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Biomedical subjects

K Maruyama

Publications and source records attributed to K Maruyama.

At least 145 records · Page 8Linked to original sources
PubMed2000

A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism.

OBJECTIVE: To determine whether familial isolated hyperparathyroidism (FIHP) is a variant of multiple endocrine neoplasia type 1 (MEN1) we analyzed the MEN1 gene in such a kindred. DESIGN AND METHODS: The study included the 70-year-old proband and nine relatives. Blood was drawn for biochemical evaluation and germline mutation analysis by direct sequencing of the MEN1 gene amplified by PCR. A hyperplastic parathyroid gland obtained from a family member served for a loss of heterozygosity (LOH) study. RESULTS: Three members from two generations in this kindred were found to have primary hyperparathyroidism, while none had clinical or biochemical evidence of MEN1, MEN2 or hyperparathyroidism--jaw tumor syndrome. Analysis of germline DNA in the proband showed a missense mutation (GGC-->GAC) at codon 305 in exon 7 of the MEN1 gene that predicts an amino acid change from glycine to aspartic acid (G305D). This mutation segregated with primary hyperparathyroidism in the kindred, and, in addition, there were two asymptomatic mutant-gene carriers at relatively advanced ages. In contrast, the mutation was not detected in genomic DNA from five unaffected individuals and from 50 healthy subjects. The LOH study showed a loss of the wild-type allele, which confirmed that a functional defect of the MEN1 gene product, menin, is etiological for FIHP. CONCLUSIONS: FIHP is a genetically heterogeneous disease with a subset linked to MEN1, most likely representing a variant of MEN1. The late onset and the reduced penetrance of disease found in this kindred may be related to the site and the type of mutation, although the precise mechanism involved is unknown at present.

Adult↗
PubMed2000

Molecular interactions between presenilin and calpain: inhibition of m-calpain protease activity by presenilin-1, 2 and cleavage of presenilin-1 by m-, mu-calpain.

Several mutations of presenilin (PS)-1, 2 result in early onset Alzheimer disease. Using the yeast two-hybrid system, the interaction between PS2 loop domain and the C-terminal region of mu-calpain was previously identified. Calpain is a calcium dependent-protease and there are two isoforms, m-calpain and mu-calpain, which differ in the calcium concentration required for activation. m-Calpain needs about 10(-3) M calcium ions, whereas mu-calpain about 10(-5) M. When PS and calpain were separately expressed in COS cells by cDNA transfection and then combined in vitro, or both were co-transfected to be co-expressed in vivo in COS cells, PS1 and PS2 reduced the casein proteolysis activity of m-calpain but not that of mu-calpain. Some of the PS mutations related to Alzheimer disease decreased this inhibitory activity. On the other hand, PS1 was cleaved by m-calpain and mu-calpain at a different site from those already reported (constitutive cleavage or alternative cleavage). These results suggest a regulatory function of presenilin on the calpain system.

Animals↗
PubMed2000

[The effects of intravenous milrinone for the patient undergoing CABG].

The hemodynamic effects of intravenous infusion of milrinone were evaluated in 25 patients undergoing CABG using an internal mammary artery graft. Milrinone was administered to 9 patients at the time of weaning from cardiopulmonary bypass, at a dosage of 3 to 5 micrograms/kg/min. Postoperative cardiac function was compared in this group versus the other 17 patients who were treated without milrinone. We determined such parameters as cardiac index, wedge pressure and mean pulmonary pressure. Our findings did not show any significant difference between the 2 groups. We also studied a subject of low-output patients (EF < 0.5). In the patients with low-cardiac output, the use of milrinone in addition to standard postoperative administration of low-dose dopamine reduced mean pulmonary pressure and wedge pressure. Thus, milrinone not only improved the left ventricular function, but also expanded the pulmonary vascular bed.

Aged↗
PubMed2000

Comparison of cyanamide and disulfiram in effects on liver function.

