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Biomedical subjects

M Kawabata

Publications and source records attributed to M Kawabata.

At least 19 recordsLinked to original sources
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↗
PubMed2000

Marked anterograde decremental conduction over a rapidly conducting accessory pathway after radiofrequency ablation.

We report on a patient with the Wolff-Parkinson-White syndrome who temporarily exhibited a marked anterograde decremental conduction over a rapidly conducting accessory atrioventricular pathway after successful radiofrequency ablation. By recording the intracardiac electrogram via the ablation catheter placed at the successful ablation site, we were able to exclude the possibility of the occurrence of anterograde decremental conduction in the atrial or ventricular myocardium between the accessory pathway and the recording electrodes.

Catheter Ablation↗
PubMed2000

Left-right asymmetric expression of lefty2 and nodal is induced by a signaling pathway that includes the transcription factor FAST2.

The left-right (L-R) asymmetric expression of lefty2 and nodal is controlled by a left side-specific enhancer (ASE). The transcription factor FAST2, which can mediate signaling by TGF beta and activin, has now been identified as a protein that binds to a conserved sequence in ASE. These FAST2 binding sites were both essential and sufficient for L-R asymmetric gene expression. The Fast2 gene is bilaterally expressed when nodal and lefty2 are expressed on the left side. TGF beta and activin can activate the ASE activity in a FAST2-dependent manner, while Nodal can do so in the presence of an EGF-CFC protein. These results suggest that the asymmetric expression of lefty2 and nodal is induced by a left side-specific TGF beta-related factor, which is most likely Nodal itself.

Animals↗
PubMed2000

Donor lymphocyte infusion for treatment of life-threatening respiratory syncytial virus infection following bone marrow transplantation.

We describe two patients who developed respiratory syncytial virus (RSV) pneumonia after BMT. One died of RSV pneumonia after three courses of steroid pulse therapy. Surprisingly, RSV antigen was identified in the bronchoalveolar lavage fluid (BALF) obtained post mortem. Steroid pulse therapy might have suppressed anti-RSV immunity, leading to persistent RSV infection for more than 1 month. The other patient received donor lymphocyte infusions (DLI) for relapsed plasma cell leukemia, while having active RSV pneumonia. His respiratory condition improved after DLI, and RSV antigen disappeared in BALF and nasal swabs. DLI might be effective in cases of life-threatening RSV pneumonia.

Acute Disease↗
PubMed2000

Schnurri interacts with Mad in a Dpp-dependent manner.

BACKGROUND: Decapentaplegic (Dpp) is a member of the transforming growth factor-beta superfamily. Dpp governs various developmental processes in Drosophila through the transcriptional regulation of a variety of genes. Signals of Dpp are transmitted from the cell membrane to the nucleus by Medea and Mad, both belonging to the Smad protein family. Mad was shown to bind to the Dpp-responsive element in genes such as vestigial, labial, and Ultrabithorax. The DNA binding affinity of Smad proteins is relatively low, and requires other nuclear factor(s) to form stable DNA binding complexes. schnurri (shn) was identified as a candidate gene acting downstream of Dpp receptors, but its relevance to Mad has remained unknown. RESULTS: We characterized the biochemical functions of Shn. Shn forms homo-oligomers. Shn is localized in the nucleus, and is likely to have multiple nuclear localizing signals. Finally, we found that Shn interacts with Mad in a Dpp-dependent manner. CONCLUSIONS: The present results argue that Shn may act as a nuclear component of the Dpp signalling pathway through direct interaction with Mad.

Animals↗
PubMed2000

Competitive reverse transcription-polymerase chain reaction assay for quantification of human multidrug resistance 1 (MDR1) gene expression in fresh leukemic cells.

We have analyzed MDR1 gene expression in 69 clinical samples obtained from 64 patients with leukemic hematologic malignancies by using a competitive reverse transcription-polymerase chain reaction assay with a heterologous competitor RNA. To exclude a false-positive result caused by concomitant normal lymphocytes that physiologically express MDR1, in samples we determined a cut-off value of 8 amol MDR1 transcript per microgram of RNA by simultaneous measurement of rhodamine 123 dye efflux either in lymphocyte or gated leukemic cell populations. Consequently, 23 of 69 samples were concluded to be MDR1-positive in leukemic cells per se. The MDR1 expression rate was significantly correlated with factors such as a history of preceding chemotherapy, elder age of the patient, and certain disease types (eg, leukemia progressed from myelodysplastic syndrome). Moreover, the complete response rate after chemotherapy was significantly higher in MDR1-negative patients than in MDR1-positive patients (52% vs 17%, respectively; P = .01). The assay established will enable the quantification of MDR1 gene expression in blood samples from patients with leukemic hematologic malignancies and will be applicable to clinical laboratories as a routine test.

