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Biomedical subjects

M Kawabata

Publications and source records attributed to M Kawabata.

At least 37 records · Page 2Linked to original sources
PubMed2001

Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins.

Smads are signal mediators for the members of the transforming growth factor-beta (TGF-beta) superfamily. Upon phosphorylation by the TGF-beta receptors, Smad3 translocates into the nucleus, recruits transcriptional coactivators and corepressors, and regulates transcription of target genes. Here, we show that Smad3 activated by TGF-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a RING finger protein, ROC1, through its C-terminal MH2 domain in a ligand-dependent manner. An E3 ubiquitin ligase complex ROC1-SCF(Fbw1a) consisting of ROC1, Skp1, Cullin1, and Fbw1a (also termed betaTrCP1) induces ubiquitination of Smad3. Recruitment of a transcriptional coactivator, p300, to nuclear Smad3 facilitates the interaction with the E3 ligase complex and triggers the degradation process of Smad3. Smad3 bound to ROC1-SCF(Fbw1a) is then exported from the nucleus to the cytoplasm for proteasomal degradation. TGF-beta/Smad3 signaling is thus irreversibly terminated by the ubiquitin-proteasome pathway.

Active Transport, Cell Nucleus↗
PubMed2001

Effect of aggregation of amphotericin B on lysophosphatidylcholine micelles as related to its complex formation with cholesterol or ergosterol.

The effect of aggregation of amphotericin B (AmB), as well as the complex formation of AmB with cholesterol or ergosterol, was investigated in micelles and vesicles. AmB in lysophosphatidylcholine (LPC) micelles adopted a more favorable monomeric form than that in other drug formulations. At an LPC/AmB ratio of 200, AmB existed only in monomeric form. Such monomeric behavior is likely dependent upon the fluidity and size of the micelles. In LPC micelles composed of 90% monomeric AmB, AmB-ergosterol complex formation occurred with an increase in the sterol concentration, but the complex formation of AmB-cholesterol was slight. On the other hand, in LPC micelles composed of 40% monomeric AmB, the complex formation of AmB-cholesterol as well as AmB-ergosterol was extensive. These results suggest that the complex formation of AmB with both sterols is highly dependent upon the aggregated state of AmB. In addition, using monolayers, mixtures of AmB/LPC/ergosterol were became more stable with rising temperature, while the stability of mixtures of AmB/LPC/cholesterol remained unchanged, implying that complex formation of AmB with cholesterol is different from that of AmB with ergosterol.

Amphotericin B↗
PubMed2001

The region from phenylalanine-17 to phenylalanine-28 of a yeast mitochondrial ATPase inhibitor is essential for its ATPase inhibitory activity.

Mitochondrial ATP synthase (F(1)F(o)-ATPase) is regulated by an intrinsic ATPase inhibitor protein. In the present study, we investigated the structure-function relationship of the yeast ATPase inhibitor by amino acid replacement. A total of 22 mutants were isolated and characterized. Five mutants (F17S, R20G, R22G, E25A, and F28S) were entirely inactive, indicating that the residues, Phe17, Arg20, Arg22, Glu25, and Phe28, are essential for the ATPase inhibitory activity of the protein. The activity of 7 mutants (A23G, R30G, R32G, Q36G, L37G, L40S, and L44G) decreased, indicating that the residues, Ala23, Arg30, Arg32, Gln36, Leu37, Leu40, and Leu44, are also involved in the activity. Three mutants, V29G, K34Q, and K41Q, retained normal activity at pH 6.5, but were less active at pH 7.2, indicating that the residues, Val29, Lys34, and Lys41, are required for the protein's action at higher pH. The effects of 6 mutants (D26A, E35V, H39N, H39R, K46Q, and K49Q) were slight or undetectable, and the residues Asp26, Glu35, His39, Lys46, and Lys49 thus appear to be dispensable. The mutant E21A retained normal ATPase inhibitory activity but lacked pH-sensitivity. Competition experiments suggested that the 5 inactivated mutants (F17S, R20G, R22G, E25A, and F28S) could still bind to the inhibitory site on F(1)F(o)-ATPase. These results show that the region from the position 17 to 28 of the yeast inhibitor is the most important for its activity and is required for the inhibition of F(1), rather than binding to the enzyme.

