Biomedical subjects

M Kitamura

Publications and source records attributed to M Kitamura.

At least 109 records · Page 6Linked to original sources

PubMed1999

Bioflavonoid quercetin inhibits interleukin-1-induced transcriptional expression of monocyte chemoattractant protein-1 in glomerular cells via suppression of nuclear factor-kappaB.

Flavonoids are semiessential food components that possess anti-inflammatory properties. This report describes a novel potential of bioflavonoid quercetin as an inhibitor of monocyte chemoattractant protein-1 (MCP-1) in glomerular cells. Cultured mesangial cells as well as isolated glomeruli expressed MCP-1 mRNA in response to interleukin-1beta (IL-1beta). Quercetin dramatically inhibited the cytokine-triggered MCP-1 expression. To explore the mechanisms involved, effects of quercetin on the putative transcriptional activators of MCP-1, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), were examined. Exposure of the cells to IL-1beta caused activation of NF-kappaB without significant upregulation of AP-1 activity. NF-kappaB inhibitor MG132 diminished the IL-1-induced expression of MCP-1 in mesangial cells and isolated glomeruli, whereas c-Jun/AP-1 inhibitor curcumin did not affect this process. Consistently, NF-kappaB-inactive mesangial cells expressing a super-repressor mutant of IkappaBalpha showed blunted expression of MCP-1 by IL-1beta. In contrast, AP-1-inactive mesangial cells expressing a dominant-negative mutant of c-Jun exhibited the same level of MCP-1 mRNA as that in control cells. These results suggest that: (1) quercetin has the ability to attenuate activation of NF-kappaB; and (2) it inhibits IL-1-triggered MCP-1 expression via suppression of NF-kappaB, but not AP-1, in glomerular cells.

Animals↗

PubMed1999

The antioxidant N-acetylcysteine induces mesangial cells to create three-dimensional cytoarchitecture that underlies cellular differentiation.

Prolonged culture of mesangial cells produces multifocal nodular structures, i.e., "hillocks," consisting of cells and extracellular matrix. Hillock formation is associated with induction of a differentiated phenotype of mesangial cells, with suppressed mitogenesis and downregulation of alpha-smooth muscle actin (alpha-SMA). Currently, little is understood regarding physiologically relevant factors that facilitate this cytodifferentiation. This study explores whether and how the cellular redox state modulates hillock formation. Exposure of confluent rat mesangial cells to the antioxidant N-acetylcysteine (NAC), an inducer of glutathione, dramatically facilitated hillock formation. This effect was mimicked by external addition of the reduced form of glutathione ethyl ester. In contrast, the oxidizing agents diamide and menadione inhibited the development of hillocks triggered by either NAC, glutathione, or prolonged culture. The induction of hillocks by NAC was correlated with downregulation of alpha-SMA as well as attenuated activity of the CArG box element (the cis-element relevant to the expression of the alpha-SMA gene and growth-associated genes). These results indicate that, by a redox-sensitive mechanism, NAC induces mesangial cells to create three-dimensional cytoarchitecture that underlies cellular differentiation.

Acetylcysteine↗

PubMed1999

Aldehyde oxidase-dependent marked species difference in hepatic metabolism of the sedative-hypnotic, zaleplon, between monkeys and rats.