Adolescent↗
PubMed2000

Characterization of a bone morphogenetic protein-responsive Smad-binding element.

Bone morphogenetic proteins (BMPs) are pleiotropic growth and differentiation factors belonging to the transforming growth factor-beta (TGF-beta) superfamily. Signals of the TGF-beta-like ligands are propagated to the nucleus through specific interaction of transmembrane serine/threonine kinase receptors and Smad proteins. GCCGnCGC has been suggested as a consensus binding sequence for Drosophila Mad regulated by a BMP-like ligand, Decapentaplegic. Smad1 is one of the mammalian Smads activated by BMPs. Here we show that Smad1 binds to this motif upon BMP stimulation in the presence of the common Smad, Smad4. The binding affinity is likely to be relatively low, because Smad1 binds to three copies of the motif weakly, but more repeats of the motif significantly enhance the binding. Heterologous reporter genes (GCCG-Lux) with multiple repeats of the motif respond to BMP stimulation but not to TGF-beta or activin. Mutational analyses reveal several bases critical for the responsiveness. A natural BMP-responsive reporter, pTlx-Lux, is activated by BMP receptors in P19 cells but not in mink lung cells. In contrast, GCCG-Lux responds to BMP stimulation in both cells, suggesting that it is a universal reporter that directly detects Smad phosphorylation by BMP receptors.

Activins↗
PubMed2000

Clinical investigation of pulmonary Mycobacterium avium complex infection in human T lymphotrophic virus type I carriers.

BACKGROUND: Little is known about pulmonary Mycobacterium avium complex (MAC) infection in human T lymphotrophic virus type I (HTLV-I) carriers. A study was undertaken to investigate and clarify the characteristics of pulmonary MAC infection in these subjects. METHODS: Twenty nine patients with pulmonary MAC infection without any underlying pulmonary disorder were investigated. The clinical features and radiographic appearance of HTLV-I carriers and non-carriers were compared and the bronchoalveolar lavage (BAL) fluid of these 29 patients and eight normal female control subjects was analysed. RESULTS: The prevalence of the HTLV-I carrier state in patients with pulmonary MAC infection was 34.5% (10/29) compared with 16.7% (529/3169) among all patients admitted to our department between 1994 and 1998 (odds ratio (OR) 2.63, 95% confidence interval (CI) 1.21 to 5.68). The HTLV-I carriers were all women and all had clinical symptoms, but they did not show systemic dissemination. Peripheral multifocal bronchiectasis with nodular shadowing was seen frequently on the chest computed tomographic (CT) scans of HTLV-I carriers. The area of the pulmonary lesions was more extensive than in non-carriers (p<0.05). White blood cell (WBC) counts and C reactive protein (CRP) levels on admission were significantly lower in HTLV-I carriers than in non-carriers (WBC: difference (D) = 1565/microl, 95% CI -68.9 to 3198.4/microl; CRP: D = 1.8 mg/dl, 95% CI -0.35 to 3.89 mg/dl). The concentrations of neutrophil elastase (NE) and interleukin (IL)-8 in BAL fluid were significantly higher in HTLV-I carriers than in non-carriers (NE: D = 1342 microg/l, 95% CI 704 to 1980.3 microg/l; IL-8: D = 304.5 pg/ml, 95% CI 89.7 to 519. 4 pg/ml). CONCLUSIONS: Pulmonary MAC infection causes more diffuse and widespread lesions in HTLV-I carriers than in non-carriers.

Aged↗
PubMed2000

Increased serum level of vascular endothelial growth factor in pulmonary tuberculosis.

Pulmonary tuberculosis, one of the granulomatous diseases, has few serological markers for its activity. Recently, an increased serum level of vascular endothelial growth factor (VEGF) was detected in patients with Crohn's disease, also a granulomatous disease. We hypothesized that VEGF might be associated with the pathogenesis of pulmonary tuberculosis. We investigated the serum level of VEGF in 43 patients with active pulmonary tuberculosis, 29 patients with old tuberculosis, and 25 patients with acute bronchitis. We were able to examine the serum VEGF levels every 3 mo for a period of 6 mo in seven patients with active pulmonary tuberculosis. We examined the presence of VEGF in the resected lungs of three patients with active pulmonary tuberculosis by immunohistochemistry. The serum levels of VEGF were significantly higher in patients with active pulmonary tuberculosis than in patients with old tuberculosis and acute bronchitis. The decrease in titer of serum VEGF paralleled the clinical improvement of patients with pulmonary tuberculosis. Immunohistochemical staining of the resected lungs demonstrated the presence of VEGF in alveolar macrophages surrounding the lesion. Therefore, VEGF may be associated with the pathogenesis of pulmonary tuberculosis.