BACKGROUND: Cyanamide, an aversive drug widely used in Japan, develops ground-glass inclusion bodies in the hepatocytes at high incidences, which may be associated with portal inflammation and fibrosis. When cyanamide-treated alcoholics relapse drinking, the combined effect of cyanamide and alcohol produce more severe portal inflammation along with the emergence of ground-glass inclusions. Disulfiram also causes hepatitis, but there have been no comparative studies of effects of cyanamide and disulfiram on liver function. METHODS: We reviewed the laboratory data of 408 alcoholics admitted for a 3 month course of alcohol detoxification and rehabilitation. Patients tested negative for hepatitis virus markers and were diagnosed as not having cirrhosis. Among the subjects, 222 patients received cyanamide treatment (a daily dose of 70 mg) without a history of disulfiram treatment, and 186 received disulfiram (a daily dose of 200 mg) without a history of cyanamide treatment. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels obtained at 0, 4, 8, and 12 weeks of administration of each aversive drug were compared between the two alcoholic groups. RESULTS: Elevation of serum transaminases (AST > ALT) probably due to alcoholic liver disease quickly fell after abstinence. In patients who took cyanamide, the ALT levels were significantly higher at 4 and 12 weeks than in those who took disulfiram. Re-elevations of ALT after alcohol detoxification were more frequently observed in those who took cyanamide than in those who took disulfiram (19.4% vs. 5.9%, p < 0.001). The re-elevations of ALT were slight to moderate, being more than 3-fold in three (1.4%) patients who took cyanamide and four (2.2%) who took disulfiram. The re-elevations occurred more frequently in those with a history of cyanamide treatment before the present treatment than in those who took cyanamide for the first time (31.1% vs. 16.4%, p < 0.05). CONCLUSIONS: Cyanamide, compared with disulfiram, was more frequently associated with elevations of ALT that persisted after abstinence.

Adult↗
PubMed2000

Cyanamide-induced liver dysfunction after abstinence in alcoholics: a long-term follow-up study on four cases.

BACKGROUND: Cyanamide, an aversive agent widely used in Japan, is known to induce various degrees of hepatic lesion with ground-glass inclusion bodies. When cyanamide-treated alcoholics relapse into drinking, more severe inflammation develops in the liver. However, it is controversial whether progressive hepatic lesions develop in complete abstainers as a result of long-term cyanamide treatment. CASE REPORTS: Case 1: A 53-year-old male alcoholic received cyanamide treatment for 4.5 months and completely abstained without cyanamide treatment for 6 years. A liver biopsy shortly after abstinence showed extensive pericellular fibrosis, but a biopsy after 6 years showed very mild fibrosis. Case 2: A 43-year-old male alcoholic remained completely abstinent with cyanamide treatment for 5 years and complained of general fatigue. His serum transaminases were slightly elevated and hepatic hyperechogenicity was observed on ultrasonography. Only mild pericellular fibrosis was present in the liver biopsy specimen obtained shortly after abstinence, but after 5 years the second liver biopsy showed that thin septum-like fibrosis that formed portal-to-portal and portal-to-central linkage had developed and ground-glass hepatocytes had emerged extensively. Case 3: A 29-year-old female alcoholic complained of general fatigue and a slight fever after 1.5 years of abstinence with cyanamide treatment. Slight elevation of serum transaminases and hepatic hyperechogenicity were observed. The liver biopsy showed extensive ground-glass hepatocytes and thin septum-like fibrosis that formed portal-to-portal linkage. Case 4: A 61-year-old male alcoholic who remained completely abstinent while taking cyanamide for 3 years showed slight elevation of serum transaminases. Liver biopsy showed extensive ground-glass hepatocytes and extension of thin septum-like fibers from portal tract to the lobule. Ultrasonography revealed hepatic hyperechogenicity. CONCLUSION: In some abstainers who take cyanamide for several years, thin septum-like liver fibrosis progresses along with the emergence of ground-glass hepatocytes. Hepatic hyperechogenicity on ultrasonography and slight elevation of serum transaminases might erroneously lead to a diagnosis of hepatic steatosis without liver histology.

Adult↗
PubMed2000

[Overloading to neck extensor muscles is an aggravating factor to induce further neck drop in isolated neck extensor myopathy (Katz). A case report].

A 78-year-old woman was hospitalized because of progressive anterior neck drop over 4 months prior to admission. She was normal except for mild weakness of her neck, trapezius and biceps brachii muscles. EMG revealed mild myopathic changes in the neck extensors, trapezius, deltoid and sternocleidomastoid muscles. Bilateral splenius capitis muscles had high intensities on T2-weighted and STIR pulse-sequenced MRI. However, there were no inflammatory changes in the right splenius muscle biopsy. Accordingly, the abnormal MRI finding seems not to result from an inflammatory process but from an physiological increase of intracellular water content due to sustained muscle contraction. Because apparent neuromuscular diseases responsible for neck drop were excluded, her clinical features met the criteria of isolated neck extensor myopathy (INEM, Katz). After strict bed-rest for one month, her neck drop improved dramatically. When she returned to the previous life style after discharge, her symptoms of the neck drop reappeared. Although the cause of INEM remains unclear, the present case indicates that the condition is reversible at least in the early stage of the disease, and the overloading to the neck extensor muscles is an aggravating factor of the neck drop in INEM.

