[Carbonic anhydrase II deficiency].
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Acidosis, Renal Tubular↗
Biomedical subjects
H Murakami
Publications and source records attributed to H Murakami.
Molecular mechanisms of development of multiple endocrine neoplasia 2 by RET mutations.
Biological and biochemical effects of multiple endocrine neoplasia type 2A (MEN-2A), type 2B (MEN-2B) and familial medullary thyroid carcinoma (FMTC) mutations on Ret function were investigated by transfection of NIH 3T3 cells. All mutations examined conferred transforming activity on Ret at variable levels. Cysteine mutations detected in MEN-2A and FMTC induced disulphide-linked homodimers of Ret on the cell surface, leading to activation of its intrinsic tyrosine kinase. Of these cysteine-mutated proteins, Ret with a codon 634 mutation had the highest transforming activity. The activity of Ret with a codon 609, 611, 618 or 620 mutation was approximately three- to five-fold lower than that of Ret with a codon 634 mutation. The first four mutations impaired the Ret cell surface expression or its correct maturation, resulting in the low transforming activity. On the other hand, the MEN-2B mutation appeared to activate Ret by an intramolecular mechanism without dimerization. In addition, we investigated the role of tyrosines present in the intracellular domain for the transforming activity of the mutant Ret proteins. As a result, we found that tyrosine 905 is essential for the transforming activity of the MEN-2A-Ret mutant protein whereas tyrosines 864 and 952 are critical for that of the MEN-2B-Ret mutant protein. Moreover, it turned out that tyrosine 1062 regulates the activity of both MEN-2A-Ret and MEN-2B-Ret and represents a binding site for the Shc adaptor protein.
Carcinoma, Medullary↗
[A survey of malignant gliomas accompanied with visceral malignancies].
From January 1984 to December 1997, a total of six patients with malignant gliomas accompanied with visceral malignancies were treated in our department. We reviewed their radiological findings and clinical course. They consisted of four patients with glioblastoma and two patients with anaplastic astrocytoma. Classified according to visceral malignancies, three cases had colon cancer and the rest consisted of thyroid, uterus and prostate cancers. In radiological examinations of the brain (CT scans and MR images), these gliomas were relatively well-circumscribed, as if they were metastatic brain tumors. Of all these six cases, two cases survived more than five years and there were two cases in which there was recurrence within a year. Particularly, in four cases, whose gliomas developed after the treatment for visceral malignancies, two cases survived long-term (more than five years) and there was recurrence in only one case. We speculated that visceral malignancies could affect the nature of glioma progression. Thinking about its mechanisms, we hypothesized as follows; (1) visceral malignancies may activate non-specific, or common antitumor, immunity. (2) visceral malignancies may produce some factors which could affect the biological nature of gliomas. (3) glioma accompanied with visceral malignancy may have genetic uniqueness. Although the cases were limited in number, the present study may be helpful in designing the treatment for such cases and in elucidating the invasive nature of gliomas.
Adult↗
[Legionella pneumonia--epidemiology, clinical characteristics and development of diagnosis].
We have characterized clinical and diagnostic features in 18 cases of Legionella pneumonia. Age average of patients was 62.0 years old (male: female = 14:4) and underlying diseases were observed in 12 patients. Legionella pneumonia were diagnosed in 3, 5, 7 and 9 cases by culture, serum antibody measurement, urinary antigen detection and PCR, respectively. Sixteen cases were caused by L. pneumophila, while the other 2 cases were due to L. bozemanii and L. pneumophila or L. dumoffii. Chest X-rays of those patients showed multiple pneumonia shadows in 14 cases, alveolar shadows in 10 cases, pleural effusion in 5 cases. Blood-gas analysis on admission indicated hypoxemia in all cases with abnormal A-a DO2. Laboratory findings showed abnormal data in WBC, CRP, LDH, CPK and liver function tests (ex. GOT, GPT) in most cases. Serum antibody testing showed positive by 5 weeks after onset of pneumonia, but 10 cases of Legionella pneumonia diagnosed by other techniques were judged to be negative. In urinary antigen detection test, 6 and 2 cases showed positive 1 and 4 weeks after onset of pneumonia, respectively. Macrolide antibiotics were administered in all cases during the episode, but delay of macrolide administration was observed in 3 of 4 cases of dead outcome. Serum antibody measurement, urinary antigen detection and PCR, in addition to culture of bacteria, may be required for exact diagnosis of Legionella infection.
