Biomedical subjects

Jun Watanabe

Publications and source records attributed to Jun Watanabe.

At least 91 records · Page 5Linked to original sources

PubMed2004

Warfarin-intractable, intraatrial thrombogenesis in a 52-year-old woman with mitral stenosis and chronic atrial fibrillation.

Thromboembolic events are serious complications of atrial fibrillation (AF). We histologically investigated intraatrial thrombogenesis in a 52-year-old woman with mitral stenosis and chronic AF who had recurrent attacks of cerebral infarction despite continuous warfarin therapy. She underwent cardiac surgery for mitral valve replacement and maze procedure including left atrial thrombectomy. Macroscopic thrombi were found on the endocardium and their surfaces appeared rough and dark red in most areas. Histological examination showed that a single thrombus mass was composed of several tissue layers or blocks on the endocardium. Immunohistochemistry revealed stratum-like accumulations of small platelet aggregate/fibrin clot complexes in the superficial, fresh thrombus layers and multiple neovessel formation in the basal organized tissue layers. This case study suggests that intraatrial thrombi may develop in a stepwise fashion on the endocardium involving platelet aggregate/fibrin clot complex formation.

Adult↗

PubMed2004

Absorption and metabolic extraction of diltiazem from the perfused rat small intestine.

The metabolic extraction of diltiazem was examined in conjunction with its absorption, using rat small intestine perfused in situ by the single-pass method, to clarify its intestinal metabolism. This is a topic of increasing interest which has not been fully clarified, particularly as far as the extent of metabolic extraction and the enzymes involved (cytochrome P450 (CYP) 3A and/or others) are concerned. The intestinal availability (Fi) of diltiazem was evaluated at steady-state by dividing the fraction absorbed into the mesenteric venous blood (Fa,b) by the fraction that disappeared from the intestinal lumen (Fa). The Fi of diltiazem (0.05 mM) was 0.126 and, hence, the extraction ratio (Ei=1-Fi) was 0.874, indicating that diltiazem undergoes extensive first-pass metabolism during its passage through the intestinal mucosa. The Ei was unchanged when the concentration was increased to 0.5 mM, suggesting that metabolism is linear over this concentration range. Thereafter, Ei decreased with concentration, demonstrating saturable metabolism, and reached an insignificant level at the highest concentrations of 30 and 50 mM. The decrease in Ei, or increase in Fi, was brought about by an increase in Fa,b (from about 0.02 to about 0.05) in the concentration range up to 10 mM and by a decrease in Fa (from about 0.15 to about 0.05) at concentrations higher than that. These results suggest that the extraction observed at the lower concentrations is almost solely attributable to metabolic extraction of a saturable nature. However, ketoconazole and cyclosporin A, which are specific CYP3A inhibitors, inhibited the metabolic extraction of diltiazem (0.05 mM) by only about 20% at the concentration (40 microM) at which they inhibited CYP3A almost completely, suggesting that the contribution of CYP3A to intestinal diltiazem metabolism is not marked. Thus, the present study demonstrates that diltiazem undergoes extensive first-pass metabolism in the rat small intestine, although the contribution of CYP3A seems to be relatively minor.

Absorption↗

PubMed2004

Crystallization and preliminary X-ray analysis of plant class I chitinase from rice.

We report here on crystallization and preliminary X-ray analysis of plant class I chitinase from rice (OsChia1b). Similar single crystals of full-length OsChia1b were obtained under two independent conditions. The crystals grown under these conditions diffracted up to 2.1 and 2.5 angstroms resolution, respectively, at a synchrotron beamline, and were found to belong to the tetragonal space group P4(3)2(1)2.

Chitinases↗

PubMed2003

Deficit of CD38/cyclic ADP-ribose is differentially compensated in hearts by gender.