Acute Disease↗
PubMed2000

Serum levels of vascular endothelial growth factor dependent on the stage progression of lung cancer.

STUDY OBJECTIVE: In lung cancer, vascular endothelial growth factor (VEGF) is an important cytokine and is correlated with tumor vessel density, malignant pleural effusions, and coagulation-fibrinolysis factors in vitro. We investigated the correlation between serum VEGF level and stage progression in lung cancer to study the predicted value of VEGF level. We also studied whether coagulation-fibrinolysis factors and PaO(2) levels, which are also important factors for the prediction of the clinical course, are correlated with VEGF. METHODS: Forty-nine patients with lung cancer were investigated prospectively. VEGF levels of sera and malignant effusions, and plasma concentrations of coagulation-fibrinolysis factors were measured by enzyme-linked immunosorbent assay. We measured PaO(2) levels in all patients at rest. RESULTS: Serum levels of VEGF were increased significantly according to stage progression. Additionally, plasma concentrations of D dimer, thrombin-antithrombin complex (TAT), and tissue plasminogen activator/plasminogen activator inhibitor type I complex were elevated significantly according to stage progression. The serum VEGF level had a significant positive correlation with the TAT and D dimer levels. Serum VEGF levels had a significant negative correlation with PaO(2) levels. The incidence of cerebral vascular disorder was significantly higher in the patients with systemic hypoxemia than in those without (p<0.05). Mean VEGF levels in malignant effusions in eight patients (five with pleural effusions, two with pericardial effusions, and one with both) were extremely high, especially in pericardial effusions ([mean +/- SD] pleural effusions, 531.9+/-285.4 pg/mL; pericardial effusion, 3,071.6+/-81.3 pg/mL). CONCLUSION: We predict that in lung cancer, VEGF production and the abnormality of the coagulation-fibrinolysis system differ depending on the stage of progression of disease. Serum VEGF levels would be affected by PaO(2) levels in lung cancer.

Adenocarcinoma↗
PubMed2000

A case of duodenal papillary carcinoma complicated by repeated acute pancreatitis.

We present a patient with duodenal papillary carcinoma who repeatedly developed acute pancreatitis preoperatively. The patient was a 65-year-old male. In February 1997, the patient consulted a local hospital due to vomiting, high fever, and jaundice. With the diagnosis of obstructive jaundice, percutaneous transhepatic biliary drainage (PTBD) was performed, revealing a distal bile duct obstruction. Because duodenal papillary carcinoma was diagnosed based on endoscopic findings, the patient was admitted to Kurume University Hospital. Hypotonic duodenography (HDG) disclosed a protruding lesion with an irregular surface in the descending part of the duodenum, resulting in a diagnosis of positive duodenal invasion (du1). Because computed tomography (CT) demonstrated a protruding lesion on the medial side of the second portion of the duodenum, positive pancreatic invasion (panc2) was diagnosed. On March 18 and April 22, sudden abdominal pain, leukocytosis, and an increase in serum amylase were noted. CT revealed that the pancreas was diffusely enlarged, showing an ill-defined boundary between the pancreas and adipose tissue and fluid collection. On CT, the lesion was evaluated as Grade 3 and moderate. For treatment, pancreatic enzyme inhibitors and antibiotics were intravenously injected. Peritoneal perfusion was concomitantly performed during the second treatment. Because symptoms remitted thereafter, a pylorus preserving pancreatoduodenectomy (PpPD) was carried out. The postoperative histologic examination revealed negative pancreatic invasion. Concerning the etiology of acute pancreatitis, not pancreatic invasion, but impaction of the liberated tumor mass in the common canal was considered responsible for the repeated pancreatitis because the tumor showed a cauliflower-like shape.

Acute Disease↗
PubMed2000

A case of intrahepatic gallstone formation around nylon suture for hepatectomy.