Amino Acid Motifs↗
PubMed2001

Targets of transcriptional regulation by transforming growth factor-beta: expression profile analysis using oligonucleotide arrays.

Transforming growth factor-betas (TGF-betas) are potent inhibitors of cell proliferation, and disruption of components of the TGF-beta signaling pathway leads to tumorigenesis. Mutations of transmembrane receptors and Smads mediating intracellular signaling have been reported in various cancers. To identify transcriptional targets of TGF-beta, we conducted an expression profile analysis. HaCaT cells derived from human keratinocytes and highly sensitive to TGF-beta were treated with TGF-beta in the absence or presence of cycloheximide (CHX). mRNAs extracted from the HaCaT cells were used for hybridization of oligonucleotide arrays representing approximately 5600 human genes. TGF-beta increased the expression of PAI-1, junB, p21 cdk inhibitor, Smad7, betaIG-H3, and involucrin that have been reported to be up-regulated by TGF-beta, validating the usefulness of this approach. The induction of betaIG-H3 by TGF-beta was completely abolished by CHX, suggesting that the transcription of betaIG-H3 is not directly regulated by TGF-beta. Unexpectedly, we identified more genes down-regulated by TGF-beta than up-regulated ones. TGF-beta repressed the expression of epithelial specific Ets that may be involved in breast and lung tumorigenesis, which could contribute to tumor suppression by TGF-beta. Among a panel of cell cycle regulators, TGF-beta induced the expression of p21 cdk inhibitor; however, the induction of other cdk inhibitors was not significant in the present study. Taken together, the results suggest that TGF-beta may suppress tumorigenesis through positive and negative regulation of transcription.

Cell Cycle↗
PubMed2001

Enhanced inhibition of lymphocyte activation by Mycobacterium avium complex in human T lymphotrophic virus type I carriers.

BACKGROUND: We have previously reported that disseminated pulmonary Mycobacterium avium complex (MAC) infection is more common in human T lymphotrophic virus type I (HTLV-I) carriers than in non-carriers. However, the reason for this remains unclear. It has been shown that glycopeptidelipid (GPL), one of the lipid components of the cell envelope of MAC, is able to reduce the lymphocyte blastogenic response to mitogens. The purpose of this study was to clarify whether or not the inhibitory effect of GPL differs between HTLV-I carriers and non-carriers. METHODS: Peripheral blood lymphocytes were obtained from 29 patients who had recovered from pulmonary MAC infection (10 of whom also had HTLV-I infection) and the lymphocyte counts and T cell subpopulations of the peripheral blood lymphocytes in HTLV-I carriers and non-carriers were compared. The inhibitory effect of GPL on the lymphocyte blastogenic response to phytohaemagglutinin (PHA) was tested in these 29 cases and in 15 healthy controls who had never suffered from MAC (seven of whom also had HTLV-I infection). All HTLV-I positive cases were carriers. RESULTS: There was no significant difference in the numbers or subset proportions of T cells between HTLV-I carriers and non-carriers. Lymphocyte activation by PHA was significantly inhibited by GPL in MAC positive and negative HTLV-I carriers compared with MAC negative non-carriers and MAC negative healthy controls (p<0.001). CONCLUSIONS: We suggest that MAC infection leads to strong inhibition of lymphocyte activation in HTLV-I carriers. This may account, in part, for the severity of pulmonary MAC infection in HTLV-I carriers.

Aged↗
PubMed2001

Variation in malaria endemicity in relation to microenvironmental conditions in the Admiralty Islands, Papua New Guinea.