To elucidate whether myocardial CD38/cyclic ADP-ribose (cADPR) signaling plays a physiological role, we investigated the heart of CD38 knockout mice (CD38KO). In CD38KO, the myocardial cADPR content was reduced by 85% compared with wild-type mice (WT). Cardiac hypertrophy developed only in males. At 36 degrees C, none of the parameters for Ca(2+) transients and forces of the papillary muscles differed between WT and CD38KO. In contrast, at 27 degrees C, at which cADPR does not work, the peak [Ca(2+)](i) was increased and the decline in [Ca(2+)](i) was accelerated in CD38KO compared with WT. In CD38KO, the protein expression of SR Ca(2+) ATPase type2 (SERCA2) and the SERCA2-to-phospholamban ratio were increased compared with WT. The ryanodine receptor protein was increased only in female CD38KO compared with WT. These data suggest that the CD38/cADPR signaling plays an important role in intracellular Ca(2+) homeostasis in cardiac myocytes in vivo. Its deficiency was compensated differentially according to gender.

ADP-ribosyl Cyclase↗

PubMed2003

Should increasing the dose or adding an AT1 receptor blocker follow a relatively low dose of ACE inhibitor initiated in acute myocardial infarction?

OBJECTIVE: Based on currently available clinical evidence, we should use high-dose angiotensin converting enzyme inhibitor (ACE-I) for patients with acute myocardial infarction (MI), initiating it at incremental doses to avoid excessive hypotension. Recent animal studies with acute MI models failed to demonstrate the superiority of the combination therapy of ACE-I and angiotensin receptor blocker (ARB) to high-dose ACE-I treatment with comparable blood pressure reductions, which however might be attributed to the initiation of the targeted doses from the beginning. The aim of this study was to compare the effect of increasing the dose of ACE-I with that of adding ARB following a relatively low dose of ACE-I on the survival and left ventricular (LV) remodeling after MI. METHODS: Rats underwent left coronary artery ligation and were treated with either ACE-I temocapril (5 mg/kg/day) or vehicle for 2 weeks, which was initiated 3 days after the surgery. The rats treated with temocapril were further randomly assigned to receive either high-dose temocapril (10 mg/kg/day) or combination therapy (temocapril 5 mg/kg/day+olmesartan 2.5 mg/kg/day), which was continued for another 6 weeks. RESULTS: Both treatments similarly reduced the blood pressure, improved survival and ameliorated LV enlargement. In contrast, several parameters of LV function were significantly ameliorated only by the high-dose ACE-I but not by the combination therapy. CONCLUSIONS: After the initiation of a relatively low dose of ACE-I in acute MI, increasing the dose of ACE-I or adding ARB may equally improve survival and LV remodeling in the setting of an equal hypotensive effect. Further study with a longer treatment protocol is required to determine whether the several favorable effects on LV function elicited only by the high-dose ACE-I treatment provide further beneficial effects on survival and LV remodeling compared with the combination therapy.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2003

Targeted tissue oxidation in the cerebral cortex induces local prolonged depolarization and cortical spreading depression in the rat brain.

Spreading depression (SD) has been linked to several neurological disorders as epilepsy, migraine aura, trauma, and cerebral ischemia, which were also influenced by disorderliness of the brain redox homeostasis. To investigate whether local tissue oxidation directly induces SD, we oxidized a restricted local area of the rat cerebral cortex using photo-dynamic tissue oxidation (PDTO) technique and examined the cerebral blood flow (CBF) and direct current (DC) potential in and around the oxidized area. Intensive PDTO induced prolonged depolarization only in the photo-oxidized area, which led to global changes of CBF and DC potential: synchronous negative shifts of DC potential (with an amplitude of approximately 20 mV) and hyperperfusion of CBF occurred. The changes in DC potential and CBF spread at a rate of around 3mm/min beyond the oxidized area to the whole hemisphere of the cerebral cortex, indicating that intensive local oxidation induces SD in the rat brain.

Animals↗

PubMed2003

Gastrointestinal transit of liquids in unfed cynomolgus monkeys.

