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Biomedical subjects

M Fukuda

Publications and source records attributed to M Fukuda.

At least 667 records · Page 37Linked to original sources
PubMed1994

Recombinant chromosome 18 resulting from a maternal pericentric inversion.

We report on a newborn girl with duplication of 18q12.2-->18qter and deficiency of 18p11.2-->18pter which resulted from meiotic recombination of the maternal pericentric inversion, inv(18)(p11.2q12.2). Her clinical manifestations were compatible with those of partial trisomy 18q syndrome. We review the previously reported 9 cases in 8 families of rec(18) resulting from recombination of a parental pericentric inversion.

Abnormalities, Multiple↗
PubMed1994

Genomic organization of glycophorin A gene family revealed by yeast artificial chromosomes containing human genomic DNA.

Human glycophorins A, B, and E are members of the glycophorin gene family located at chromosome 4, band q31. These genes were apparently generated by two successive gene duplications, and the following evolutionary pathway was proposed based on the genomic sequences. First, the ancestral gene was duplicated, and one of the duplicated genes evolved directly into the GPA gene. Another duplicated gene acquired a 3' sequence from the precursor genomic segment and was then duplicated to yield glycophorin B and E genes (Onda, M., Kudo, S., Rearden, A., Mattei, M.-G. and Fukuda, M. (1993) Proc. Natl. Acad. Sci. USA 90, 7220-7224). Although the above hypothesis was proposed, it has been difficult to provide solid evidence for this, because no genomic clones studied encompass two members of the gene family. In this study we isolated several yeast artificial chromosome (YAC) clones encoding the entire region or a portion of this gene locus. The physical gene mapping was carried out by testing the presence of specific sequences using a polymerase chain reaction. Moreover, the YAC clones were digested by rare cutting restriction enzymes, and the resultant large DNA fragments were separated by pulse-field electrophoresis. Southern blot analyses of those DNA fragments were carried out using various probes encoding specific portions of glycophorin genes. The results obtained revealed that the distance between glycophorin A and B genes is almost the same as that between glycophorin B and E genes. Moreover, it was shown that no precursor genomic sequence was present in the sequences downstream from the GPB or GPE gene, suggesting that the duplication of glycophorin B/E progenitor gene was made through unequal crossing over homologous recombination. These combined results suggest that two duplication events took place tandemly to produce these three members of the glycophorin gene family.

Chromosomes, Artificial, Yeast↗
PubMed1994

Chronic ocular ischemia associated with the Eisenmenger's syndrome.

We studied the ocular findings of two adult patients with the Eisenmenger's syndrome who had atrial septal defects that were diagnosed before the age of 10 years but not operated on and pulmonary hypertension. Both eyes of these patients showed microaneurysms, multiple small blot hemorrhages, or capillary dilation in the temporal peripheral fundus. Multiple microaneurysms and retinal collaterals were confirmed by fluorescein angiography. One of the patients developed bilateral rubeosis iridis with slow progression. These retinal lesions and the rubeosis iridis are probably related to chronic ocular ischemia caused by chronic systemic hypoxia.

Adult↗
PubMed1994

Glyburide enhances insulin gene expression and glucose-induced insulin release in isolated rat islets.

Long-term glyburide therapy has been reported to improve glucose-induced insulin secretion in patients with NIDDM. We examined the effects of glyburide on the synthesis and release of insulin and insulin gene expression in isolated islets in vitro. Incubation with glyburide (500 ng/ml) significantly increased insulin release without affecting the insulin content. The PPI mRNA level was not increased after incubation for 1 h but was increased after incubation for 20 h. Incubation with 5 ng/ml of glyburide for 1 h or 20 h had no effect on the content or release of insulin, but incubation with 5 ng/ml of glyburide for 20 h significantly increased the PPI mRNA level and enhanced insulin release induced by 11 mM glucose. These results suggest that a high concentration of glyburide stimulates insulin release directly, while a low concentration of glyburide increases the PPI mRNA level and may thereby enhance glucose-induced insulin release.

Animals↗
PubMed1994

Lysosomal targeting of Limp II membrane glycoprotein requires a novel Leu-Ile motif at a particular position in its cytoplasmic tail.

A class of integral membrane glycoproteins specific to lysosomes has been identified, and they are classified into two separate groups depending on whether or not their cytoplasmic sequence contains a tyrosine residue. Lamp-1 and lamp-2 have a tyrosine-containing motif in their cytoplasmic segments, and this motif was found to direct the glycoproteins to lysosomes. Limp II glycoprotein, on the other hand, lacks a tyrosine in its cytoplasmic segment and it must be directed to lysosomes by a different signal (Fukuda, M. (1991) J. Biol. Chem. 266, 21327-21330). In order to elucidate the targeting signal of Limp II, a cDNA encoding its cytoplasmic segment was fused with a reporter molecule, a chimeric protein of human gonadotropin alpha chain-vesicular stomatitis G-protein transmembrane. After various mutations its expression was examined by immunofluorescence. First it was shown that a chimeric protein with a Limp II wild-type tail is transported to lysosomes. Deletion of the three amino acids of the cytoplasmic tail at the carboxyl terminus abolished this sorting to lysosomes. Substitution of individual amino acids revealed that the Leu-Ile motif in the Leu-Ile-Arg-Thr sequence at the carboxyl terminus is crucial to the sorting signal. When this motif was brought closer to the transmembrane domain by deletion of nine amino acids next to the transmembrane domain, this sorting function was abolished. In addition, substitution of alanine for the serine, which is at 5 residues from the transmembrane also abolished the sorting capacity, although there was no evidence that the phosphorylation of serine is involved in sorting. Altered proteins that were not transported to lysosomes were found to accumulate at the cell surface and, unlike proteins with a wild-type cytoplasmic tail, were unable to undergo endocytosis. These results indicate that the carboxyl-terminal amino acid sequence, including the Leu-Ile motif and the sequence that connects the motif to the transmembrane domain, is critical for the sorting of Limp II to lysosomes.