For 197 adults and adolescents in four villages of three small islands in the Admiralty Islands, Papua New Guinea, antimalarial antibody titers were examined using the indirect fluorescent antibody test (IFAT) and malaria parasites were detected by the microtiter plate hybridisation (MPH) method using polymerase chain reaction (PCR) technique. The parasite rate (either Plasmodium falciparum or P. vivax, or both) averaged 39.2%, varying from 31.1% to 44.8% among the four villages due to natural and artificial microenvironmental conditions related to breeding sites of mosquitoes (Anopheles farauti). The lack of flat zones owing to geomorphological formation contributed to the lowest parasite rate in the extremely small island. However, human-modified environments such as a wet-land (naturally formed but artificially reformed) and an open well played significant roles in other inter-village differences. The present findings imply significant roles of microenvironment in diversified malaria prevalence and suggest some ways of mitigation of malarial hazards.

Adolescent↗
PubMed2001

Usefulness of transcutaneous Doppler jugular venous echo to predict pulmonary hypertension in COPD patients.

Pulmonary hypertension is an important factor that determines the prognosis of chronic obstructive pulmonary disease (COPD) patients. Echocardiography is a noninvasive and useful bedside method for measurement of pulmonary artery pressure. However, this method is sometimes difficult because of the overinflated lungs in COPD patients. This study attempted to estimate pulmonary hypertension in COPD patients using transcutaneous Doppler jugular vein flow velocity recording. The mean pulmonary artery pressure (MPAP) of 64 COPD patients was examined using cardiac catheterization. The right jugular vein flow velocity was measured within 24 h using transcutaneous Doppler echo, after which the ratio of diastolic flow (Df) and systemic flow (Sf) velocity was calculated. Subsequently, the statistical correlation of MPAP and the Df/Sf ratio was examined. MPAP was also measured using standard cardiac echo methods and the results were compared. The Df/Sf velocity ratio showed significant correlation with MPAP in COPD patients (r=0.844, p<0.0001). The sensitivity was 71.4%, and the specificity 95.3% (cut-off ratio= 1.0). Jugular venous Doppler echo could be performed in all patients while other cardiac echo methods could not be performed in all patients. The specificity of the methods used was higher than other cardiac echo methods. Transcutaneous jugular vein flow velocity measurement may be applicable to bedside prediction of pulmonary hypertension in chronic obstructive pulmonary disease patients.

Aged↗
PubMed2001

Expression of vascular endothelial growth factor in pulmonary aspergilloma.

OBJECTIVE: Vascular endothelial growth factor (VEGF), a cytokine associated with malignant neoplasms, is increased in a number of inflammatory and infectious disorders. But little is known about VEGF in pulmonary aspergilloma (PA). In order to clarify the predictive value of VEGF in PA, we examined serum VEGF levels in PA patients as well as expression of VEGF in the PA lesion. Patients Twenty-one patients with PA (6 with hemoptysis and the rest without hemoptysis) were investigated. METHODS: In all patients, serum VEGF levels were measured by enzyme-linked immunosorbent assay. We examined the statistical correlations of serum VEGF levels with the ratio of affected area to total lung volume and VEGF with PaO2 levels. In patients with hemoptysis, we measured the serum VEGF levels three months after the initiation of therapy. We examined the expression of VEGF in the resected lung tissue of 4 patients with PA using immunohistochemistry. RESULTS: Serum VEGF levels showed a significant positive correlation with the ratio of affected to total lung area and a significant negative correlation with PaO2 levels. Serum VEGF levels in patients with hemoptysis were significantly higher than in those without hemoptysis. The serum levels of VEGF in patients with hemoptysis decreased significantly in parallel with the alleviation of hemoptysis. Immunohistochemical staining demonstrated the expression of VEGF in alveolar macrophages in the lesion of PA patients. CONCLUSION: We suggest that VEGF can be used as a serum marker to determine the extent of the lesion, hypoxia and hemoptysis in PA.

Adult↗
PubMed2001

Evaluation of simultaneous excision of pancreatic cancer and the surrounding blood vessels.