In this study, the gastric emptying rate and oro-caecal transit time of two liquid volumes (20 and 60 ml) were compared in unfed cynomolgus monkeys. First, the acetaminophen method was used to determine the gastric half-emptying time (t(50%)). The mean t(50%) from seven monkeys was 21.2 min for the 20-ml volume and 27.8 min for the 60-ml volume. This mean t(50%) in monkeys is similar to that reported previously in fasting humans. Next, the sulfasalazine-sulfapyridine method was used to determine median oro-caecal transit times for the 2 liquid volumes; these times were 2.5 h for the 20-ml volume and 2.3 h for the 60-ml volume, which are about 1.5 h shorter than previously reported transit times in humans. An increase in volume administered did not significantly change either the t(50%) or oro-caecal transit time. The data also show that variability in both t(50%) and oro-caecal transit time within each monkey is not as great as the large variability between monkeys. Consequently, cynomolgus monkeys are good model animals to use for studies on the gastric emptying of drug-containing liquids after fasting; however, analysis of results from bioavailability studies must compensate for differences in the oro-caecal transit time between monkeys and humans.

Animals↗

PubMed2003

Effect of food on gastrointestinal transit of liquids in cynomolgus monkeys.

We investigated the gastrointestinal transit of liquids, as well as various gastric pH profiles, in fed cynomolgus monkeys. Twelve grams of a biscuit-type solid food were provided 1 h before the test. The acetaminophen method was used to determine the gastric half-emptying time (t(50%)), which provided an estimate of the gastric emptying rate. The gastric emptying rate of liquids was significantly reduced after food intake in monkeys. The mean t(50%) value was 143.5 min and comparable to that of humans after eating. However, there was a large variability in the t(50%) between individual animals as shown by the coefficient of variance of approximately 80%. Next, the median oro-caecal transit time in fed monkeys was determined to be 1.8 h, using the sulfasalazine-sulfapyridine method. There was no significant difference in oro-caecal transit time between unfed and fed monkeys; thus, food intake has no significant effect on the oro-caecal transit time of liquids in either monkeys or humans. However, the oro-caecal transit time in humans is about 2 h longer than that in monkeys. Our experiments using several different foods suggested that the typical human gastric pH profile could not be simulated in fed monkeys.

Acetaminophen↗

PubMed2003

Impact of hypercholesterolemia on acidosis-induced coronary microvascular dilation.

An increase in coronary flow conductance during acidosis is an important compensatory mechanism in various diseased conditions. On the other hand, hypercholesterolemia causes microvascular dysfunction as well as macrovascular disorders. We investigated the impact of hypercholesterolemia on the coronary microvascular response to acidosis. Coronary arterioles (< 150 microm) isolated from rabbit hearts were cannulated to micropipettes in a vessel chamber and the microvascular responses were observed. After preconstriction was established, the extravascular pH was gradually reduced from 7.4 to 7.0. The effects of glibenclamide, ATP-sensitive K(+) (K(ATP)) channel blocker, (1 microM, n = 4) or pertussis toxin (100 ng/mL, n = 7) on the acidosis-induced microvascular responses were examined. In another set of experiments, rabbits were randomly assigned to normal chow (NC group, n = 18) or high cholesterol (2 %) diet (HC group, n = 20). After 8 weeks of feeding, the responses of isolated coronary arterioles to acidosis, ADP, nitroprusside, and levcromakalim were examined in the two groups. Coronary arterioles significantly dilated as the pH was reduced and the dilation was significantly inhibited by glibenclamide or pertussis toxin. Acidosis-induced dilation in the HC group was significantly attenuated compared to the NC group (36.5 +/- 2.1 % vs 73.7 +/- 4.8 % at pH = 7.0 P < 0.05). There were no significant differences in the dilations by ADP, nitroprusside and levcromakalim between the two groups. In conclusion, acidosis-induced dilation of rabbit coronary arterioles is mediated by the activation of the pertussis toxin-sensitive G protein and K(ATP) channels, and the dilation of coronary arterioles is impaired in hypercholesterolemia. The impairment occurs upstream of K(ATP) channel opening.

Acidosis↗

PubMed2003

A transgenic mouse model for the detailed morphological study of astrocytes.

We have generated a transgenic mouse model in which astrocytes express an enhanced green fluorescent protein (EGFP) under the control of the mouse glial fibrillary acidic protein (GFAP) promoter. EGFP, which is characteristically found throughout the cell, was expressed in these animals even in astrocytic fine processes, and EGFP expressing cells demonstrated morphological characters of protoplasmic, fibrous, or reactive astrocytes. In contrast, GFAP immunoreactivity was found only in the perinuclear region and in the main processes. The transgenic mouse model therefore provides a valuable tool for the detailed morphological investigation of astrocytes.

