[A case of Lambert-Eaton myasthenic syndrome during malignant lymphoma].
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Aged↗
Biomedical subjects
M Kitagawa
Publications and source records attributed to M Kitagawa.
Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1.
Signal transducers and activators of transcription (STAT) proteins can be conditionally activated in response to epidermal growth factor (EGF) and interferon (IFN)-gamma. STAT activation was correlated with cell growth inhibition in response to EGF and IFN-gamma. Activated STAT proteins specifically recognized the conserved STAT-responsive elements in the promoter of the gene encoding the cyclin-dependent kinase (CDK) inhibitor p21 WAF1/CIP1 and regulated the induction of p21 messenger RNA. IFN-gamma did not inhibit the growth of U3A cells, which are deficient in STAT1, but did inhibit the growth of U3A cells into which STAT1 alpha was reintroduced. Thus, STAT1 protein is essential for cell growth suppression in response to IFN-gamma. The STAT signaling pathway appears to negatively regulate the cell cycle by inducing CDK inhibitors in response to cytokines.
Base Sequence↗
PKN associates and phosphorylates the head-rod domain of neurofilament protein.
PKN is a fatty acid-activated serine/threonine kinase that has a catalytic domain highly homologous to that of protein kinase C in the carboxyl terminus and a unique regulatory region in the amino terminus. Recently, we reported that the small GTP-binding protein Rho binds to the amino-terminal region of PKN and activates PKN in a GTP-dependent manner, and we suggested that PKN is located on the downstream of Rho in the signal transduction pathway (Amano, M., Mukai, H., Ono, Y., Chihara, K., Matsui, T., Hamajima, Y., Okawa, K., Iwamatsu, A., and Kaibuchi, K. (1996) Science 271, 648-650; Watanabe, G., Saito, Y., Madaule, P., Ishizaki, T., Fujisawa, K., Morii, N., Mukai, H., Ono, Y. Kakizuka, A., and Narumiya, S. (1996) Science 271, 645-648). To identify other components of the PKN pathway such as substrates and regulatory proteins of PKN, the yeast two-hybrid strategy was employed. By this screening, a clone encoding the neurofilament L protein, a subunit of neuron-specific intermediate filament, was isolated. The amino-terminal regulatory region of PKN was shown to associate with the head-rod domains of other subunits of neurofilament (neurofilament proteins M and H) as well as neurofilament L protein in yeast cells. The direct binding between PKN and each subunit of neurofilament was confirmed by using the in vitro translated amino-terminal region of PKN and glutathione S-transferase fusion protein containing the head-rod domain of each subunit of neurofilament. PKN purified from rat testis phosphorylated each subunit of the native neurofilament purified from bovine spinal cord and the bacterially synthesized head-rod domain of each subunit of neurofilament. Polymerization of neurofilament L protein in vitro was inhibited by phosphorylation of neurofilament L protein by PKN. The identification and characterization of the novel interaction with PKN may contribute toward the elucidation of mechanisms regulating the function of neurofilament.
Binding Sites↗
Cyclin-dependent kinase-2 (Cdk2) forms an inactive complex with cyclin D1 since Cdk2 associated with cyclin D1 is not phosphorylated by Cdk7-cyclin-H.