4-Quinolones↗
[alpha-thalassemia accompanied with Gilbert's syndrome].
A 15-year-old boy was admitted to our hospital because of microcytic hypochromic erythrocytosis and hyperbilirubinemia in October 1996. The laboratory findings were RBC: 597 x 10(4)/microliter, Hb: 13.1 g/dl, Ht: 40.8%, MCV: 70fl, MCH: 22pg, total bilirubin: 3.2 mg/dl (indirect: 2.2 mg/dl), s-Fe: 99 micrograms/dl, and ferritin: 25 ng/ml. Routine liver function tests were normal. There were no findings of hemolysis except for an increase in serum indirect bilirubin and reticulocytes. Decreased erythrocyte osmotic fragility was observed. The patient's mother and sister also showed microcytic hypochromic erythrocytosis. PCR analysis of genomic DNA from this patient, his mother, and his sister confirmed the diagnosis of the alpha-thalassemia trait. However, the bilirubin-UDP-glucuronosyltransferase 1 (B-UGT 1) gene mutation and the findings of the fasting test indicated the simultaneous presence of Gilbert's syndrome. The association of these two diseases in the same patient appears to be rare, especially in Japan because of the low incidence of thalassemia in this country. We concluded that the hyperbilirubinemia was caused by decreased bilirubin clearance, not by increased erythrocyte destruction.
Adolescent↗
[Effect of hyaluronidase on porcine pancreatic elastase-induced lung injury].
The present study was conducted to investigate the effects of hyaluronidase on elastase-induced lung injury in rats. Male Wistar rats were divided into 4 groups: 1) Control group, single tracheal instillation of 0.3 ml saline; 2) PPE group, single tracheal instillation of 120 micrograms porcine pancreatic elastase (PPE); 3) HD group, intravenous injection of 240 mg/kg hyaluronidase (HD); and 4) HE + PPE group, intravenous injection of HD before single tracheal instillation of PPE. Cellular component and protein concentration in bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) activity and hyaluronan content in lungs were examined 24 hours after treatment. After 8 weeks of treatment, hyaluronan content in the lungs and physiological parameters such as total lung capacity (TLC), functional residual capacity (FRC) and static compliance (Cst) were examined. The number of BALF nucleated cells in the HD + PPE group 6 h after treatment, and lung MPO activity in the HD group after 1 h and 3 h. were both higher than the corresponding measurements in the PPE group. After 6 h of treatment, the number of BALF nucleated cells in the HD + PPE group was significantly higher than in the HD group. The BALF albumin concentrations in the HD + PPE and HD groups were also significantly higher than in the control group. After 8 weeks of treatment, the measurements of TLC and Cst indicated greater emphysematous changes in the HD + PPE group. These results suggest that decreased interstitial HA accelerates acute inflammation and emphysematous changes in elastase-induced lung injury.
Animals↗
Intussuception as a complication of chronic lymphocytic leukemia.
The case of a 58-year-old man with chronic lymphocytic leukemia (B-cell type) who later developed an intussuception of the small intestine due to a tumor is described. The histopathological findings of the removed tumor were compatible with those of diffuse small lymphocytic lymphoma (B-cell type). The residual tumor became smaller with CHOP therapy. It is considered that CLL cell infiltration into the small intestine resulted in intussuception. Since many tumors and lymphomas can form polypoid lesions causing an intussuception. This is a possible complication of CLL and it could occur even when the WBC count is well controlled.
Humans↗
Binding of NF-Y transcription factor to one of the cis-elements in the myeloperoxidase gene promoter that responds to granulocyte colony-stimulating factor.
