19) were performed in 16-wk-old Lewis rats. Five donors and seven nontransplanted normal Lewis rats (controls) were also studied. Rats that survived >10 mo after BA were killed after blood biochemistry and neobladder imaging. Harvested bladders were examined with hematoxylin and eosin and proliferating cell nuclear antigen (PCNA). When the rats were killed, there were 16 rats in the LPBTx group and 12 rats in the ICP group; ICP rats were significantly smaller than LPBTx rats (p < 0.05). Mean duration of follow-up for the LPBTX group was 17.3 mo, for the ICP group was 13.7 mo, for the donor group was 16.1 mo, and for the control group was 19.7 mo. Mean serum pH in the LPBTx group was 7.41 +/- 0.78 and in the ICP group was 7.25 +/- 0.38. Mean base excess in the ICP group was significantly lower than in the LPBTx group (p < 0.05). Incidence of bladder calculi in the LPBTx group (6.3%) was significantly lower than in the ICP group (33.3%; p < 0.05). There was no dysplasia/malignancy/increase in PCNA in the LPBTx group. PCNA increased in the ICP group, compared with controls (p < 0.05); two (16.7%) of 12 of ICP rats had dysplasia with mitosis. Bladder capacity increased in LPBTx and ICP compared with controls (both p < 0.05). We hope to show that BA using LPBTx may result in a neobladder with fewer complications than BA using ICP; LPBTx may also decrease the risk for malignancy.

Anastomosis, Surgical↗
PubMed2005

Beta-arrestin2 enhances beta2-adrenergic receptor-mediated nuclear translocation of ERK.

Beta-arrestin mediates desensitization and internalization of beta-adrenergic receptors (betaARs), but also acts as a scaffold protein in extracellular signal-regulated kinase (ERK) cascade. Thus, we have examined the role of beta-arrestin2 in the betaAR-mediated ERK signaling pathways. Isoproterenol stimulation equally activated cytoplasmic and nuclear ERK in COS-7 cells expressing beta1AR or beta2AR. However, the activity of nuclear ERK was enhanced by co-expression of beta-arrestin2 in beta2AR-but not beta1AR-expressing cells. Pertussis toxin treatment and blockade of Gbetagamma action inhibited beta-arrestin2-enhanced nuclear activation of ERK, suggesting that beta-arrestin2 promotes nuclear ERK localization in a Gbetagamma dependent mechanism upon receptor stimulation. beta2AR containing the carboxyl terminal region of beta1AR lost the beta-arrestin2-promoted nuclear translocation. As the carboxyl terminal region is important for beta-arrestin binding, these results demonstrate that recruitment of beta-arrestin2 to carboxyl terminal region of beta2AR is important for ERK localization to the nucleus.

Animals↗
PubMed2005

A case of rectal atresia associated with recto-bulbar urethral fistula.

Rectal atresia is a rare condition in which the anus and sphincter muscles are normally developed, with usually no fistulous communication with the urinary tract. An unusual case of rectal atresia associated with recto-bulbar urethral fistula treated by a combination of colo-anal anastomosis and mucosal proctectomy via a posterior sagittal approach is reported for the first time.

Colostomy↗
PubMed2005

New pancreas-preserving total duodenectomy technique.

Pancreas-preserving total duodenectomy (PPTD) was first described by Chung et al. in 1994. Since then, several surgeons have used PPTD to treat diseases that involve the duodenum diffusely but not the head of the pancreas, mostly familial adenomatous polyposis (FAP). The PPTD method has been changed in each report and seems to have improved over time. We performed PPTD on three patients with different diseases--one with intestinal hemorrhage due to small intestinal amyloidosis; another with numerous duodenal gastrinomas in a patient with multiple endocrine neoplasia type 1 (MEN-1) and Zollinger-Ellison syndrome (ZES); and the third with numerous duodenal polyposis and FAP--using a new method that is simpler and safer than those previously reported. When resecting the whole duodenum, we performed mucosectomy of the major papillar portion and saved the structure of the major papilla. After an approximately 8 mm long sphincteropapillotomy, the opened major papilla was anastomosed to an incisional opening of the small intestine. The orifice of the main pancreatic duct (MPD) was stented by a catheter, and the MPD was kept intact under direct vision during the operative procedures. The head of the pancreas was fixed with the small intestine by interrupted 4-0 silk sutures. Reconstruction of the alimentary tract was performed after either the Billroth I or the Billroth II method. This is the first report of PPTD in which the entire MPD was preserved to simplify the biliopancreatic-ductal reconstruction.

