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Biomedical subjects

M Maki

Publications and source records attributed to M Maki.

At least 73 records · Page 4Linked to original sources
PubMed1997

Celiac patients predominantly inherit HLA-DPB1*0101 positive haplotype from HLA-DQ2 homozygous parent.

The DQA1*0501 and DQB1*0201 alleles (hereafter DQ2) confer genetic susceptibility to celiac disease (CD). Some studies have indicated that the DPB1, DMB, and TAP loci, that are located close to the DQ genes, could also together with DQ or independently confer genetic susceptibility to CD. Some others have claimed that these associations result merely from linkage disequilibrium, a hallmark of the MHC, that often makes the precise mapping of susceptibility genes difficult. To evaluate further the role of class II genes in CD, we analyzed segregation of DPB1 alleles in families with CD. In particular, we analyzed families where one of the parents was homozygous for the DQ2 risk allele but heterozygous for DPB1*0101, an allele claimed to be an additional risk allele. We reasoned that if DPB1*0101 would not play a role in CD, then patients should inherit the DQ2 haplotypes randomly from a homozygous parent. We here present evidence that, in all 6 informative families, those DQ2 positive haplotypes that also include the DPB1*0101 allele, rather than those without DPB1*0101, are predominantly segregated to the index patient from the parent homozygous for the DQ2 risk marker (p = 0.03 as compared to their healthy siblings). If confirmed in larger studies the results indicate that despite DQ2 other genes in or near the MHC may associate with CD.

Celiac Disease↗
PubMed1997

Oculopharyngeal muscular dystrophy in Japan.

Oculopharyngeal muscular dystrophy (OPMD) in the European population has been frequently diagnosed, but except for one black family, the occurrence in other ethnic groups is uncertain. We identified two unrelated OPMD Japanese families, including 34 affected individuals. Major clinical manifestations were bilateral ptosis and dysphagia starting after age 40. Histologic studies of limb muscles revealed mild myogenic changes, occasional rimmed vacuoles, and small angulated fibers. By contrast, cricopharyngeal muscle showed a marked loss of fibers and massive proliferation of connective tissue. Intranuclear tubulofilamentous inclusions (ITFI) of 8.5 nm outer diameter were observed in 2-5% of the nuclei in four different biopsied muscles. One patient with recurrent aspirations underwent successful cricopharyngeal myotomy. Aerodynamic examination was useful to evaluate velopharyngeal closure function. Our investigations revealed that OPMD is a geographically widespread disorder, and ITFI may be the specific morphologic hallmark.

Biopsy↗
PubMed1997

Crystal structure of calcium bound domain VI of calpain at 1.9 A resolution and its role in enzyme assembly, regulation, and inhibitor binding.

The three dimensional structure of calcium-bound domain VI of porcine calpain has been determined to 1.9 A resolution. The crystal structure reveals five EF-hands, one more than previously suggested. There are two EF-hand pairs, one pair (EF1-EF2) displays an 'open' conformation and the other (EF3-EF4) a 'closed' conformation. Unusually, a calcium atom is found at the C-terminal end of the calcium binding loop of EF4. With two additional residues in the calcium binding loop, the fifth EF-hand (EF5) is in a 'closed' conformation. EF5 pairs up with the corresponding fifth EF-hand of a non-crystallographically related molecule. Considering the EF5's role in a homodimer formation of domain VI, we suggest a model for the assembly of heterodimeric calpain. The crystal structure of a Ca2+ bound domain VI-inhibitor (PD150606) complex has been refined to 2.1 A resolution. A possible mode for calpain inhibition is discussed.

Acrylates↗
PubMed1996

Involvement of the proteasome in the programmed cell death of NGF-deprived sympathetic neurons.

Sympathetic neurons undergo programmed cell death (PCD) upon deprivation of nerve growth factor (NGF). PCD of neurons is blocked by inhibitors of the interleukin-1beta converting enzyme (ICE)/Ced-3-like cysteine protease, indicating involvement of this class of proteases in the cell death programme. Here we demonstrate that the proteolytic activities of the proteasome are also essential in PCD of neurons. Nanomolar concentrations of several proteasome inhibitors, including the highly selective inhibitor lactacystin, not only prolonged survival of NGF-deprived neurons but also prevented processing of poly(ADP-ribose) polymerase which is known to be cleaved by an ICE/Ced-3 family member during PCD. These results demonstrate that the proteasome is a key regulator of neuronal PCD and that, within this process, it is involved upstream of proteases of the ICE/Ced-3 family. This order of events was confirmed in macrophages where lactacystin inhibited the proteolytic activation of precursor ICE and the subsequent generation of active interleukin-1beta.