The expression of the myeloperoxidase (MPO) gene is restricted to cells of the myeloid cell lineage and is induced by granulocyte colony-stimulating factor (G-CSF). In this study, a series of deletion mutations was introduced in the promoter of the human MPO gene, which was then fused to the chloramphenicol acetyltransferase gene. The G-CSF-induced promoter activity was examined in mouse myeloid precursor FDC-P1 transformants that constitutively express the G-CSF receptor. A G-CSF-responsive element (GRE) in the MPO gene was found approximately 800 base pairs upstream from the transcription initiation site. When the 5'-flanking region of the human MPO gene contained this element, it yielded promoter activity in cells cultured with G-CSF but not in cells cultured with interleukin 3. Gel shift assays with the element showed that a specific nuclear factor(s) (NF/G-CSF) binds to the element. The NF/G-CSF was purified by affinity chromatography using an oligonucleotide of GRE. Protein sequence analysis of the purified NF/G-CSF indicated that NF/G-CSF is a ubiquitous transcription factor, NF-Y, which is composed of three subunits. The recombinant NF-Y was then shown to bind to GRE in a combination of the three subunits.
Animals↗
Characterization of Ret-Shc-Grb2 complex induced by GDNF, MEN 2A, and MEN 2B mutations.
We analyzed the intracellular signalling pathway through Ret activated by glial-cell-line-derived neurotrophic factor (GDNF), multiple endocrine neoplasia (MEN) 2A and 2B mutations. The results showed that all of them induce a signal transducing complex consisting of Ret, Shc, and Grb2 proteins. In addition, GDNF clearly activated a Ras-MAPK pathway in human neuroblastoma cells. Rat is expressed mainly as two isoforms that differ in the carboxy-terminal sequence: a long isoform (1114 amino acids) and a short isoform (1072 amino acids). The long isoform contains the consensus sequence for binding of the Shc PTB domain but not of its SH2 domain, whereas the short isoform has the consensus sequences for binding of both domains. In vitro binding assay revealed that the long isoform of the MEN2A-Ret protein and both isoforms of the MEN2B-Ret protein bound preferentially to the Shc PTB domain. On the other hand, the short isoform of MEN2A-Ret bound to the PTB and SH2 domains. In neuroblastoma cells expressing both isoforms of Ret, its activation by GDNF also resulted in the binding of both domains. GDNF and MEN 2A mutations activate Ret by inducing its dimerization, whereas the MEN 2B mutation increases Ret catalytic activity without dimerization. Our results thus suggest that Ret dimerization might be required for binding of the Shc SH2 domain to the short isoform.
3T3 Cells↗
Jak1 plays an essential role for receptor phosphorylation and Stat activation in response to granulocyte colony-stimulating factor.
The proliferation and differentiation of neutrophils is regulated by granulocyte-specific colony-stimulating factor (G-CSF). G-CSF uses a receptor of the cytokine receptor superfamily and, in common with all members of the family, induces the tyrosine phosphorylation and activation of members of the Janus protein tyrosine kinase (Jak) family. In both myeloid cells and a human fibrosarcoma cell line expressing the G-CSF receptor, G-CSF induces the tyrosine phosphorylation and activation of Jak1, Jak2, and Tyk2. In addition, G-CSF induces the tyrosine phosphorylation of the receptor and members of the signal transducers and activators of transcription (Stat) family, including Stat3, as well as Stat1 and Stat5, depending on the cells involved. Using mutant cell lines lacking various Jaks, we show here that Jak1 is critical for G-CSF-mediated Stat activation, whereas Jak2 or Tyk2 are either not required or play redundant or ancillary roles. In the absence of Jak1, G-CSF induces activation of Jak2 and Tyk2, but fails to induce receptor tyrosine phosphorylation and induces dramatically reduced levels of Stat activation. A kinase-inactive Jak2, when overexpressed in cells lacking endogenous Jak2, can suppress Jak1 activation, receptor phosphorylation, and Stat activation, suggesting competition in the receptor complex either for Jak1 binding or substrates. Because the requirement for Jak1 is very similar to that previously shown for interleukin-6 signaling, the data support the concept that the G-CSF receptor and gp130 are both structurally and functionally similar.
Animals↗
Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype.