A marked difference in hepatic activity of aldehyde oxidase between rats and monkeys was found to be responsible for the previously reported marked species difference in the metabolism of Zaleplon in vivo. In the postmitochondrial fractions, S-9s, from liver homogenates of these animals, Zaleplon was transformed in the presence of NADPH into the side chain oxidation product, N-desethyl-Zaleplon, and the aromatic ring oxidation product, 5-oxo-Zaleplon. In the rat S-9, N-desethyl-Zaleplon and 5-oxo-Zaleplon were a major and a very minor metabolites, respectively. However, in the monkey S-9, Zaleplon was transformed into 5-oxo-Zaleplon at a much higher rate than that for N-desethyl-Zaleplon formation. N-Desethyl-Zaleplon was formed in the monkey S-9 at a rate almost equal to that in the rat S-9. N-Desethyl-5-oxo-Zaleplon was formed at a minor rate only in the monkey S-9 through N-desethyl-Zaleplon as an obligatory intermediate. The hepatic activity for the formation of 5-oxo-Zaleplon in the monkey and rat was localized in cytosol and did not require NADPH. Sensitivity to various inhibitors and requirement of water as oxygen source, using H218O, strongly suggested that the hepatic cytosolic formation of 5-oxo-Zaleplon was mediated by aldehyde oxidase. N-Desethyl-Zaleplon was formed in the presence of NADPH by microsomes from the liver of rats and monkeys, and its formation was strongly suggested using various cytochrome P-450 inhibitors to be mediated by a number of cytochrome P-450 isoforms, such as 3A, 2C, and 2D subfamilies.

Acetamides↗

PubMed1999

[Treatment of azoospermic patient with genitourinary tuberculosis: a case report].

A case of azoospermia due to genitourinary tuberculosis is reported with discussion on the treatment of infertility in such a case. A 38-year-old man visited us complaining of 4-year sterility. We suspected obstructive azoospermia due to previous genitourinary tuberculosis because of his treatment history, calcifications in the seminal vesicles and nodules in the right epididymis. After microsurgical epididymal sperm aspiration (MESA) was performed twice without success, we extracted sperm from his testis (testicular sperm extraction, TESE) and fertilized his wife's egg by intracytoplasmic sperm injection.

Adult↗

PubMed1999

[A case of type 4 gastric cancer with peritoneal dissemination treated with intra-aortic chemotherapy].

A 45-year-old woman was admitted to our hospital because of lower abdominal pain and anorexia. A barium gastrography and gastroscopy showed a type 4 gastric cancer in the upper gastric body. Histologic study on biopsy specimens from the tumor revealed poorly differentiated adenocarcinoma. Computed tomography revealed bilateral hydronephrosis, and barium enema showed diffuse stenosis of the sigmoid colon because of peritoneal dissemination. This patient was treated by intra-aortic infusion therapy with sequential MTX and 5-FU. After five courses of the administration, barium enema revealed reexpansion of the lumen of sigmoid colon with normalization of the tumor markers. The patient was discharged without symptoms. Intra-aortic infusion therapy with sequential MTX and 5-FU was considered an effective treatment for unresectable gastric cancer.

Adenocarcinoma↗

PubMed1999

Gene therapy for diabetic nephropathy.

Gene therapy has been considered for a broad array of diseases. Recent investigation has suggested that gene therapy may be applied to the treatment of diabetes mellitus and associated pathologies involving several organs. In the kidney, glomerulopathy is the most typical pathologic feature. This article addresses potential strategies towards gene therapy for diabetic glomerular disease.

Diabetic Nephropathies↗

PubMed1999

[A case of liver metastases from gastric cancer responding to induced hypertensive chemotherapy with angiotensin II].

A 69-year-old man, who had undergone distal gastrectomy for Borrmann type 3 gastric cancer two years ago, experienced a recurrence of multiple liver metastases. Then intra-arterial hepatic cannulation connecting to a subcutaneously implanted port system was indwelt via left subclavial artery. Mitomycin C (20 mg) was injected through out the induced hypertension (1.5 times of his median blood pressure) with intravenously-administered angiotensin II (Delivert), and 5-FU (250 mg/day) was continuously followed for 5 days. He received a total of five courses of this treatment every 4 to 7 weeks. The liver metastases disappeared on CT scan after 4 courses, and a complete response (CR) has been maintained with no use of other chemotherapy. The patient has obtained good quality of life for 32 months after the start of this chemotherapy. Induced hypertensive chemotherapy could be one of the effective treatments for liver metastases from gastric cancer.