Acetylcysteine↗
PubMed1996

An alpha-mercaptoacrylic acid derivative is a selective nonpeptide cell-permeable calpain inhibitor and is neuroprotective.

Overactivation of calcium-activated neutral protease (calpain) has been implicated in the pathophysiology of several degenerative conditions, including stroke, myocardial ischemia, neuromuscular degeneration, and cataract formation. Alpha-mercaptoacrylate derivatives (exemplified by PD150606), with potent and selective inhibitory actions against calpain, have been identified. PD150606 exhibits the following characteristics: (i) Ki values for mu- and m-calpains of 0.21 microM and 0.37 microM, respectively, (ii) high specificity for calpains relative to other proteases, (iii) uncompetitive inhibition with respect to substrate, and (iv) it does not shield calpain against inactivation by the active-site inhibitor trans-(epoxysuccinyl)-L-leucyl-amido-3-methylbutane, suggesting a nonactive site action for PD150606. The recombinant calcium-binding domain from each of the large or small subunits of mu-calpain was found to interact with PD150606. In low micromolar range, PD15O6O6 inhibited calpain activity in two intact cell systems. The neuroprotective effects of this class of compound were also demonstrated by the ability of PD150606 to attenuate hypoxic/hypoglycemic injury to cerebrocortical neurons in culture and excitotoxic injury to Purkinje cells in cerebellar slices.

Acrylates↗
PubMed1996

[A case of dilated cardiomyopathy with early back-diffusion of 123I-BMIPP].

A 28-year-old woman was pointed out cardiomegaly and diffuse hypokinesis of left ventricle by ultrasonography in community hospital. Coronary angiography showed normal coronary artery and, left ventriculography revealed diffuse hypokinesis (LVEF 40%). She was diagnosed idiopathic dilated cardiomyopathy by myocardial biopsy and other clinical information. Myocardial scintigraphy with 201Tl. revealed dilatation of left ventricle and diffuse inhomogeneous accumulation of 201 Tl. Dynamic 123I-BMIPP SPECT image 2 minutes after injection showed BMIPP accumulation in all segment, though, static image 15 minutes after injection indicated reduced BMIPP accumulation. These findings suggested existence of the early back-diffusion in inferior segment. Early back-diffusion of BMIPP may become a marker of abnormal fatty acid metabolism in patient with dilated cardiomyopathy.

Adult↗
PubMed1996

[Exposure to the technologists from radioactive patients during nuclear medicine studies].

In order to evaluate the exposure to the nuclear medicine technologists from patients who had been administrated with radiopharmaceuticals, we measured the exposure in 5 common diagnostic procedures (bone, lung, tumor scan, and brain, myocardial SPECT, n = 8 to 52) using a silicon semiconductor pocket dosimeter. We also measured the spatial dose rates at 5 cm, 50 cm, and 100 cm from skin surface of the patients (n = 10 to 21) using an ionization chamber, both 5 min after injection and right before the studies with the same procedures above. We further measured the spatial dose rate distributions around the patients in the 4 procedures (bone, renal, blood pool scan, and brain SPECT, n = 2 to 3). In results, the exposure to the technologists in each procedure was small (0.5, 0.5, 0.7, 1.6, and 0.3 muSv in each bone, lung, tumor scan, and brain, myocardial SPECT, respectively), compared with the dose limits of the medical workers. However, the dose-response relationships in cancer and hereditary effects, referred to as the stochastic effects, have been assumed linear and no threshold models; therefore, the exposure should be minimized. For this purpose, the measurements of spatial dose rates and spatial dose rate distributions were thought to be useful. The differences of these results among procedures were caused by the differences of dose distributions and physical and biological half lives of the radiopharmaceuticals. The results of the measurements in 7 consecutive weeks suggested that the direct measurement of the exposure using a high sensitive digital pocket dosimeter might result a reduced exposure to the technologists.

Adult↗
PubMed1995

Analysis of a novel defective HTLV-I provirus and detection of a new HTLV-I-induced cellular transcript.