We investigated the transforming activity of the ret proto-oncogene with a mutation in cysteine 609, 611, 618, 620, 630, or 634 detected in patients with multiple endocrine neoplasia type 2A (MEN 2A), familial medullary thyroid carcinoma (FMTC), or Hirschsprung's disease. Of these cysteine mutations, codon 634 mutations are known to be correlated with the development of MEN 2A, whereas codon 609, 618, or 620 mutations were detected in two-thirds of FMTCs and in several cases of Hirschsprung's disease. Analysis of a total of 18 mutant genes revealed that codon 634 mutations have the highest transforming activity. The activity of ret with a codon 609, 611, 618, or 620 mutation and with a codon 630 mutation was approximately 3- to 5-fold and 2-fold lower than that of ret with a codon 634 mutation, respectively. In addition, different amino acid substitutions for the same cysteine displayed comparable transforming activity. The expression of the cell surface form of Ret with codon 609, 611, 618, or 620 mutation was very low compared with that of Ret with codon 634 mutation, indicating that the former four mutations might impair transport of Ret to the plasma membrane, as observed for several Hirschsprung mutations affecting the Ret extracellular domain. These results thus suggest that mutations in cysteine 609, 611, 618, or 620 may have the potential to develop Hirschsprung's disease in addition to MEN 2A and FMTC.
3T3 Cells↗
Immunological abnormalities in splenic marginal zone cell lymphoma.
The clinical features of patients with splenic marginal zone cell lymphoma (SMZCL) have rarely been reported. In the present study, immunological abnormalities, particularly hematological abnormalities, observed in SMZCL were described. Autoimmune hemolytic anemia, immune thrombocytopenia, and appearance of lupus anticoagulant were observed in 2 of 3 patients with SMZCL. Other abnormal data including monoclonal gammopathy and cold agglutinin were also observed in 2 of the 3 patients. Immunological abnormalities may be characteristic complications in patients with SMZCL and must be followed carefully, since they may be a reliable marker of this type of lymphoma activity.
Aged↗
Electrophysiology of rabbit ventricular myocytes following sustained rapid ventricular pacing.
The present study examined changes in electrophysiological properties of ventricular myocytes isolated from rabbit hearts after 2-3 weeks of rapid ventricular pacing. Left ventricular end-diastolic pressure at completion of the pacing period was nearly four-fold greater than in age-matched controls, although there was no significant change in heart weight/body weight ratio. Action potentials recorded in current-clamp mode at low stimulation frequencies were significantly longer in duration and phase 1 diminished in isolated myocytes from paced hearts compared with control. In voltage-clamp experiments. L-type Ca2+ current (ICa) density was not different between groups of myocytes, but the maximum current (at + 10 mV) elicited by 10 microM isoproterenol was approximately 40% less in myocytes from paced hearts. In contrast, maximum ICa elicited by 10 microM forskolin was similar in both groups. The 4-aminopyridine-sensitive transient outward current (Ito) was 65% less (at + 60 mV) in myocytes from paced hearts than from control. However, after approximately 24 h in culture, Ito density in these myocytes returned toward control values. Despite marked reduction in Ito density, the inward rectifier current (IK1) was not different between groups. These data demonstrate that Ito is significantly and reversibly decreased in myocytes from rapidly paced hearts, which may partly account for marked changes in action potential morphology. Although basal ICa was not altered in this group of myocytes compared with control, its modulation by beta-agonists was markedly blunted, probably through a decrease in receptor density or coupling to adenylyl cyclase. These changes in myocyte K+ and Ca2+ channel behavior in paced hearts may relate to impaired contractility and arrhythmogenesis that is characteristic of the intact failing heart.
Action Potentials↗
Combined use of detachable coil against persistent mechanical hemolysis after transcatheter occlusion using Rashkind umbrella device in adult patient with patent ductus arteriosus.
Mechanical hemolysis after transcatheter occlusion of the patent ductus arteriosus using the Rashkind umbrella device has been postulated as a rare, but serious complication, even necessitating surgical repair. A rare, case of an adult patient with massive hemolytic anemia, successfully controlled by the combined use of several detachable coil devices is reported. The use of coil devices might be considered as a therapeutic option in such cases.
Anemia, Hemolytic↗
Assignment of the human gene for KBF2/RBP-Jk to chromosome 9p12-13 and 9q13 by fluorescence in situ hybridization.