Aged↗

PubMed1999

[Efficacy of terminal warm blood cardioplegia in combination with Bretschneider-HTK solution for myocardial protection].

Many reports indicated that terminal warm blood cardioplegia (TWBC) was useful for reduction of the reperfusion injury in cardiac operations. We introduced Bretschneider-HTK solution (B-HTK) from April 1992, and combined use of the TWBC and the B-HTK was performed from May 1996. The purpose of this study was to evaluate clinical efficacy of the TWBC in combination with B-HTK for myocardial protection. In patient with valve operations from May 1995 to May 1997, clinical results were compared between the B-HTK with TWBC group (34 patients) and the B-HTK alone group (37 patients). Between two groups, there was no significant difference in patient characteristics, preoperative NYHA class, cardiopulmonary bypass time, aortic cross clamp time, minimum rectal temperature, rewarming and circulatory support time, incidence of IABP and blood concentration of max CPK, max GOT. Furthermore, the cardiac index in 1 postoperative day showed some trend to be higher in the combined TWBC group than that in the B-HTK alone group. But there was no significant difference between two groups in the LV shortening fraction at 14 postoperative day. Incidence of DC defibrillation was significantly lower in the combined TWBC group than that in the B-HTK alone group. These results suggested that combination of the TWBC might be useful for reduction of the reperfusion injury following myocardial protection with B-HTK solution.

Aged↗

PubMed1999

Modulation by endogenous nitric oxide of acid secretion induced by gastric distention in rats: enhancement by nitric oxide synthase inhibitor.

The mechanism underlying acid hypersecretion induced by gastric distention was investigated in rats, especially in relation to endogenous nitric oxide (NO). Under urethane anesthesia, rat stomach was distended by instillation of saline (1-10 ml) through the acute fistula that was provided through a pylorus. Gastric samples were collected every 1 h, and the acid secretion was measured by titration with 100 mM NaOH. Gastric acid secretion was increased by distention, and the degree of stimulation was dependent on the volume of saline instillation; a maximal response occurred with 6-ml instillation, which maintained the intraluminal pressure of about 20 cm H(2)O. The increased acid secretory response induced by distention was completely blocked by omeprazole and significantly mitigated by vagotomy, sensory deafferentation, atropine, or famotidine but markedly enhanced by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). On the other hand, the enhanced acid response in the presence of L-NAME occurred in an L-arginine-sensitive manner and was almost totally abolished by vagotomy and sensory deafferentation as well as by atropine. Gastric distention increased the release of NO metabolites and histamine into the gastric lumen. The NO metabolite release in the distended stomach was significantly decreased by vagotomy or L-NAME, whereas the histamine output was decreased by vagotomy but increased by L-NAME in an L-arginine-sensitive manner, respectively. These results suggest that 1) gastric distention increases acid secretion, initially through the perception by sensory neurons of the mechanical stimulation and mainly through the efferent vagocholinergic pathway, with the process being modified by endogenous NO, and 2) this molecule, released in a vagal-dependent manner, exerts a negative influence on acid secretion, at least in part by suppressing histamine release from the histamine-containing cells.

Animals↗

PubMed1999

Synthesis and pharmacological activity of pyrazolopyrrolopyrimidine derivatives having vasorelaxing activity.

A new series of 5-substituted and 5-nonsubstituted pyrazolopyrrolopyrimidine derivatives were synthesized, and their vasorelaxing and hypotensive activities were evaluated. The syntheses were efficiently accomplished through the use of three key intermediates (7, 16, and 24), as shown in Schemes I-III. The desired pharmacological activities were confirmed on the basis of vasorelaxing activity in rat aorta (in vitro) and hypotensive activity in rats (in vivo). Specifically, compound 25 exhibited the strongest activity and appears to be a promising clinical lead for the development of a new antihypertensive agent.

Animals↗

PubMed1999

[Hard-copy (film) versus soft-copy (CRT) reading performance between compressed and uncompressed images: SOLs in abdominal CT images].