Animals↗

PubMed2003

Clinical characteristics of ureteral calculi detected by nonenhanced computerized tomography after unclear results of plain radiography and ultrasonography.

PURPOSE: Prospective non-enhanced computerized tomography (CT) was performed for patients presenting with renal colic and showing negative or equivocal results on plain x-ray of the kidneys, ureters and bladder (KUB) as well as ultrasonography (US) to evaluate the usefulness of plain CT. We also evaluated the clinical characteristics of urinary calculi detected under such conditions. MATERIALS AND METHODS: Between January 2000 and June 2002, 560 patients presented with acute unilateral renal colic. Of these patients 238 negative or equivocal for ureteral calculus on KUB and US underwent non-enhanced CT. The diagnostic value of plain CT in patients with negative or equivocal KUB and US was determined, and results and other clinical findings were compared. Clinical characteristics of ureteral stones detected by plain CT were compared with those of stones diagnosed by KUB and US. RESULTS: By plain CT 143 (60.1%) and 6 (2.5%) cases of pain were determined to have been caused by ureteral stones and other pathogeneses, respectively. No definitive diagnosis was obtained in 89 (37.4%). Stone size detected by plain CT was significantly smaller than controls (3.77 vs 6.37 mm, p <0.0001) and tended to be located in the middle or lower ureter (76.2% or 109 of 143 vs 52.2% or 168 of 322, p <0.0001). Symptoms spontaneously improved in 137 (95.8%) after conservative therapy while 6 underwent intervention, a rate significantly lower (p <0.0001) than controls (32.9% or 106 of 322). CONCLUSIONS: Non-enhanced CT is a useful modality for diagnosis of patients presenting with acute renal colic but whose results are negative or equivocal on KUB and US. Excretory urography is rarely needed because stones undetected on KUB and US tend to be small and in the middle or lower ureter, and spontaneous passage is expected.

Adult↗

PubMed2003

Interstitial laser coagulation of the prostate for management of acute urinary retention.

PURPOSE: We evaluated the clinical efficacy and benefit of interstitial laser coagulation of the prostate (ILCP) in patients with benign prostatic hyperplasia (BPH) presenting with acute urinary retention. MATERIALS AND METHODS: Patients presenting with acute urinary retention were prospectively evaluated. Patients underwent ILCP and outcomes were evaluated by post-void residual urine, maximum flow rate, International Prostate Symptom Score, and disease specific quality of life score at baseline, 1, 3, 6 and 12 months. RESULTS: A total of 85 patients were enrolled in the study and 53 were diagnosed with acute urinary retention secondary to BPH. A total of 33 were not catheter-free after a week and 28 of them agreed to undergo ILCP. Mean preoperative prostate volume was 54.6 ml (range 23.0 to 130.0) and mean residual volume presenting with retention was 602 ml (range 200 to 1,150). There were no intraoperative or postoperative adverse events except urinary infection in 2 patients. Mean catheterization duration was 6.3 days (range 3 to 18) and all patients became catheter-free postoperatively. Mean followup was 16.9 months (range 7 to 31). Mean maximum flow rate (+/-SD) was 11.2 ml per second (+/-5.7) 3 months after treatment. Mean International Prostate Symptom Score and quality of life scores decreased from 23.1 (+/-6.4) at baseline to 8.0 (+/-5.3) at 3 months (p <0.001), and 5.0 (+/-1.2) to 1.9 (+/-1.6, p <0.001), respectively. Mean estimated prostate volume decreased by 19.4% (54.6 to 44.0 ml) 6 months postoperatively (p <0.001). Only 2 patients had recurrent urinary retention during followup. CONCLUSIONS: Our study suggested that ILCP is a safe and effective therapy for patients with BPH presenting with acute urinary retention.

Acute Disease↗

PubMed2003

Up-regulation and nuclear localization of beta-catenin in endometrial carcinoma in response to progesterone therapy.