The transcription factor KBF2 has been characterized as a factor that binds to the NFkB site of mouse major histocompatibility complex (MHC) class I genes and its amino acid sequence has been shwn to be identical to those of members of the recombination signal-sequence binding protein (RBP-Jk) family. Previous studies by Amakawa et al. (Genomics 17, 306-315, 1993) demonstrated that the functional gene is localized at human chromosome 3q25. However, in the present study we showed by in situ hybridization with the functional KBF2/RBPJk cosmid clone that the gene is localized at 9p12-13 and 9q13, namely, at the same loci as pseudogenes that were reported previously (Zhang et al, Jpn J Human Genet 39, 391-401, 1994).
Animals↗
Reduction of oxysterol levels up-regulates HMG-CoA reductase activity in rat liver.
Cholesterol regulates hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity by feedback inhibition. It has been suggested that oxidized derivatives of cholesterol (oxysterols) play an important role, as an intracellular mediator, in the feedback inhibition of cholesterol biosynthesis. We, therefore, investigated the role of intracellular oxysterols in the regulation of HMG-CoA reductase activity. Rats were fed with food (control), cholesterol, clofibrate as a potentiator of the microsomal monooxygenase cytochrome P-450 enzyme system, ketoconazole as a strong inhibitor of the system, or butylated hydroxytoluene (BHT) as an antioxidant. We analyzed and compared hepatic microsomal oxysterol levels among the groups. The results of this study indicated that the oxysterol level, especially 7beta-hydroxycholesterol and 7-ketocholestrol, in the liver was lowered by the administration of ketoconazole and BHT, and HMG-CoA reductase activity was increased in response to these agents. However, there was no change in the HMG-CoA reductase activity, after the administration of clofibrate. We conclude that reduced levels of oxysterol may release the inhibitory effect on the HMG-CoA reductase enzyme and lead to up-regulation of the enzyme.
Animals↗
Possible involvement of protein kinase C in the aberrant regulation of erythropoiesis in polycythemia vera.
To examine the possible involvement of protein kinase C (PKC) in the regulation of aberrant erythropoiesis of polycythemia vera (PV), we investigated the effects of PKC inhibitors on in vitro burst-forming unit of erythroid (BFU-E)-derived colony formation by bone marrow (BM) and peripheral blood (PB) cells obtained from five PV patients. 1-(Isoquinoline-sulfonyl)-2-methylpiperazine dihydrochloride (H-7), an inhibitor of PKC, suppressed the colony formation by BM and PB cells of PV patients in a dose-dependent manner, similar to those in the normal individuals. However, the 50% inhibitory concentrations (IC50) of H-7 in PV BM and PB cells were significantly higher than those in normal BM and PB cells, respectively. The BFU-E-derived colony formation by PV BM and PB cells was also less affected by Staurosporine, another PKC inhibitor, than those in a normal subject. Furthermore, in the study of PV, the IC50 of endogenous colonies formed in the absence of erythropoietin was much higher than that of colonies formed by the stimulation of erythropoietin. By contrast, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide dihydrochloride (HA1004), a cyclic AMP-dependent kinase inhibitor, did not have such inhibitory effects. These findings suggest that PKC, as a second messenger, is involved in the regulation of aberrant erythropoiesis of PV.
Adult↗
Trp64Arg mutation of beta3-adrenergic receptor in essential hypertension: insulin resistance and the adrenergic system.
A putative pathogenic mutation in the beta3-adrenergic receptor gene (Trp64Arg) has been reported to be associated with higher diastolic blood pressure as well as clinical features of the insulin resistance syndrome and an earlier onset of non-insulin-dependent diabetes mellitus (NIDDM) in Pima Indians and Finns. Because essential hypertension is reported to be associated with insulin resistance, we studied the mutation in Japanese patients with essential hypertension to clarify associations of this mutation with hypertension, insulin resistance, and basal adrenergic state in hypertensive subjects. The allele frequency of the mutation (Arg) in patients with essential hypertension was similar to that in control subjects (35 of 202 alleles [17.3%] v 27 of 146 [18.5%], respectively, P > .7). Insulin sensitivity measured by hyperinsulinemic euglycemic glucose clamp and plasma norepinephrine and epinephrine levels were also similar in hypertensive subjects with and without the mutation. These data suggest that Trp64Arg mutation in the beta3-adrenergic receptor gene does not play a major role in susceptibility to essential hypertension or in insulin resistance and basal adrenergic state in hypertension.
Adult↗