Cyclin-dependent kinases (Cdks) form complexes with cyclins, and as a consequence they generally express kinase activities. One of these Cdks, Cdk2, is known to bind with cyclins A and E, and plays an important role in the progression of the cell cycle via phosphorylation of target proteins such as the product of the retinoblastoma tumor-suppressor gene (pRB). It has been suggested that Cdk2 bound with cyclin D1 and Cdk2-cyclin-D1 complex show neither H1 histone nor pRB kinase activity. However, it is not clear whether Cdk2-cyclin-D1 has unknown targets and why Cdk2 is not activated by binding with cyclin D1. We investigated these questions using Cdk, cyclin and Cdk-cyclin complexes produced in a baculovirus expression system. Cdk2 formed a complex with cyclin D1 in this system. After extensive purification, Cdk2 was still bound to cyclin D1. The Cdk2-cyclin-D1 complex did not phosphorylate any tested substrates, such as H1 histone, pRB, SV40 large T antigen, p53, E2F-1 or a preparation of nuclear proteins from HeLa cells; in contrast, Cdk2-cyclin-E and Cdk2-cyclin-A phosphorylated these proteins. Moreover, the Cdk2-cyclin-D1 complex was not activated by incubation with Cdk4 or cyclin E. Thus, Cdk2 and cyclin D1 formed a stable complex that was not activated. In order to determine why Cdk2-cyclin-D1 lacks kinase activity, we investigated the phosphorylation of Cdk2. Under-shifted Cdk2, the active form of Cdk2, was not detected in the Cdk2-cyclin-D1 complex in the baculovirus system. In human WI-38 cells, cyclin D1 began to form a complex with Cdk2 as well as with Cdk4 from the mid-G1 phase of the cell cycle. The Cdk2 bound to cyclin D1 in human cells was also the inactive form that was slowly migrated. Moreover, we found that Cdk2 bound to cyclin D1 was not phosphorylated by Cdk7-cyclin-H, while Cdk2 bound to cyclin E, as well as free Cdk2, was was phosphorylated by Cdk7-cyclin-H. Additionally, Cdk2 phosphorylated by Cdk7-cyclin-H did not bind to cyclin D1. These results strongly suggest that Cdk2 forms a stable complex with cyclin D1 but is not activated because the Cdk2 molecule in the complex is not phosphorylated by Cdk7-cyclin-H and the phosphorylated Cdk2, an active form, does not bind to cyclin D1.
Animals↗
The role of the unique motifs in the amino-terminal region of PKN on its enzymatic activity.
The yeast two-hybrid system and in vitro binding assay were carried out to characterize the interaction between the amino-terminal and carboxyl-terminal region of PKN. It was revealed that the amino-terminal region containing the regulatory domain associated with the carboxyl-terminal catalytic region. A synthetic peptide, corresponding to the amino acid residues of PKN from 39 to 53, with substitution of isoleucine46 with serine was shown to become a potent substrate for PKN, and its wild type synthetic peptide inhibited the phosphorylation by PKN. These results suggest that the amino-terminal region of PKN contains the pseudosubstrate sequence and acts as an autoinhibitory region.
Amino Acid Sequence↗
Triple marker screening in native Japanese women.
Prenatal screening using the maternal serum markers alpha-fetoprotein, human chorionic gonadotropin, and unconjugated oestriol was investigated in a native Japanese population. Comparison with a Caucasian U.S. population revealed differences which led to modification of the generally used equations for risk calculations. Prenatal screening was shown to be clinically useful.
Adult↗
Optimal conditions for collection of blood samples for assay of alpha 2-macroglobulin-trypsin complex-like substance (MTLS).
We have developed an enzyme-linked immunosorbent assay (ELISA) for the specific quantification of alpha 2-macroglobulin-trypsin complex-like substance (MTLS). To exclude artifacts in measured values of MTLS, the conditions for collection of blood samples are critical. In the present study, we have determined the optimal conditions for blood collection and investigated the role of MTLS as a clinical tool for diagnosis in pancreatitis. Results obtained are as follows: (1) MTLS levels of all sera were more than 10-fold higher than the corresponding plasma; (2) MTLS levels of heparinized plasma were the lowest among plasma with three anticoagulants (sodium citrate, sodium EDTA and heparin); (3) some kinds of blood collection tubes containing heparin were not suitable for the sampling; (4) MTLS values of plasma obtained by blood collection tubes containing Trasylol and sodium EDTA were demonstrated more stable and lower than those obtained by heparin tubes; and (5) under these conditions, we can exclude elevation of MTLS values caused by inappropriate blood sampling and find the time course of the elevation reflecting clinical course of a patient with acute pancreatitis and a patient after endoscopic retrograde cholangiopancreatography (ERCP). The optimal conditions for collection of blood samples were as follows. Blood sampling should be performed by blood collection tubes containing Trasylol (50 microliters/ml blood) and sodium EDTA (1.5 mg/ml blood). The samples were immediately stored at 4 degrees C and centrifuged at 3,000 rpm for 15 min. The plasma were stored in plastic tubes at 4 degrees C until assayed.