Ovarian hormones are considered to be capable of regulating expression of beta-catenins. A possible role of beta-catenin in alteration of cell morphology has been proposed, but little is known about beta-catenin expression during changes in the tumor morphology of endometrial carcinomas induced by progesterone therapy. To clarify changes in expression of beta-catenin and their relation to morphological alteration, expression of hormone receptors and several cell kinetic markers, sequential biopsy and hysterectomy specimens of 23 endometrial carcinoma and 6 complex hyperplasia with atypia (atypical hyperplasia) cases receiving progesterone therapy were investigated. In vitro assay was also conducted using two endometrial carcinoma cell lines (HEC265 and Ishikawa) expressing progesterone receptors (PRs). An increase of nuclear beta-catenin accumulation was evident during progesterone therapy in endometrial carcinomas and atypical hyperplasias. The nuclear labeling indices were significantly associated with gene mutations and alteration in morphological features in response to progesterone, independently of the status of Ki-67, p21WAF1 and p27Kip1, and hormone receptors. In HEC265 having a beta-catenin gene mutation (A32V), cytoplasmic beta-catenin levels were elevated by progesterone treatment, linked to down-regulation of PR expression, but such changes were relatively minor in Ishikawa without the gene alterations. These findings demonstrate a possible role of progesterone in regulation of beta-catenin expression in endometrial tumors. Moreover, nuclear beta-catenin accumulation, like gene abnormalities, is associated with the alteration of tumor morphology due to progesterone, indicating that beta-catenin may be a clinically useful marker of hormone therapeutic effects.

Active Transport, Cell Nucleus↗

PubMed2003

Endopyeloureterotomy using the holmium:YAG laser for the management of adult ureteral and ureteropelvic junction obstructions.

AIM: To determine the efficacy of endopyeloureterotomy using a holmium:YAG laser for the management of adult benign ureteral and ureteropelvic junction obstructions. PATIENTS AND METHODS: We reviewed the clinical outcomes of eight primary procedures performed in 5 patients. The causes of the strictures were idiopathic in five and stone impaction in three procedures. All strictures except one were approached in a retrograde fashion with either a rigid (8.0 Fr) or flexible (9.3 Fr) ureteroscope. The only energy source employed was the laser, and no balloon dilation was performed. In all cases, a 4.8-Fr ureteral stent was left indwelling, and retrograde ureteropyelography was performed within 6-8 weeks to remove the catheter. RESULTS: Follow-up was performed in all patients for a mean period of 14.9 (minimum 10) months. Two strictures in 1 patient failed to be stent free, while six strictures were patent on postoperative radiographic imaging. There were no perioperative complications. CONCLUSIONS: Endopyeloureterotomy using a holmium:YAG laser is safe and effective. Its relative noninvasiveness and its retrograde approach make it a first-line alternative for the management of benign upper urinary tract strictures in adults.

Female↗

PubMed2003

Saturable absorption of glycerol in the rat intestine.

The permeability of glycerol, a small hydrophilic solute, across the intestinal membrane would be low, if passive diffusion restricted to the paracellular route is the principal transport mechanism as generally assumed for this class of solutes. However, in the present study using a closed loop of rat small intestine in situ, we found that the absorption of glycerol was faster than that of urea, a probe solute widely assumed to permeate exclusively via the paracellular route. This finding is inconsistent with the paracellular permeation hypothesis, which predicts that the absorption of glycerol, which is larger than urea in terms of molecular size, could not be faster than that of urea. We also found that glycerol absorption was saturable. These findings suggest the involvement of carrier-mediated transport in intestinal glycerol absorption. Glycerol absorption in the colon was also saturable, suggesting the involvement of carrier-mediated transport, although it was much slower than that in the small intestine. Carrier-mediated glycerol transport might play an important role in absorbing glycerol liberated from dietary triglyceride. It would be interesting to further examine the possibility that a carrier-mediated glycerol transport system (or systems) might be involved in drug absorption and also that it might be utilized for oral drug delivery.

Animals↗

PubMed2003

Search for carrier-mediated transport systems in the rat colon.