Of the 139 patients who underwent excision for invasive cancer in the pancreatic duct at Kurume University Hospital between January 1965 and December 1998, the subjects were 38 patients in whom blood vessels around the cancer were simultaneously excised. The surgical methods were pancreatoduodenectomy (PD) in 31 patients, distal pancreatectomy (DP) in 5, and total pancreatectomy (TP) in 2. The excised blood vessels were the portal vein alone in 32 patients, the artery alone in 1, and both portal vein and artery in 5. Excision of the portal vein was performed by circumcision in 25 patients and by segmentectomy in 12. The range of circumcision was 1.0-7.0 cm (mean, 3.5 +/- 1.4 cm), and the blocking time of the portal vein was 8-36 min (mean, 19.5 +/- 8.8 min). Of the 25 patients who underwent circumcision, reconstruction was performed by end-to-end anastomosis in 23 and by transplantation of the autologous vein between the ends in 2. Of the 12 patients who underwent segmentectomy, direct suture was performed in 10, and transplantation of an autologous vein patch was performed in 2. Postoperative complications occurred in 14 of the 32 patients. In 5 of the 6 patients who underwent excision of the artery, reconstruction was performed by end-to-end anastomosis in 3 and by transplantation of the autologous vein between the ends in 2. Postoperative complications did not occur in the patient who had undergone excision of the artery alone, but 4 of the 5 patients who had undergone simultaneous excision of the portal vein and artery had postoperative complications, of whom 2 died during the period of hospitalization. Three patients with pv0, pv1 or pv2 survived for more than 3 years. Because some of the patients who had undergone excision of the portal vein alone survived for a long time and this method is relatively safe, this surgery can be generally applied, but simultaneous excision of the portal vein and artery should be carefully applied because the incidences of postoperative complications and death during the period of hospitalization are high. With the development of surgical techniques and postoperative control, simultaneous excision of pancreatic cancer and the surrounding blood vessels has become safe, but this method should only be applied to patients who have the potential to recover completely.

Hepatic Artery↗
PubMed2001

Xanthogranulomatous cholecystitis.

Seven cases of xanthogranulomatous cholecystitis are presented, and their clinicopathological appearance is described. Three men and 4 women with xanthogranulomatous cholecystitis, aged 53-72 years old, were reviewed. Five patients had had previous attacks of acute cholecystitis lasting from 3 weeks to 6 months. Abdominal ultrasonography was performed in all patients, and computed tomography in 5 patients. Cholelithiasis and sludge were present in all patients. The gallbladder wall was thickened in all patients. On computed tomography, one patient showed no abnormal finding, and 4 patients had abnormal findings such as increased wall thickness and irregularity, and pericholecystic abnormalities. A diagnosis of gallbladder carcinoma was made preoperatively in 1 patient. During laparotomy, the gallbladders in all patients showed signs of chronic cholecystitis, and cholecystectomies were performed. Histological findings showed xanthogranulomatous cholecystitis, and 4 patients had stones in the gallbladder wall. Despite the characteristic histologic appearance of xanthogranulomatous cholecystitis, radiologic findings are nonspecific, varying from signs observed in other forms of cholecystitis to the appearance of a gallbladder neoplasm. We report here 7 cases of xanthogranulomatous cholecystitis and review the literature.

Aged↗
PubMed2001

A case of hepatocellular carcinoma rupturing after angiography.

We report a case of primary hepatocellular carcinoma (referred to as hepatocellular carcinoma below) apparently rupturing after angiography. The patient was a 62-year-old male who was admitted for the treatment of hepatocellular carcinoma. Ultrasonography (US) and computed tomography (CT) on admission showed a tumor occupying the entire left lobe of the liver and partly protruding outside the liver and a tumor embolus in the portal vein. We performed preoperative angiography, after which fever and abdominal discomfort appeared. Two days after the angiography, abdominal pain and a rapid increase in the size of the abdominal tumor were noted. US also revealed an unquestionable increase in the size of the tumor, leading to a diagnosis of intratumoral hemorrhage due to the rupture of hepatocellular carcinoma. Since child classification A, clinical stage I and ICG 11.7% indicated an adequate functional reserve of the liver, we performed an emergency operation. Laparotomy revealed that the tumor occupied almost the entire left lobe of the liver, partly protruded outside it, and was bleeding from part of its anterior surface. The volume of intra-abdominal hemorrhage was about 100 ml. A portal tumor embolus was present in the portal vein from the horizontal part to the trunk. We performed resection of the left and caudate lobes of the liver with removal of the portal tumor embolus. The resected specimens showed a hemorrhage in and around the tumor. We speculated that in a hepatocellular carcinoma that involves the surface of the liver and is complicated by tumor embolism of the portal vein, angiography could trigger the rupture of the carcinoma.