The objective of this study was to examine the feasibility of soft-copy (CRT) reading and suitable compression. Forty abdominal CT images with a space-occupying lesion (SOL) in liver and 40 normal images were selected for receiver-operating-curve (ROC) analysis. Each image was compressed by JPEG extended mode into 1/10 its original capacity, and then an expanded image was printed on film. Ten radiologists evaluated the presence of liver SOLs (primary and secondary tumors) on soft-copy (CRT) and hard-copy (film) images. Each radiologist reviewed four types of images (original and compressed hard-copy and original and compressed soft-copy images). Values of the area under the curve in the various ROC analyses were 0.858 (FILM) and 0.842 (CRT) for original images and 0.879 (FILM) and 0.846 (CRT) for compressed images. The results of ROC analysis showed better reading performance with hard-copy than soft-copy images, but the difference was not statistically significant. Compressed images showed a higher value (0.879) than original images (0.858), a difference that was statistically significant (p < 0.029) by the paired t-test but not by the jackknife method. The results indicate that soft-copy reading is a clinically acceptable alternative to hard-copy reading. We have had no difficulty in reading abdominal CT images compressed to 1/10 of the original size by the JPEG method. This study was supported in part by a grant from the Japanese Ministry of Health and Welfare.

Humans↗

PubMed1999

[Optimum anticoagulation control after bileaflet mechanical valve replacement: a prospective multi-institutional study].

This study was undertaken to assess optimum anticoagulation control after bileaflet mechanical valve replacement by using the international normalized ratio of prothrombin time (PT-INR). From January to December 1995, 261 patients (pts) underwent mechanical valve replacement in the aortic (n = 95), mitral (n = 126), aortomitral (n = 39) or isolated tricuspid (n = 1) valve position in 8 medical centers in Tokyo, Japan. The St. Jude Medical valves were implanted in 184 pts and the Carbomedics valves in 77. There were 17 valve-related events as follows: 11 thromboembolic events (3.62%/pt-yr) including 10 transient ischemic attacks. 5 non-fatal bleeding events (1.65%/pt-yr), 2 reoperations (0.66%/pt-yr). At 18 postoperative months, free rates from all deaths (actuarial survival) thromboembolism, reoperation and all valve-related events were 95.3%, 95.7%, 98.7% and 88.9%, respectively. Under anticoagulant therapy, thrombin-antithrombin III complex and D-dimmer remained in high levels at 1 month after operation, and both values decreased to the control level at 6 months. In patients with thromboembolic events, PT-INR tended to be less than 2.0. The patients with bleeding events showed some increase of PT-INP or received anti-platelet agents. The 5 to 95 percentile of PT-INR at 6 months was 1.2 to 3.0 in the patients without valve-related events. These results suggested that optimum range of PT-INR might be between 1.2 and 3.0 after bileaflet mechanical valve replacement in patients without high risk of thromboembolism and between 2.0 and 3.0 in patients with the high risk.

Adolescent↗

PubMed1999

[Incidence of recurrence after hepatic resection and prophylactic hepatic arterial infusion chemotherapy for liver metastases from colon cancer].

We studied recurrence after hepatic resection and prophylactic hepatic arterial infusion chemotherapy for liver metastases from colon cancer, retrospectively. Eighty-six patients underwent curative hepatic resection for liver metastases, and 41 of them received arterial infusion chemotherapy. Eight patients (20%) developed only remnant liver metastases, 6 patients (15%) had hepatic and extrahepatic recurrences, and 10 patients (24%) developed only extrahepatic recurrences. Regional therapy including hepatic resection for residual liver metastases should be indicated for recurrences after hepatic arterial infusion chemotherapy.

Antineoplastic Agents↗

PubMed1999

[A successful surgical case of billowing mitral leaflet syndrome (Barlow syndrome) combined with severe mitral regurgitation].