Anticoagulants↗
Plasma alpha 2-macroglobulin-trypsin complexlike substance (MTLS) in pancreatic disease.
alpha 2-macroglobulin-trypsin complexlike substance (MTLS) was determined in plasma of pancreatic and nonpancreatic diseases using a two-step enzyme immunoassay to study the diagnostic and pathophysiological significance of MTLS. Plasma levels of MTLS in acute pancreatitis (mean +/- SD = 265.6 +/- 346.2 ng/ ml, n = 9), calcified chronic pancreatitis (128.6 +/- 257.4, n = 13), and noncalcified chronic pancreatitis (13.5 +/- 12.5, n = 10) were significantly higher than that in controls (3.6 +/- 1.8, n = 81). In other diseases such as gastric cancer, hepatoma, diabetes mellitus, and gallstones, MTLS values were not different from those of control. Plasma MTLS values showed low correlation with serum trypsin, elastase 1, pancreatic amylase, lipase, and pancreatic secretory trypsin inhibitor (PSTI). The elevation of plasma MTLS values in acute pancreatitis suggests that plasma MTLS levels reflect that protease is inappropriately activated in pancreatic acinar cell and released into the circulation and that the determination of MTLS can be useful for diagnosis and pathophysiology of acute pancreatitis and chronic pancreatitis.
Adult↗
A case of transverse colon cancer secondarily involving the liver, duodenum, and pancreas.
A 68-year-old woman presented with transverse colon cancer invading the liver, duodenum, and pancreas. The patient underwent a curative resection including a right hemicolectomy, partial hepatectomy, and pancreaticoduodenectomy (PD). The pathological examination showed adenocarcinoma of the colon with a direct extension into the duodenum, liver, and pancreas. Several lymph nodes were also involved. The patient is still alive and disease-free 2 years and 6 months after the operation. This case illustrates that even in patients with locally advanced colon cancer, a favorable prognosis can be obtained by aggressive surgery incorporating the resection of the adjacent involved organs.
Adenocarcinoma↗
Histomorphometric study of ribs with looser zones in Itai-itai disease.
Twelve Looser zones and 17 healing bands of the ribs obtained from autopsy cases of Itai-itai disease were analyzed by bone histomorphometry. Furthermore, proper cancellous tissue of the ribs from 24 autopsy cases of Itai-itai disease with Looser zones or with the healing bands, 27 autopsy cases of Itai-itai disease without such lesions, and 29 control cases were studied by the same method to pursue the histogenesis of Looser zones. In translucent zones of Looser zones, 94% of the cancellous bone was occupied by thick woven bone in which 72% was woven osteoid and 22% was woven mineralized bone. In adjacent scleroses, 71% of the cancellous bone was occupied by woven bone in which 37% was woven mineralized bone, and 34% was woven osteoid; 53% of the cancellous bone consisted of mineralized bone. As compared with those in translucent zones, woven osteoid was decreased, and mineralized bone was increased significantly in the cancellous bone of adjacent scleroses. A significant increase of lamellar mineralized bone and a decrease of woven bone in healing bands were observed as compared with those in Looser zones. These findings suggest that the healing starts from the edge of the Looser zone, and slowly proceeds toward the center. In the cancellous bone of the ribs, the volume, thickness, and surface of osteoid and woven bone were significantly increased in patients with Itai-itai disease, with Looser zones as compared with those without Looser zones. It was concluded that Looser zones seem to occur in severe osteomalacic bones that contain abundant woven bone in the patients of Itai-itai disease.
Aged↗
Regulation of IFN-alpha/beta genes: evidence for a dual function of the transcription factor complex ISGF3 in the production and action of IFN-alpha/beta.