HTLV-I generally integrates at least one full-length copy in adult T-cell leukemia (ATL) cells. A group of patients without full-length provirus have a unique conserved truncation of the provirus which retains env-pX-3'LTR. Tumor cells of a patient from this group were genetically analyzed. Analysis of the 5' and 3' cellular flanking region adjacent to the provirus suggest that the defective provirus was integrated immediately downstream of a promoter of an unknown cellular gene. The activity of the promoter was weak but was responsive to Tax-like HTLV-I LTR. The provirus may have utilized it as a substitute for the 5'LTR and thus 3'LTR may have become an alternative promoter for the cellular gene, which may give similar viral-cellular interactions to that of general cases with full-length proviruses. Surprisingly, the 3' cellular flanking region which is thought to be controlled originally by the promoter is constitutively expressed specifically in an HTLV-I producing ATL cell line HUT1O2G, in which the corresponding region is not modified by provirus. The detection of this HTLV-I-induced transcript provides a probe to find an HTLV-I inducible unknown cellular gene that may be related to the pathogenesis of ATL.

Adult↗
PubMed1995

Purification of mu-calpain by a novel affinity chromatography approach. New insights into the mechanism of the interaction of the protease with targets.

A calmodulin-binding motif is a common structural feature of a number of calpain substrates (1). Since a calmodulin-like domain has been identified in both subunits of the calpain molecule, the proposal was made that the domain(s) would recognize the calmodulin-binding motifs of the substrates prior to the enzymatic modification by calpain. In keeping with the proposal, a successful attempt to purify mu-calpain from human erythrocytes was made by using an affinity chromatography approach in which the synthetic peptide C49, containing the calmodulin-binding domain of the plasma membrane Ca(2+)-ATPase, was coupled to a Sepharose matrix. The calmodulin-like domain of the catalytic subunit of human mu-calpain expressed in Escherichia coli was also retained by the C49-Sepharose column. Both mu-calpain and the calmodulin-like domain interacted with C49 in a Ca(2+)-dependent way and were eluted from the column by Ca(2+)-chelating agents. The finding confirmed the interaction between the calmodulin-binding domain of the plasma membrane Ca(2+)-ATPase and the calmodulin-like domain of mu-calpain. Experiments were performed to establish whether irreversibly inactivated mu-calpain or its expressed C-terminal portion containing the calmodulin-like domain could activate the hydrolysis of ATP by the plasma membrane Ca2+ pump, in keeping with evident ATPase stimulation of the same pump by calmodulin. A stimulation was observed, but it was much weaker than that induced by calmodulin.

Amino Acid Sequence↗
PubMed1995

Preference of calcium-dependent interactions between calmodulin-like domains of calpain and calpastatin subdomains.

Calpastatin molecule contains four repeated inhibition domains, each having highly conserved internal regions A, B and C. The synthetic oligopeptides of regions A and C had no calpain inhibition activity while region B oligopeptide showed weak inhibition activity. Real-time biomolecular interaction analysis using a BIAcore instrument revealed that the bacterially expressed calmodulin-like domain of the calpain large subunit (L-CaMLD) and that of the small subunit (S-CaMLD) interacted, in a Ca(2+)-dependent fashion, preferentially with the immobilized synthetic oligopeptide of region A and that of region C, respectively. Calmodulin showed no specific binding to these oligopeptides. The tripartite structure of the calpastatin functional domain may confer the specific interactions with the protease domain and the two CaMLDs of calpain.

Amino Acid Sequence↗
PubMed1995

Suppression of calphobindin I (CPB I) production in carcinoma of uterine cervix and endometrium.

Calphobindin I (CPB I) is a member of the family of Ca(2+)-dependent phospholipid binding proteins collectively termed as annexins. CPB I (Annexin V) has recently been shown to be an endogenous inhibitor of protein kinase C, a key enzyme in the cellular signal transduction and its inhibition by CPB I is presumed to be related ultimately to carcinogenesis. We therefore examined the level of production of CPB I in uterine cancer cells. Immunohistochemical analysis, northern blot, and in situ hybridization showed that the production of CPB I was markedly suppressed at the level of transcription in both cervical and endometrial carcinoma cells when compared to their normal counterparts. Decrease in production of CPB I may lead to dysregulated activation of protein kinase C and, accordingly, may be involved in a disorder of cell differentiation, proliferation, and carcinogenesis.