Aged↗
PubMed1999

Prothoracicotropic activity of SBRPs, the insulin-like peptides of the saturniid silkworm Samia cynthia ricini.

Synthesis and secretion of the insect molting hormone ecdysteroid in the prothoracic glands (PGs) are stimulated by the prothoracicotropic hormone (PTTH) secreted by the brain. Bombyxins, insulin-like peptides of the silkworm Bombyx mori, show prothoracicotropic activity when administered to the saturniid silkworm Samia cynthia ricini, but they are inactive to B. mori itself. Recently, the genes for the bombyxin homologs of S. cynthia ricini (referred to as Samia bombyxin-related peptides, SBRPs) were cloned. To examine the prothoracicotropic activity of SBRPs on S. cynthia ricini, we synthesized two representative molecules, SBRP-A1 and -B1. They promoted pupa-to-adult development with ED(50) of 50 and 10 ng/pupa (EC(50) of 5 and 1 nM), respectively.

Amino Acid Sequence↗
PubMed1999

Molecular localization and state of amphotericin B in PEG liposomes.

We investigated the molecular localization and state of amphotericin B (AmB) encapsulated in polyethylene glycol (PEG)-coated liposomes. AmB-encapsulating PEG-liposomes composed of dipalmitoylphosphatidylcholine (DPPC), cholesterol (CH) and distearoyl-N-(monomethoxy poly(ethylene glycol)succinyl) phosphatidylethanolamine (DSPE-PEG, average MW of the PEG chain 2000) were prepared by hydration with 9% sucrose solution and extrusion. The amount of AmB encapsulated in the liposomes increased with incorporation of DSPE-PEG and decreased with that of CH. The molecular localization and state of AmB were investigated by PEG/dextran two-phase partition, potassium permeability measurement, fluorescence quenching measurement and circular dichroism (CD) spectroscopy. The results suggest that there are two types of AmB localization in PEG-liposomes, one of which corresponds to the complex of AmB with DSPE-PEG on the membrane surface, while the other corresponds to the pore form of AmB in the hydrophobic core of the liposomal membrane. AmB in PEG liposomes was present in both aggregated and monomeric states.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1999

C terminus of presenilin is required for overproduction of amyloidogenic Abeta42 through stabilization and endoproteolysis of presenilin.

Mutations in presenilin (PS) genes cause early onset familial Alzheimer's disease (FAD) by increasing production of the amyloidogenic form of amyloid beta peptides ending at residue 42 (Abeta42). To identify a PS subdomain responsible for overproduction of Abeta42, we analyzed neuro2a cell lines expressing modified forms of PS2 that harbor an N141I FAD mutation. Deletion or addition of amino acids at the C terminus and Ile448 substitution in PS2 with the N141I FAD mutation abrogated the increase in Abeta42 secretion, and Abeta42 overproduction was dependent on the stabilization and endoproteolysis of PS2. The same C-terminal modifications in PS1 produced similar effects. Hence, we suggest that the C terminus of PS plays a crucial role in the overproduction of Abeta42 through stabilization of endoproteolytic PS derivatives and that these derivatives may be the pathologically active species of PS that cause FAD.

Amino Acid Substitution↗
PubMed1999

Possibility of active targeting to tumor tissues with liposomes.

In terms of active targeting by immunoliposomes, two anatomical compartments are considerable for targeting sites. One is located a readily accessible site in intravascular, and another is a much less accessible target site located in the extravascular. However, it was made clear that the active targeting with immunoliposomes is determined by two kinetically competing processes, such as binding to the target site and uptake by the RES. To overcome these contradictions, we have designed a new type of long-circulating immunoliposome, which was PEG-immunoliposome attached antibodies at the distal end of PEG chain, so called the pendant type immunoliposome. The pendant type immunoliposome showed much higher targetability than the ordinary immunoliposomes to both targeting sites of lung endothelial cells and solid tumor tissue. This is due to the free PEG chains (not linked to the antibody) effectively avoiding the RES uptake of liposomes, resulting in elevated the blood concentration and enhanced the target binding of immunoliposomes. The presence of free PEG does not interfere with the binding of the terminally linked antibody to the antigen. For targeting to the vascular endothelial surface in the lung, 34A antibody, which is highly specific to mouse pulmonary endothelial cells, was conjugated to make the pendant type immunoliposomes (34A-PEG-ILP). 34A-PFG-ILP showed significantly higher targeting degree than the ordinary type of immunoliposomes. For targeting to the solid tumor tissue, Fab' fragment of 21B2 antibody which is anti-human CFA and transferrin (TF) were used. Both pendant type immunoliposomes (Fab'-PFG-ILP and TF-PEG-ILP) showed the low RES uptake and the long circulation time, and resulted in enhanced accumulation of the liposomes in the solid tumor. TF-PEG-ILP was internalized into tumor cells with receptor mediated endocytosis, after extravasation into tumor tissue. The pendant type immunoliposome can escape from the gaps between adjacent endothelial cells and openings at the vessel termini during tumor angiogenesis by passive convective transport much rather than ligand directed targeting. Active targeting to tumor tissue with the pendant type immunoliposome is particularly important for many highly toxic anticancer drugs for cancer chemotherapy. An ultimate goal of pendant type immunoliposome is the incorporation of a fusogenic molecule that would induce fusion of liposome following their binding to the target cells or their internalization by endocytosis. Such liposomal formulations should be useful for endocytotic internalization of plasmid DNA and other bioactive materials.