Angiography↗
PubMed2001

Carcinoma of the ampulla of Vater associated with other organ malignancies.

Because of its location with respect to the biliary system, carcinoma of the ampulla of Vater is considered to manifest earlier in its course of development than carcinoma of the pancreas. The most common physical finding is jaundice, which occurs in 93-100% of cases [1,2]. This retrospective study describes the results of the treatment and prognosis for double primary cancers in which cancer of the ampulla of Vater was associated with malignancies in other organs in 5 patients who were diagnosed and treated at Kurume University Hospital. The patients included 5 men with an average age of 72.8 years. There were 3 synchronous double and 2 metachronous double cancer patients. Regarding prognoses of these patients, 1 patient with associated lung cancer died because of postoperative complications after pneumonectomy, 1 patient died due to carcinomatosa peritonei developing from the ampulla Vater carcinoma, and 1 patient died because of metastatic liver tumors from the ampullary carcinoma. In multiple cancers including ampulla Vater carcinoma, gastrointestinal cancers such as gastric or colon cancer occur frequently. Therefore, a careful gastrointestinal examination should be done preoperatively. We report our experience with 5 cases of ampullary carcinoma associated with malignancies in other organs and review the literature.

Aged↗
PubMed2001

Clinicopathological evaluation of surgical treatment for early gallbladder cancer.

We evaluated the therapeutic principles for early gallbladder cancer based on clinicopathological characteristics and outcomes in 27 patients encountered at the Kurume University Hospital between January, 1975 and December, 1999. Concerning the depth of wall penetration, 15 patients had mucosal cancers (m-cancers), and 12 patients muscularis propria cancers(mp-cancers). The gross patterns were lp (pedunculated) in 16 patients, ls (sessile) in 3 patients, IIa (flat elevated) in 4 patients, and IIb (flat) in 4 patients. The operative procedure used was cholecystectomy (C) in 12 patients, 4 of whom underwent lymph node dissection. Full-thickness cholecystectomy (FTC) was carried out in 3 patients, one of whom had lymph node dissection. Combination of C and gallbladder bed resection (GbBR) was performed in 7 patients, 6 of whom had lymph node dissection. Combination of C and bile duct resection (BDR), and lymph node dissection was performed in 1 patient. Combination of C and GbBR and BDR, and lymph node dissection was performed in 6 patients. All the patients who underwent lymph node dissection were negative for metastasis. Of the 27 patients, 2 underwent laparoscopic operation: one with m-cancer was 79 years old, and the other with mp-cancer 86 years old. In the m-cancers, no lymphatic, venous or perineural infiltration was observed. In contrast, in the mp-cancers, lymphatic and venous infiltration each were observed in 4 patients (33.3%), although no perineural infiltration was observed. A diagnosis of gallbladder cancer was made postoperatively in 6 patients, of whom 4 had the IIb pattern and all were complicated by gallstone, indicating the difficulty of diagnosing the IIb pattern. The 5-year survival rates for the m- and mp-cancers were as high as 90.9% and 80.8%, respectively. As a curative surgical technique for m- and mp-cancers, lymph node dissection should be performed in addition to FTC, GbBR, and BDR, in combination. When a postoperative histopathologic diagnosis of gallbladder cancer has been made, no second-look operation should be performed for m-cancers, but lymph node dissection of up to the second group should be performed for mp-cancers in a second-look operation.

Aged↗
PubMed2001

[Evaluation and improvement of medical and nursing service and caregiving for the elderly using MDS. 3. Revised recording system of diagnoses and symptoms suitable for use in Japan].