Annexin A5↗
PubMed1995

Use of a human immunodeficiency virus type 1 Rev mutant without nucleolar dysfunction as a candidate for potential AIDS therapy.

Applications of transdominant mutants of human immunodeficiency virus type 1 (HIV-1) regulatory proteins, especially Rev mutant, have been attempted for gene therapy against AIDS, because the Rev protein is essential for viral replication. We have previously reported that a mutant Rev protein (dRev) lacking its nucleolar targeting signal remained out of nuclei in expressed cells and strongly inhibited the function of Rev. To investigate the effects of dRev on HIV-1 replication, we established several dRev-expressing human cell lines with two different vector systems and examined virus production in these cells. An HIV-1-derived vector containing drev cDNA was constructed and introduced into CD4-positive HeLa cells and cells of the human T-cell line CCRF-CEM (CEM). In dRev-expressing HeLa cells, virus replication, syncytium formation, and cell death caused by HIV-1 infection were remarkably suppressed, and the same vector also conferred a resistant phenotype on CEM cells. The production was also suppressed in CEM cells containing the drev gene driven by a cytomegalovirus promoter. In addition, we found that dRev did not cause nucleolar dysfunction in a transient assay, in contrast to other transdominant mutants and wild-type Rev. Since dRev cannot migrate into the nuclei, it is expected not to interfere with nuclear/nucleolar functions of the host cell. We conclude that dRev is one promising candidate as an antiviral molecule for gene therapy against AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Somatostatinoma of the pancreas associated with von Hippel-Lindau disease.

A 39-year-old man was admitted because of lumbago, vomiting and massive gastrointestinal bleeding. Oliguria developed a few days later, which was followed by hyperkalemia and cardiac arrest. Autopsy disclosed multiple renal cell carcinomas with diffuse metastasis to the liver, adrenal gland, psoas muscle and vertebrae. In addition, a somatostatinoma was found in the pancreas. From these findings and past history of cerebellar hemangioblastoma and spinal hemangioma he was diagnosed to have von Hippel-Lindau disease. Von Hippel-Lindau disease with islet cell tumor is very rare and is reported here with a review of literature.

Adult↗
PubMed1995

[Two cases of dilated cardiomyopathy with the relationship between the effect of beta-blocker therapy and the changes of myocardial clearance of 123I-metaiodobenzylguanidine].

Two cases diagnosed dilated cardiomyopathy received beta-blocker therapy, and underwent 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy before and after the treatment. In case 1, symptoms and cardiac function were improved in 1 month and 4 months after the treatment (LVEF increased from 19% to 32% and 40%), and myocardial clearance of MIBG decreased from 50% to 27% and 29%. In case 2, both symptoms and cardiac function were not improved in 1 month and 3 months after the treatment (LVEF was changed from 11% to 10% and 13%), and myocardial clearance was not significantly different between before (50%) and after (1 month: 46%, 3 months: 50%) the treatment. It was indicated that myocardial clearance of MIBG might depend on the extent of the improvement of cardiac function and symptoms, and might reflect the effects of beta-blocker therapy.

3-Iodobenzylguanidine↗
PubMed1994

Tumor necrosis factor alpha-induced phosphorylation of I kappa B alpha is a signal for its degradation but not dissociation from NF-kappa B.

Activation of the NF-kappa B/Rel family of transcription factors is regulated by a cytoplasmic inhibitor, I kappa B alpha. Activity of I kappa B alpha is in turn modulated by phosphorylation and proteolysis. It has been postulated that phosphorylation of I kappa B alpha leads to its dissociation from NF-kappa B, and free I kappa B alpha is targeted for rapid degradation. However, this phosphorylation-mediated dissociation event has not been demonstrated in vivo. We demonstrate that, contrary to this hypothesis, phosphorylation of I kappa B alpha induced by tumor necrosis factor alpha in HeLa cells does not induce dissociation. We propose a model in which (i) induced phosphorylation of I kappa B alpha does not result in its dissociation from NF-kappa B, (ii) phosphorylation of I kappa B alpha serves as a signal for degradation, and (iii) degradation of I kappa B alpha occurs while it is still complexed with NF-kappa B.

Calpain↗