Journal Article↗
PubMed1999

Size-dependent extravasation and interstitial localization of polyethyleneglycol liposomes in solid tumor-bearing mice.

We have examined the size dependence of extravasation and interstitial localization of polyethyleneglycol-coated liposomes (PEG-liposomes) in the solid tumor tissue by means of electron microscopic observation. Liposomes composed of distearoyl phosphatidylcholine, cholesterol and distearoylphosphatidylethanolamine derivative of polyethyleneglycol (PEG) were prepared in various size ranges. PEG-liposomes with an average diameter of 100-200 nm showed the most prolonged circulation time and the greatest tumor accumulation in all the solid tumors employed in this experiment. Although large PEG-liposomes with a diameter of 400 nm showed a short circulation time in normal mice, the results in splenectomized mice indicated that they do have an intrinsic prolonged circulation character in vivo. However, large PEG-liposomes could not extravasate into solid tumor tissue. These results indicate that the size of liposomes is critical for extravasation. The electron microscopic observations revealed the almost exclusive engulfment of extravasated liposomes by tumor-associated macrophages; very few were taken up by tumor cells.

Animals↗
PubMed1999

Structure and distribution of rat menin mRNA.

Menin is a protein product of a tumor suppressor gene MEN1, mutations of which are responsible for multiple endocrine neoplasia type 1, an autosomal dominant familial cancer syndrome. We isolated rat menin cDNA clones from a fetal rat brain cDNA library. We also determined the nucleotide sequence of the protein coding region of mouse menin cDNA, which was partly registered in the expressed sequence tag (EST) database. Deduced amino acid sequences of rat and mouse menin are highly homologous to human menin. All of the previously reported disease-associated missense mutations and single amino acid deletions were observed at the residues that are conserved among these three species. Rat MEN1 transcripts were detected not only in the endocrine tissues but also in the tissues of the nervous, digestive, reproductive and immune systems. The MEN1 transcripts were abundantly expressed in the developing rat brain on day 14-18 of gestation. Immunoblotting and immunocytochemical analysis of the COS-7 cells transfected with a rat menin-expression vector revealed that the translated product has a molecular mass of approximately 70 kDa, and is localized mainly in the nucleus. These findings are consistent with those reported on human menin.

Amino Acid Sequence↗
PubMed1999

Encapsulation characteristics of nystatin in liposomes: effects of cholesterol and polyethylene glycol derivatives.

In this study, we characterized the encapsulation of amphipathic nystatin into liposomes with or without cholesterol (CH) and a polyethylene glycol derivative, distearoyl-N-(monomethoxy poly(ethylene glycol)succinyl)phosphatidylethanolamine (DSPE-PEG). The highest encapsulation efficacy of nystatin into liposomes (151 microg nystatin/mg lipid) was obtained with a cholesterol-free lipid composition containing 6 mol% of DSPE-PEG. The encapsulation efficacy was decreased by the incorporation of CH and improved by the incorporation of DSPE-PEG. In liposomes composed of dipalmitoylphosphatidylcholine (DPPC)/CH (2:1, mol/mol), the highest encapsulation efficacy of nystatin liposomes (84 microg/mg lipid) was achieved by the addition of DSPE-PEG and hydration with 9% sucrose solution, as compared with 13 microg/mg lipid without DSPE-PEG. The encapsulated amount increased with increasing amount of DSPE-PEG used and plateaued at 6 mol% of DSPE-PEG. The optimum molecular weight of PEG in DSPE-PEG was 2000 and a larger molecular weight resulted in lower encapsulation. The incorporation of CH affected the self-association of nystatin with lipid membranes, which was detected by fluorescence measurement. The molecular interaction between an amino group in nystatin and a phosphate group in DSPE-PEG plays an important role in efficient encapsulation of nystatin. Finally, the encapsulation characteristics of nystatin were compared with those of amphotericin B (AmB). Nystatin more readily associated with CH-free lipid membranes, but, AmB more readily interacted with DSPE-PEG. The results indicated that the differences in the molecular association of AmB or nystatin with lipids or DSPE-PEG are reflected in the encapsulation characteristics in liposomes.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1999

Membrane-anchored metalloprotease MDC9 has an alpha-secretase activity responsible for processing the amyloid precursor protein.