Diagnoses and symptoms are recorded by physicians in the chapter E of the Minimum Data Set (MDS), if they are relevant to disabilities of activities of daily living, cognition, behavior, medical treatments or risk of death. We improved the chapter so that it is suited to disease patterns in Japan in a format useful not only for nursing and ADL care but for medical treatment in our practice. In E1, diseases directly underlying the current disability states were recorded in the international classification of Disease, 9th Revision (ICD9). In 24, 670, 195, and 45 patients respectively, there were 0, 1, 2, and 3 separate recorded diseases. A Total of 63 ICD9 codes were observed, but only four codes; 290, 332, 431, and 434, were underlying diseases for 3% or more patients. These codes included mostly ischemic and degenerative disease of the brain.

Aged↗
PubMed2000

BMP type II receptor is required for gastrulation and early development of mouse embryos.

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta superfamily, play a variety of roles during mouse development. BMP type II receptor (BMPR-II) is a type II serine/threonine kinase receptor, which transduces signals for BMPs through heteromeric complexes with type I receptors, including activin receptor-like kinase 2 (ALK2), ALK3/BMPR-IA, and ALK6/BMPR-IB. To elucidate the function of BMPR-II in mammalian development, we generated BMPR-II mutant mice by gene targeting. Homozygous mutant embryos were arrested at the egg cylinder stage and could not be recovered at 9.5 days postcoitum. Histological analysis revealed that homozygous mutant embryos failed to form organized structure and lacked mesoderm. The BMPR-II mutant embryos are morphologically very similar to the ALK3/BMPR-IA mutant embryos, suggesting that BMPR-II is important for transducing BMP signals during early mouse development. Moreover, the epiblast of the BMPR-II mutant embryo exhibited an undifferentiated character, although the expression of tissue-specific genes for the visceral endoderm was essentially normal. Our results suggest that the function of BMPR-II is essential for epiblast differentiation and mesoderm induction during early mouse development.

Animals↗
PubMed2000

Smad6 is a Smad1/5-induced smad inhibitor. Characterization of bone morphogenetic protein-responsive element in the mouse Smad6 promoter.

Smad6 is an inhibitory Smad that is induced by bone morphogenetic proteins (BMPs) and interferes with BMP signaling. We have isolated the mouse Smad6 promoter and identified the regions responsible for transcriptional activation by BMPs. The proximal BMP-responsive element (PBE) in the Smad6 promoter is important for the transcriptional activation by BMPs and contains a 28-base pair GC-rich sequence including four overlapping copies of the GCCGnCGC-like motif, which is a binding site for Drosophila Mad and Medea. We generated a luciferase reporter construct (3GC2-Lux) containing three repeats of the GC-rich sequence derived from the PBE. BMPs and BMP receptors induced transcriptional activation of 3GC2-Lux in various cell types, and this activation was enhanced by cotransfection of BMP-responsive Smads, i.e. Smad1 or Smad5. Moreover, direct DNA binding of BMP-responsive Smads and common-partner Smad4 to the GC-rich sequence of PBE was observed. These results indicate that the expression of Smad6 is regulated by the effects of BMP-activated Smad1/5 on the Smad6 promoter.

Animals↗
PubMed2000

Epitope-specific impairment of production of antibody against merozoite surface glycoprotein 1 of Plasmodium falciparum in symptomatic patients with malaria.

We analyzed the relationships between levels of antibody specific for merozoite surface glycoprotein-1 (MSP1) of Plasmodium falciparum and clinical manifestations in humans. We prepared recombinant MSP1 proteins representing block 3 (M3), block 6 (M6), blocks 1-6 (M1/6), and block 17. When we divided the slide-positive individuals in Guadalcanal into symptomatic and asymptomatic groups, the former group showed lower IgG levels against M6 and block 17, but not against M3, than did the asymptomatic group (P < 0.01). The possibility of nonspecific suppression was unlikely, given that the levels of antibody against poliomyelitis virus observed in the two groups were almost the same. Among the IgG subclasses tested, production of cytophilic IgG3 seemed to be dominant. When we analyzed epitopes recognized by antibodies against block 17, a peptide (SSSNFLGIS) was preferentially recognized by sera from asymptomatic individuals. These results suggest that clinical symptoms occurring during falciparum malaria seem to be associated with the development of levels of antibody against particular epitopes on MSP1, which is under the control of an immunoregulatory mechanism.

Adolescent↗