Adenomatous Polyposis Coli↗
PubMed2005

Impact of reconstruction methods on outcome of pancreatoduodenectomy in pancreatic cancer patients.

Local recurrence is one of the most frequent forms of pancreatic cancer recurrence, although local recurrence is rare for other periampullary cancers. Because the type of recurrence and outcome differ depending on the type of cancer, these factors should be considered when the type of reconstruction is chosen. Fifty-four pancreatoduodenectomies were performed in patients with ductal adenocarcinoma of the pancreas from 1994 to 2001. Billroth I reconstruction was performed in 27 consecutive patients before 1999, and thereafter Billroth II reconstruction was performed in another consecutive 27 patients. Postoperative nasogastric intubation and the duration before oral ingestion were longer for Billroth I patients than Billroth II patients. Seven complications occurred in Billroth I patients, whereas there were two complications in Billroth II patients. Disease-free survival and overall survival were not different between the two groups; however, bypass operations were required in nine patients of the Billroth I group and in one patient of the Billroth II group. Percutaneous transhepatic cholangio-drainage (PTCD) procedures were required in six patients of the Billroth I goup and in two patients of the Billroth II group. The Billroth II reconstruction may have some advantages over the Billroth I reconstruction in terms of postoperative oral ingestion and avoiding bypass surgery and PTCD at the time of recurrence.

Aged↗
PubMed2005

Roux-en-Y hepaticojejunostomy or hepaticoduodenostomy for biliary reconstruction during the surgical treatment of choledochal cyst: which is better?

We reviewed our experience of Roux-en-Y hepaticojejunostomy (RYHJ) and hepaticoduodenostomy (HD) performed for the surgical repair of choledochal cyst (CC), with special emphasis on postoperative complications related to the type of biliary reconstruction performed. Eighty-six patients underwent primary cyst excision for CC from 1986 to 2002 at our institution. Forty-six cases with concurrent intrahepatic bile duct dilatation (IHBD) were excluded because HD was not used for biliary reconstruction if IHBD was present. Thus, 28 cases had RYHJ, and 12 had HD. Differences between the RYHJ and HD groups with respect to type of CC, age at cyst excision, and length of follow-up were not statistically significant. However, the incidences of postoperative complications related to biliary reconstruction, such as endoscopy-proven bilious gastritis due to duodenogastric bile reflux [4/12 (33.3%) of the HD group], and adhesive bowel obstruction/cholangitis [2/28 (7.1%) of the RYHJ group] were significantly different (p<.05). Our experience suggests that HD is not ideal for biliary reconstruction in CC because of a high incidence (33.3%) of complications due to duodenogastric bile reflux. Currently, RYHJ is our exclusive technique of choice for biliary reconstruction during the surgical repair of CC.

Anastomosis, Roux-en-Y↗
PubMed2005

Connective tissue growth factor and progressive fibrosis in biliary atresia.