Amino Acid Sequence↗
PubMed1994

Expression of a differentiation antigen and poly-N-acetyllactosaminyl O-glycans directed by a cloned core 2 beta-1,6-N-acetylglucosaminyltransferase.

Chinese hamster ovary (CHO) cells do not contain detectable amounts of core 2 beta-1,6-N-acetylglucosaminyltransferase, C2GnT, and thus lack various modifications in their branched O-linked oligosaccharides. In the present study, the O-linked oligosaccharides and the occurrence of a differentiation antigen were analyzed in CHO cells stably transfected with cDNA encoding human leukosialin alone (CHO-leu) or with cDNAs encoding both leukosialin and C2GnT (CHO-leu.C2GnT). The analysis of O-glycans, released from [3H]glucosamine-labeled cells, revealed that CHO-leu cells synthesize O-glycans with a Gal beta 1-->3GalNAc backbone, whereas CHO-leu.C2GnT cells synthesize in addition O-glycans with a Gal beta 1-->3(Gal beta 1-->4GlcNAc beta 1-->6)GalNAc backbone. Moreover, CHO-leu.C2GnT cells express poly-N-acetyllactosaminyl extensions from the GlcNAc beta 1-->6 branch in O-glycans, while CHO-leu cells express no detectable amount of poly-N-acetyllactosaminyl O-glycans. It was also demonstrated that leukosialin in CHO-leu.C2GnT cells is recognized by the T305 monoclonal antibody, while the same antibody did not react at all with CHO-leu cells. In addition, the transient expression cloning scheme using the T305 monoclonal antibody as a selectin marker and COS-1 cells, which endogenously express C2GnT as recipient cells, resulted in the isolation of cDNA encoding leukosialin. These results indicate that C2GnT determines the expression of poly-N-acetyllactosamines in O-glycans and together with leukosialin, an onco-differentiation antigen recognized by the T305 antibody.

Animals↗
PubMed1994

Differential E-selectin-dependent adhesion efficiency in sublines of a human colon cancer exhibiting distinct metastatic potentials.

Previously we have shown that high metastatic colonic carcinoma cells express relatively more lamp molecules and sialyl Le(x) structures on the cell surface than their corresponding low metastatic counterparts (Saitoh, O., Wang, W.-L., Lotan, R., and Fukuda, M. (1992) J. Biol. Chem. 267, 5700-5711). In the present study, we extended these findings by testing whether these high and low metastatic colonic carcinoma cells differ in their adhesion efficiency to E-selectin-expressing cells. First, it was found that the high metastatic cells, as compared to their low metastatic counterparts, bind more efficiently to activated human endothelial cells that express E-selectin. This was also true when the adhesion was tested for Chinese hamster ovary cells stably expressing E-selectin. In addition, it was found that the high metastatic cells also adhere more efficiently to mouse endothelioma cells after activation with interleukin-1 beta. It was also shown that the adhesion can be inhibited by soluble lamp-1 or soluble leukosialin that contain sialy Le(x) termini. The inhibition was not, however, observed when these soluble glycoproteins lack sialyl Le(x) structures. The results indicate that the efficiency of the E-selectin-mediated binding of colonic carcinoma cells to human and mouse endothelial cells correlates with the metastatic potential of the cells and suggest that this adhesive event may be one of the critical factors for the metastatic spread of tumor cells. Soluble forms of leukosialin or lamp-1 may be useful as therapeutic agents for the inhibition of E-selectin-mediated binding to tumor cells.

Animals↗
PubMed1994

Improved oral absorption of enteric coprecipitates of a poorly soluble drug.

An anticancer agent, N-[[[4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl]amino]carbonyl]-2 - nitrobenzamide (HO-221, 1), shows poor oral absorption and is only slightly soluble in water (0.055 microgram/mL at 37 degrees C). The coprecipitates with polyvinylpyrrolidone or a vinylpyrrolidone and vinylacetate copolymer (copolyvidone) showed a marked increase of the dissolution rate and attainment of temporary supersaturation of 1. The oral bioavailability of these preparations in dogs at a dose of 1 of 5 mg/kg was approximately 60%, which was 3.5 times greater than that of a micronized preparation. Further, the enteric coprecipitate with hydroxypropyl methylcellulose phthalate 200731, which showed a dissolution profile similar to that of the copolyvidone preparation at pH 6.5 but no dissolution at pH 1.2, revealed the almost complete oral absorption. Because intraduodenal administration of the copolyvidone coprecipitate showed a higher absorption than that of per oral administration, it was suggested that the partial precipitation of crystallites in the nonenteric coprecipitates occurred before reaching the absorption site, the small intestine.