Several nutrients and drugs, which are known to be absorbed by specific carrier-mediated transport systems in the small intestine, had their transport investigated in the rat colon, by measuring uptake into everted sacs, to find if carrier-mediated transport systems may also be present in the colon. Among those transported by Na+-dependent carriers in the small intestine, D-glucose and taurocholate were found to be transported in an Na+-dependent manner in the colon, while 5-fluorouracil and ascorbate were not. It was also found that the colonic transports of D-glucose and taurocholate were saturable. These results suggest the presence in the colon of Na+-dependent carrier-mediated transport systems for D-glucose and taurocholate, but not for 5-fluorouracil and ascorbate. For nicotinate and methotrexate, which are transported by H+-dependent carriers in the small intestine, their transport was elevated at a lower pH (5.0) than the pH 7.4 in the colon, but not saturable. Therefore, the elevated transport of these acidic compounds may be explained by an increase in passive flux due to an increase in the fraction of the unionized and/or neutral forms, without postulating the presence of H+-dependent carrier-mediated transport systems in the colon. The transport activity of the suggested colonic transport systems for D-glucose and taurocholate was much lower than those of their respective counterparts in the small intestine. However, it may be possible to use them for oral drug delivery via the colon. Their physiological roles would also be of interest.

Animals↗

PubMed2003

Kinetic characterization of carrier-mediated transport systems for D-glucose and taurocholate in the everted sacs of the rat colon.

The present study was aimed at kinetically characterizing the carrier-mediated transport systems for D-glucose and taurocholate in the rat colon, compared with their respective counterparts in the small intestine. The transport of these compounds was evaluated by measuring the initial uptake into everted intestinal tissue sacs. The uptake of both D-glucose and taurocholate was highly saturable, conforming to Michaelis-Menten kinetics without an appreciable nonsaturable transport component. The Michaelis constant (K(m)) was 0.43 and 0.021 mM, respectively, for D-glucose and taurocholate and the maximum transport rate (J(max)) was 0.82 and 0.056 nmol/min/100 mg wet tissue weight (wtw), respectively. For both compounds, these values of K(m) and J(max) in the colon were one to three orders of magnitude smaller than those in the small intestine, suggesting that the transport systems in the colon have by far a higher affinity and a lower transport capacity than their counterparts in the small intestine. However, it is now evident from kinetic studies that carrier-mediated transport systems for D-glucose and taurocholate are also present in the colon. It will be interesting to explore the possibility that they could be used for oral drug delivery via the colon. Their physiological roles would also be of interest.

Animals↗

PubMed2003

Comparison of the efficacy of reperfusion therapies for early mortality from acute myocardial infarction in Japan: registry of Miyagi Study Group for AMI (MsAMI).

The current reperfusion strategy in Japan for acute myocardial infarction (AMI) is that the majority of early arrival patients are treated with primary percutaneous coronary intervention (PCI). However, the efficacy of primary PCI, intravenous thrombolysis (IV-T), intracoronary thrombolysis (IC-T) and rescue PCI has not been compared in the clinical situation. In the present study, 3,258 cases of AMI in 1992-2000 from the data base of the Miyagi Study Group for AMI were analyzed. These patients were hospitalized within 6 h of the onset of symptoms. IV-T and IC-T were initially performed in 120 and 441 patients, respectively, and 41 and 199 rescue PCI procedures, respectively, were needed. Primary PCI was performed in 1,822 cases, and no reperfusion therapy was done in 875 patients. The crude 30-day in-hospital mortality was 12.7% for IV-T, 3.7% for IC-T, 4.8% for primary PCI, 7.9% for rescue PCI, and 14.1% in patients who did not undergo reperfusion therapy. The covariate-adjusted odds ratio (95% confidence interval) was 0.38 (0.28-0.52) for primary PCI, 0.30 (0.15-0.60) for IC-T, 1.04 (0.51-2.10) for IV-T and 0.77 (0.46-1.30) for rescue PCI. The present data verify that primary PCI is superior to other reperfusion strategies in the real clinical situation and justifies the current unique strategy of reperfusion therapy for AMI used in Japan.

Adult↗