Connective tissue growth factor (CTGF) is a newly described protein that stimulates transforming growth factor-beta1 (TGF-beta1). We evaluated the expression of CTGF mRNA in operative biopsy specimens from biliary atresia (BA) patients and normal controls to assess the role of CTGF in BA. Liver biopsy specimens were taken from BA patients at the time of portoenterostomy (n=22) and compared with specimens taken from normal controls (n=6). In situ hybridization was used to stain CTGF mRNA in all specimens. The distribution of collagen type IV (C-IV) was also assessed in the same specimens as an indicator of the severity of fibrosis present at the time of biopsy. Results were analyzed to determine whether there was any correlation between CTGF and C-IV and outcome. Of the 22 postoperative BA patients, eventual outcome was good in 17 (group I), and five (group II) subsequently required liver transplantation. Control specimens (n=6) had no apparent CTGF mRNA expression, and median C-IV positive immunoreactivity was 1.23+/-0.25%. CTGF mRNA was weakly expressed in hepatic stellate cells (HSC) and hepatocytes in specimens from group I, and median C-IV-positive immunoreactivity was 3.18+/-0.86%. However, in specimens from group II, there was increased CTGF mRNA in HSC and hepatocytes. Median C-IV-positive immunoreactivity was 6.31+/-0.96%. There was a significant correlation between CTGF mRNA intensity and the amount of C-IV, which implies that CTGF expression reflects prognosis. This study provides the first evidence that CTGF is strongly expressed in BA, in particular in HSC and hepatocytes, suggesting that they may be a source of CTGF. The strong correlation with C-IV indicates that CTGF plays a major role in the pathogenesis of progressive fibrosis in BA.

Bile Ducts, Intrahepatic↗
PubMed2005

Effect of antibacterial cathelicidin peptide CAP18/LL-37 on sepsis in neonatal rats.

Cathelicidins are a family of antibacterial peptides. Human cathelicidin LL-37 inhibits the binding of endotoxin lipopolysaccharide (LPS) to CD14-positive cells and could ameliorate sepsis. The aim of this study was to observe the effect of LL-37 on sepsis in neonatal rats. Intraperitoneal injection (IPI) of LPS was used to create sepsis in suckling rats. Group 1 rats were given LPS with LL-37, group 2 rats were given LL-37 2 h after LPS, and group 3 rats were given LPS without LL-37. Control group rats were given isovolemic normal saline by IPI. Rats given LL-37 IPI were divided into seven subgroups. Following IPI, an overall assessment score (OAS) and rectal temperature (RT) were assessed hourly. Serum C-reactive protein (CRP) was also assessed at death or at sacrifice 10 h after IPI. All rats in group 3 died. For rats receiving lower doses of LL-37 in groups 1 and 2, mortality was decreased. No deaths occurred among those receiving higher doses of LL-37 in group 1; however, mortality increased in group 2. In group 1, OAS and RT deteriorated initially for those receiving lower doses of LL-37, then improved. OAS and RT did not deteriorate throughout the study in rats given higher doses of LL-37. In group 2 rats given higher doses of LL-37, OAS and RT were not significantly different from rats in group 3. CRP was significantly decreased in group 1 compared with group 3, and decreased in group 2 for lower doses only. We conclude that LL-37 may prevent sepsis and be useful in lower doses for treating sepsis. However, LL-37 appears to have adverse effects when used at higher doses for treating sepsis.

Animals↗
PubMed2005

Serum soluble vascular cell adhesion molecule-1 (VCAM-1) concentrations in children with reflux nephropathy.

Systemic inflammatory disorders causing renal tissue damage do so by the adherence of polymorphonuclear leukocytes to endothelium, a process that is mediated by cell surface adhesion molecules. We determined the circulating levels of serum vascular cell adhesion molecule-1 (VCAM-1) in vesicoureteric reflux (VUR) patients and investigated the relationship between serum VCAM-1, grade of VUR, and secondary renal scarring. Serum levels of VCAM-1 were measured in 53 children aged between 3 months and 15 years with VUR (13 had grade III, 29 had grade IV, and 11 had grade V) and 25 controls using ELISA. Radionuclide scanning was used to assess renal scarring. Renal scarring was found in 29 of the 53 subjects. Serum VCAM-1 was significantly higher in subjects with high grades of VUR without renal scarring (grade IV: 715.9+/-121.0 ng/ml; grade V: 778.5+/-33.2ng/ml) compared with subjects with grade III VUR without renal scarring (609.8+/-64.3ng/ml, p<0.01). Serum VCAM-1 was also significantly higher in subjects with high grades of VUR with renal scarring (grade IV: 791.2+/-131.9ng/ml; grade V: 1171.8+/-235.6 ng/ml) compared with subjects with grade III VUR with renal scarring (687.3+/-163.4 ng/ml, p<0.001).

Adolescent↗