We report a successful surgical case of billowing mitral leaflet syndrome combined with severe mitral regurgitation. A 45-year-old man suffered from congestive heart failure and admitted our institution for precise examination. A heart murmur was pointed out by a medical examination at his high school, and mitral valve prolapse was detected by echocardiography at 23 year of age. No medication was applied because he showed no symptom. From 44 year of age, he noted palpitation on exercise. Holter monitor showed blocked PAC and Wenckebach A-V block, and transesophageal echocardiography indicated severe mitral regurgitation due to the billowing of voluminous both leaflets. At his operation, we recognized the billowing of both leaflets with torn chordae, and size of the mitral valve orifice was 8.5 x 5 cm. The huge mitral valve was replaced with a CarboMedics 31M prosthetic valve by plicating mattress stitches of native mitral annulus. Histopathologic findings showed accumulation of acid mucopolysaccharide. Postoperative echocardiography showed reduction of the left ventricular volume and preservation of the left ventricular function. Relatively slow progression of the billowing mitral leaflet syndrome did not cause apparent symptoms of heart failure in this patient. Therefore, proper selection of the procedure and timing of surgical treatments might be important for successful long-term results after operation of the billowing mitral leaflet syndrome.

Cardiac Surgical Procedures↗

PubMed1999

Fractional myocardial flow reserve (FFRmyo) after coronary intervention as a predictor of chronic restenosis.

The angiographic assessment of coronary stenosis has many limitations, especially after coronary intervention. To determine the physiologic significance of such lesions, we measured the mean translesional pressure gradients at rest (P1), those during hyperemia induced by intracoronary administration of papaverine (12 mg in the left and 8 mg in the right coronary artery) (P2), and fractional myocardial flow reserve (FFRmyo) which is derived from the ratio of the mean distal coronary pressure and aortic pressure during hyperemia. Our objective was to determine the relations among P1, P2, and FFRmyo and restenosis as potential predictors of chronic restenosis. The grouped study consisted of 32 patients with ischemic heart disease scheduled to undergo intervention. The distal coronary pressure was measured using a 0.014 inch pressure monitoring wire (Pressure Guide, Radi Medical Systems, Uppsala, Sweden). The guidewire was advanced through the lesional segment. The mean percent diameter stenosis (%DS) was 67.9 +/- 13.3% before intervention and 22.9 +/- 15.3% after intervention. The mean P2 (9.9 +/- 5.3 mmHg) was significantly higher than the mean P1 (4.5 +/- 3.6 mmHg; p < 0.0001). There was no correlation of P1, P2 or FFRmyo with the %DS after intervention. Follow-up angiography (after 6 months) performed on all patients revealed restenosis (%DS > or =50%) in four patients (12.5%). There was no correlation between P1 and the %DS at the follow-up angiography, but the relation between P2, FFRmyo and the %DS at the follow-up angiography was significant (r = 0.599, p < 0.01; r = 0.703, p < 0.0001, respectively). As a measurement of P2, FFRmyo is useful for the determination of the endpoint of intervention in consideration of prevention of restenosis. A new endpoint may be established after further evaluation in a greater number of patients.

Aged↗

PubMed1998

Transgenic knockout mice exclusively expressing human hemoglobin S after transfer of a 240-kb betas-globin yeast artificial chromosome: A mouse model of sickle cell anemia.