BACKGROUND: Efficient production of interferons (IFNs) in virally infected cells is an essential aspect of the host defence. The transcription factor complex ISGF3 (IFN-stimulated gene factor 3) was originally identified as a critical mediator of the IFN signal; it is formed upon IFN receptor (IFNR) stimulation and binds to ISREs (IFN-stimulated response elements) to activate IFN-inducible genes. It has recently been shown that the DNA binding component of ISGF3, p48 (ISGF3gamma) also binds to virus-inducible elements in the IFN-alpha/beta genes, suggesting a potential new role of p48 in IFN production. RESULTS: Primary cells from mice with a targeted disruption of the p48 gene show severe defects in virus-induced IFN-alpha/beta gene expression. A similar defect was also observed in cells lacking type I IFNR or Stat1, further demonstrating the role of IFN signalling in the induction of these IFN genes. ISGF3 in fact binds to the virus-inducible elements within the IFN-alpha/beta promoters. We also provide evidence showing that these elements are additionally controlled by an unidentified factor(s) which presumably triggers the primary phase of IFN gene induction. CONCLUSIONS: Our results demonstrate that the IFN signal transducing complex ISGF3 plays a crucial role in IFN production and suggest that ISGF3 may participate directly in the activation of IFN-alpha/beta promoters. This dual function of ISGF3 may insure the efficient operation of this cytokine system in the host defence.
Animals↗
The existence of thyroid hormone responsive element, TRE, was confirmed in the first intron of rat alpha 1-acid glycoprotein gene.
A set of acute-phase proteins was found to have been induced in rat after triiodothyronine (T3) treatment. To study the mechanism of gene activation by T3, the rat gene of alpha 1-acid glycoprotein (AGP), one of the major acute-phase proteins, was cloned and analyzed. CAT assay identified a thyroid hormone responsive element (TRE) in the first intron of the AGP gene and showed that mutations introduced into the TRE region destroyed the TRE activity. Gel shift assay and methylation interference assay showed that the thyroid hormone receptor bound to the TRE. The TRE identified here had a palindromic structure and was highly homologous to other known TREs.
Acute-Phase Proteins↗
Effects of a bradykinin receptor antagonist (HOE140) on taurocholate-induced acute pancreatitis in rats.
The effect of a potent and long-acting bradykinin B2-receptor antagonist (HOE140) on acute pancreatitis induced by retrograde infusion of trypsin and taurocholate into the pancreatic duct was studied in rats. HOE140 was administered subcutaneously immediately before and 3 h after the induction of pancreatitis and the systemic blood pressure, ascites volume, serum amylase, 24-h survival rate, and pathology of the pancreas were evaluated. Plasma concentrations of bradykinin increased significantly 15 min after the induction of pancreatitis and decreased to basal levels at 90 min. HOE140 (0.1 mg/kg) alleviated hypotension developing immediately after the induction of pancreatitis and reduced the ascites volume. The 24-h survival rate in rats treated with 0.1 mg/kg HOE140 (70.3%) was significantly higher than that in controls (35.6%). Treatment with 0.01, 0.3, 1.0, and 3.0 mg/kg of HOE140, however, had no beneficial effect on the survival rate. Ascites volume, serum amylase, and pathology of the pancreas at 24 h were not improved by treatment with HOE140. These data suggest that HOE140 may improve the survival rate by maintaining hemodynamics in the early stage of experimental acute pancreatitis.
Acute Disease↗
Establishment of a therapeutic model for retroviral infection using the genetic resistance mechanism of the host.
Resistance to retroviral infection is often regulated by multiple genes that control different aspects of the host-virus interaction. Genetically distinct inbred strains of mice differ in their susceptibility to retrovirus and have allowed the identification of several host-resistant loci that regulate the host defense mechanism to retroviral infection. Using the murine retrovirus infection system, a therapeutic model has been developed of retrovirus infection in association with the resistant mechanism of host genes. The most effective result achieved with the model was when using bone marrow transplantation of retrovirus-resistant cells with receptor interference function, which was genetically defined by the Fv-4 resistant gene. The possible application of these findings to the gene therapy of retrovirus-induced disease of humans is discussed.
Animals↗
[Clinical study on bacteremia in patients with liver cirrhosis].