A 69-year-old female underwent left lobectomy for hepatolithiasis in February 1994. She was admitted to the Kurume University Hospital in December 1997 because computed tomography (CT) showed calcification in the porta hepatis. Ultrasonography (US) revealed a hyperechoic area with an acoustic shadow in the right hepatic duct. Dilated intrahepatic bile ducts and a mural lucent area in the right hepatic duct were noted on endoscopic retrograde cholangiography (ERC). Although the above findings suggested a diagnosis of recurrent hepatolithiasis, percutaneous transhepatic biliary drainage (PTBD) for biopsy was performed in order to rule out cancer. Biopsy showed no evidence of malignancy. Under a cholangioscope, a tip of a nylon suture was found to be protruding into the bile duct. Although a gallstone had already slipped off, the surface of the nylon suture was covered with biliary sludge. The protruding tip of the nylon suture was considered to be the nucleus of the stone. The tip was removed under cholangioscopy. Postoperative CT confirmed the absence of calcification in the porta hepatis. There has been no recurrence of hepatolithiasis after surgery. Although the formation of gallstones around the core of nylon sutures is very rare, absorbable sutures should be used during surgery of the bile duct because nonabsorbable sutures can become the nucleus of gallstones.

Aged↗
PubMed2000

[A clinicopathological study of pulmonary cryptococcosis--chest CT and pathologic correlation].

We reviewed the clinicopathological features in 12 patients (7 males and 5 females; mean age 54 yr) with pulmonary cryptococcosis. Eleven of the patients were asymptomatic and the disease was detected by chest radiograph abnormalities. The underlying systemic disease had been diagnosed as diabetes mellitus in two. Chest CT scans showed a solitary nodule in 9 of the 12 patients, multiple nodules in 2, and infiltration in 1. The nodular diameter was less than 2 cm in 10 of the 12. All nodules were located in the subpleural region. On the chest CT, cavitary nodules, scattered nodules, or both, and spiculated nodules were difficult to distinguish from pulmonary tuberculosis and primary lung cancer, respectively. According to McDonnell's pathological classification of pulmonary cryptococcosis, the resected 8 lungs revealed peripheral pulmonary granuloma in 5 and granulomatous pneumonia in 3. It is important to perform a pathological examination for the diagnosis of pulmonary cryptococcosis to avoid misdiagnosis as lung cancer or pulmonary tuberculosis.

Adult↗
PubMed1999

c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads.

Smads are intracellular signaling mediators of the transforming growth factor-beta (TGF-beta) superfamily that regulates a wide variety of biological processes. Among them, Smads 2 and 3 are activated specifically by TGF-beta. We identified c-Ski as a Smad2 interacting protein. c-Ski is the cellular homologue of the v-ski oncogene product and has been shown to repress transcription by recruiting histone deacetylase (HDAC). Smad2/3 interacts with c-Ski through its C-terminal MH2 domain in a TGF-beta-dependent manner. c-Ski contains two distinct Smad-binding sites with different binding properties. c-Ski strongly inhibits transactivation of various reporter genes by TGF-beta. c-Ski is incorporated in the Smad DNA binding complex, interferes with the interaction of Smad3 with a transcriptional co-activator, p300, and in turn recruits HDAC. c-Ski is thus a transcriptional co-repressor that links Smads to HDAC in TGF-beta signaling.

Acetyltransferases↗
PubMed1999

Interaction and functional cooperation of PEBP2/CBF with Smads. Synergistic induction of the immunoglobulin germline Calpha promoter.

Smads are signal transducers for members of the transforming growth factor-beta (TGF-beta) superfamily. Upon ligand stimulation, receptor-regulated Smads (R-Smads) are phosphorylated by serine/threonine kinase receptors, form complexes with common-partner Smad, and translocate into the nucleus, where they regulate the transcription of target genes together with other transcription factors. Polyomavirus enhancer binding protein 2/core binding factor (PEBP2/CBF) is a transcription factor complex composed of alpha and beta subunits. The alpha subunits of PEBP2/CBF, which contain the highly conserved Runt domain, play essential roles in hematopoiesis and osteogenesis. Here we show that three mammalian alpha subunits of PEBP2/CBF form complexes with R-Smads that act in TGF-beta/activin pathways as well as those acting in bone morphogenetic protein (BMP) pathways. Among them, PEBP2alphaC/CBFA3/AML2 forms a complex with Smad3 and stimulates transcription of the germline Ig Calpha promoter in a cooperative manner, for which binding of both factors to their specific binding sites is essential. PEBP2 may thus be a nuclear target of TGF-beta/BMP signaling.

Activin Receptors, Type I↗