Sickle cell anemia (SCA) and thalassemia are among the most common genetic diseases worldwide. Current approaches to the development of murine models of SCA involve the elimination of functional murine alpha- and beta-globin genes and substitution with human alpha and betas transgenes. Recently, two groups have produced mice that exclusively express human HbS. The transgenic lines used in these studies were produced by coinjection of human alpha-, gamma-, and beta-globin constructs. Thus, all of the transgenes are integrated at a single chromosomal site. Studies in transgenic mice have demonstrated that the normal gene order and spatial organization of the members of the human beta-globin gene family are required for appropriate developmental and stage-restricted expression of the genes. As the cis-acting sequences that participate in activation and silencing of the gamma- and beta-globin genes are not fully defined, murine models that preserve the normal structure of the locus are likely to have significant advantages for validating future therapies for SCA. To produce a model of SCA that recapitulates not only the phenotype, but also the genotype of patients with SCA, we have generated mice that exclusively express HbS after transfer of a 240-kb betas yeast artificial chromosome. These mice have hemolytic anemia, 10% irreversibly sickled cells in their peripheral blood, reticulocytosis, and other phenotypic features of SCA.

Anemia, Sickle Cell↗

PubMed1998

Telomerase activity in gastrointestinal stromal tumors.

BACKGROUND: Telomerase activity has been observed in 80-90% of carcinomas derived from various organs. However, to the authors' knowledge this report is the first assessment of telomerase activity in gastrointestinal stromal tumors (GISTs). METHODS: Telomerase activity was analyzed by the telomerase repeat amplification protocol assay in 29 tumors from 26 patients (23 primary tumors from 22 patients, 1 pair of primary and metastatic tumors from 1 patient, and 4 metastatic tumors from 3 patients). Phenotypes, tumor cell proliferation, and overexpression of p53 protein were evaluated immunohistochemically. RESULTS: Seven of 24 primary tumors (29%) and 5 of 5 metastatic tumors (100%) showed telomerase activity. Telomerase activity positive (+) GISTs were significantly larger (P < 0.05) and showed a significantly higher rate of proliferation than telomerase activity negative (-) tumors (P < 0.0001). All telomerase activity (+) GISTs were classified histologically as high risk tumors. Conversely, 15 of the 17 telomerase (-) GISTs were classified histologically as low risk tumors (P < 0.0001). With regard to p53 immunoreactivity, two and seven telomerase activity (+) tumors showed diffuse and sporadic positivity, respectively, whereas only five telomerase activity (-) tumors showed only focal or sporadic positivity. Telomerase activity was correlated significantly with poor prognosis (P < 0.05) in the patients in whom the primary GISTs were evaluated (n = 23). CONCLUSIONS: Telomerase activity may be a useful marker for evaluating the malignant potential of GIST. A distinct subgroup of GISTs is a target for therapy with a telomerase inhibitor.

Adult↗

PubMed1998

Oxidant stress incites spreading of macrophages via extracellular signal-regulated kinases and p38 mitogen-activated protein kinase.

Cultured macrophages exhibit spreading in response to external stimuli. It is relevant to in vivo morphologic changes of macrophages during extravasation, migration, and differentiation. The present study was performed to elucidate molecular mechanisms that regulate spreading of macrophages. Redox is a crucial factor that modulates a wide range of cell function. We found that macrophages undergo spreading in response to oxidant stress caused by hydrogen peroxide or an oxidant generating agent menadione. To identify signaling pathways involved, a role of mitogen-activated protein (MAP) kinases was investigated. Western blot analysis showed that treatment of macrophages with menadione rapidly induced phosphorylation of extracellular signal-regulated kinases (ERK1, ERK2) and p38 MAP kinase, but not c-Jun N-terminal kinase (JNK). Pharmacologic inhibition of either ERK or p38 activation blunted the macrophage spreading. Similarly, transfection with dominant-negative mutants of ERKs or a mutant p38 significantly suppressed the oxidant-triggered spreading. ERKs and p38 are known to activate serum response element (SRE) via phosphorylation of the ternary complex factor Elk-1. To further identify downstream events, we focused on a role of SRE. Stimulation of macrophages with menadione induced activation of SRE. Intervention in the SRE activation by a dominant-negative mutant of Elk-1 inhibited the menadione-induced spreading. These results suggest that oxygen radical metabolites, the well-known mediators for tissue injury, incite spreading of macrophages via the MAP kinase-SRE signaling pathways.

Animals↗