Infections and fever are frequent in patients with liver cirrhosis. Study on bacteremia in cirrhotic patients has not been reported in Japan. In a 16 year period from 1979 to 1994, we collected 39 cases with 40 episodes and 44 microorganisms of bacteremia for this study. The incidence of bacteremia in cirrhotic hospital admissions was 4.8% (39/808). Gram negative bacteria were the predominant microorganisms of bacteremia (66%, 29/44). Among them, Escherichia coli, Klebsiella pneumoniae, Vibrio sp. were the three most commonly detected microorganisms. Pseudomonas aeruginosa bacteremia has not been detected. Laboratory data of cirrhotic patients showed that positive blood culture patients had significantly lower serum albumin, prothrombin time and hepaplastin test than negative patients. Focal infection could be diagnosed in only 45% (20/44). The mortality rate was 28% (11/39), but the bacteremia related death (by septic shock) were only 2 cases. The other causes of death were hepatic failure in 9 cases. In conclusion, bacteremia is a important complication of liver cirrhosis. Blood culture is necessary in cirrhotic patients with fever.
Adult↗
Pneumonitis during interferon and/or herbal drug therapy in patients with chronic active hepatitis.
We report four cases of acute pneumonitis due either to interferon, or a herbal drug, "Sho-saiko-to", or both in combination, in patients with chronic active hepatitis, focusing on its pathogenesis and response to prednisolone therapy. These cases shared common clinical features: fever, dry cough, dyspnoea, hypoxaemia, diffuse infiltrates both on chest radiography and chest computed tomography, restrictive pulmonary functional impairment, and alveolitis on examination of transbronchial lung biopsy, all of which suggest acute interstitial pneumonia. Furthermore, lymphocytosis was observed in association with the dominant CD8+ T-cell subset in bronchoalveolar lavage fluid. A lymphocyte stimulation test using peripheral blood was positive to interferon in one case and to Sho-saiko-to in another. All patients responded to oral prednisolone therapy. Peripheral soluble interleukin-2 receptor levels decreased in parallel with improvement in the clinical course. All patients were free of symptoms with a follow-up of 1-3 yrs. We conclude that interferon- and/or Sho-saiko-to-induced acute pneumonitis may be due to allergic-immunological mechanisms rather than toxicity, and that peripheral levels of soluble interleukin-2 receptor appear to be good markers of disease activity.
Adult↗
Thyrotropin induces G1 cyclin expression and accelerates G1 phase after insulin-like growth factor I stimulation in FRTL-5 cells.
We have investigated the mechanism by which TSH pretreatment potentiates insulin-like growth factor I (IGF-I)-induced DNA synthesis in FRTL-5 cells. As previously described, pretreatment with TSH increased IGF-I-induced DNA synthesis, suggesting that the effect of TSH is mediated through the cAMP pathway. TSH and A kinase activators required at least 12 h to precondition cells to respond to IGF-I stimulation. The presence of cycloheximide abolished the effect of TSH to increase IGF-I-induced DNA synthesis. When the time course of thymidine uptake after IGF-I addition was studied, TSH pretreatment increased the maximum DNA incorporation and shortened the G1 phase interval. These results indicated that some proteins induced by TSH are required for the effect of TSH on IGF-I activity, and the proteins are important for cell cycle progression. Cyclins are key regulators of the cell cycle; therefore, we investigated the expression of cyclins D1 and E after TSH stimulation. TSH- and A kinase-activating agents increased the expression of cyclins D1 and E after 24 h. The same amounts of cyclins D1 and E induced by IGF-I were increased after TSH pretreatment. TSH pretreatment induced the expression of G1 cyclin in FRTL-5 cells, and IGF-I caused the accumulation of enough G1 cyclins to drive the cell cycle from G1 to S phase in a short time, which accounts for the effect of TSH on IGF-I induced DNA synthesis.
Animals↗
Absolute structural determination of stevastelin B.
Stevastelin B, obtained from a culture of a Penicillium sp. NK374186, is a novel depsipeptide containing three amino acids and 3,5-dihydroxy-2,4-dimethylstearic acid. The stereochemistry of the three amino acids was determined by HPLC analysis, and the relative configuration of the 3,5-dihydroxy-2,4-dimethylstearic acid was elucidated by chemical conversion and NMR analysis. The absolute stereochemistry of stevastelin B was determined by synthetic methods.
Anti-Bacterial Agents↗