MDC9, also known as meltrin gamma, is a membrane-anchored metalloprotease. MDC9 contains several distinct protein domains: a signal sequence followed by a prodomain and a domain showing sequence similarity to snake venom metalloproteases, a disintegrin-like domain, a cysteine-rich region, an epidermal-growth-factor-like repeat, a transmembrane domain and a cytoplasmic domain. Here we demonstrate that MDC9 expressed in COS cells is cleaved between the prodomain and the metalloprotease domain. Further, when MDC9 was co-expressed in COS cells with amyloid precursor protein (APP695) and treated with phorbol ester, APP695 was digested exclusively at the alpha-secretory site in MDC9-expressing cells. When an artificial alpha-secretory site mutant was also co-expressed with MDC9 and treated with phorbol ester, APP secreted by alpha-secretase was not increased in conditional medium. Inhibition of MDC9 by a hydroxamate-based metalloprotease inhibitor, SI-27, enhanced beta-secretase cleavage. These results suggest that MDC9 has an alpha-secretase-like activity and is activated by phorbol ester.

ADAM Proteins↗
PubMed1999

Relation of nebulin and connectin (titin) to dynamics of actin in nascent myofibrils of cultured skeletal muscle cells.

Cultured embryonic chicken skeletal muscle cells microinjected with rhodamine (rh)-labeled actin were stained with antibodies against nebulin and connectin (titin). In premyofibril areas, nebulin was observed as dotted structures, many of which were arranged in a linear fashion. These structures were associated with injected rh-actin. Among these linearly arranged dots of nebulin and rh-actin, numerous small nebulin dots without rh-actin incorporation were scattered. It is probable that the dots of nebulin and/or its associated protein(s) represent a preformed scaffold upon which actin monomers accumulate; exogenously introduced actin associates initially with small nebulin dots, which in turn coalesce to form rh-actin dots and are arranged linearly. In developing myofibrils, two patterns of nebulin distribution were found: "singlets" and "doublets." Recovery of rh-actin's fluorescence after photobleaching was slowest in the nonstriated dotted portions, followed by the striated myofibrillar portions with nebulin singlets and those with doublets, in that order. Thus, the distribution patterns of nebulin seem to be related to the accessibility/exchangeability of actin into nascent myofibrils. It is possible that early nebulin filaments exhibiting singlets are not tightly associated with actin filaments and that this loose association allows myofibrils to exchange nonadult isoforms of actin and other proteins into adult types. Connectin formed a striated pattern before the formation of rh-actin/nebulin striations. It appears that connectin does not have any significant role in the accessibility of actin into nascent myofibrils.

Actins↗
PubMed1999

The promoter region of human prepro-nociceptin gene and its regulation by cyclic AMP and steroid hormones.

The promoter and upstream regulatory region of the human prepro-nociceptin gene has been cloned from adaptor-ligated genomic DNA libraries by polymerase chain reaction. This 1.7 kb region contains several potential binding sites for transcription factors, among which are binding sites for TF-IID, cyclic AMP response element binding protein, glucocorticoid receptor and estrogen receptor. Multiple start points for the transcription of prepro-nociceptin are identified by an 'oligoribonucleotide-capping' method, but the major one is located at -558(G). Promoter activity assays using luciferase reporter gene constructions with the 1.7 kb fragment and a series of deletion mutations demonstrate that the core promoter is located in the region from -639 to -521 (a region surrounding the major transcription start point -558). A TATA-box motif displays weak promoter activity. An increase of cellular cyclic AMP levels by forskolin treatment up-regulates prepro-nociceptin transcription. Estrogen also up-regulates gene transcription whereas glucocorticoid down-regulates transcription, each through their corresponding receptor response elements. These regulatory effects can be blocked either by mutations of the potential cyclic AMP- or estrogen receptor response elements or by the application of antagonists for glucocorticoid and estrogen receptors. These findings provide a molecular basis for the regulatory mechanisms of human prepro-nociceptin gene expression.

Base Sequence↗