Administration, Oral↗
PubMed1994

Trilineage recovery by combination therapy with recombinant human granulocyte colony-stimulating factor and erythropoietin in patients with aplastic anemia and refractory anemia.

Ten patients with aplastic anemia (AA) and seven patients with refractory anemia (RA) were treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) and erythropoietin (rhEpo) in combination. rhG-CSF (5-20 micrograms/kg) and rhEpo (120-720 U/kg) were administered by s.c. injection three times a week for at least six months, and the administration was continued as maintenance therapy for as long as possible when hematological responses were observed. Six (60%) of the ten AA patients and four (58%) of the seven RA patients showed multilineage responses. Of these responders, six patients achieved trilineage recovery. While all of the responders were dependent on red blood cell transfusions and eight of them required platelet transfusions before treatment, they now no longer need transfusions of either red blood cells or platelets. A median treatment duration of 9 (range 1 to 28) months was required to achieve multilineage recovery. The responders showed an ability to maintain the multilineage recovery for 9+ to 47+ months and to tolerate long-term treatment. These results indicate that the long-term treatment with rhG-CSF and rhEpo may benefit a substantial percentage of patients with AA and RA and provide an optional therapy for these patients.

Adolescent↗
PubMed1994

Double labelling of major histocompatibility complex molecules and lysosomal protein lamp-1 on human dendritic cells.

In this study, double labelling for major histocompatibility complex (MHC) class I and class II molecules and for MHC molecules and the lysosomal membrane protein lamp-1 on ultrathin cryosections of dendritic cells isolated from human peripheral blood was performed. The plasma membrane proved to be positive for both MHC class I and MHC class II molecules and was labelled for only a very few lamp-1 molecules. MHC class I and MHC class II molecules did not co-localize intracellularly except in some peripherally located vesicles. However, many MHC class II-labelled vesicles were present in a juxtanuclear position but only some of them were co-labelled for lamp-1. These results indicate the presence of a separate, non-lysosomal compartment for class II molecules in dendritic cells.

Antigens, CD↗
PubMed1994

Reactive oxygen intermediates in autoimmune islet cell destruction of the NOD mouse induced by peritoneal exudate cells (rich in macrophages) but not T cells.

The non-obese diabetic (NOD) mouse spontaneously develops autoimmune Type 1 (insulin-dependent) diabetes mellitus. NOD mice exhibit massive infiltrates of T cells and macrophages into pancreatic islets (insulitis) prior to diabetes. The contribution of oxygen free radicals to the development of insulitis in NOD mice was examined by administration of its scavengers, such as superoxide dismutase and catalase. Bovine superoxide dismutase and catalase were each coupled to polyethylene glycol. The treatment with superoxide dismutase-polyethylene glycol reduced the number of islets with insulitis and increased the undamaged islet tissue, as compared with the control group. The treatment with catalase-polyethylene glycol showed a similar tendency which did not reach significance. Using a flow cytometric assay of the oxidation of 2', 7'-dichlorofluorescein, the content of reactive oxygen intermediates in islet cells in the culture system was measured and the effect of peritoneal exudate cells and T cells on their production examined. Peritoneal exudate cells, but not T cells, from NOD mice increased the content of reactive oxygen intermediates in islet cells of either the NOD mouse or the ILI mouse (MHC-identical to NOD); the addition of superoxide dismutase to the culture medium suppressed this increase in NOD or ILI islet cells. The present data support the concept that production of oxygen free radicals mediated by macrophages can damage islet beta cells, directly resulting in autoimmune Type 1 diabetes in NOD mice.

Animals↗
PubMed1994

The favourable effect of cyclophosphamide pulse therapy in the treatment of massive pulmonary haemorrhage in systemic lupus erythematosus.

Pulmonary haemorrhage (PH) is a rare but very serious complication of systemic lupus erythematosus (SLE) and the treatment is still controversial. Some authors showed the effectiveness of methylprednisolone pulse therapy for PH, although its effect was often transient. A 12-year-old Japanese girl with lupus nephritis and recurrent massive PH in SLE was treated with methylprednisolone pulse therapy. The effect on PH was transient and she needed three cycles within a month and side-effects developed. Pulse therapy with cyclophosphamide, synchronized with plasmapheresis, was tried. Thereafter she did not experience PH for 7 months, whereas lupus nephritis did not improve. Pulse cyclophosphamide would be effective for life threatening massive PH in SLE patients.

Child↗
PubMed1994

Hepatic portal venous gas associated with cholangitis following pancreaticoduodenectomy: report of a case.

A 63-year-old an developed fever and shock 2 weeks after undergoing a pancreaticoduodenectomy for carcinoma of the gallbladder with duodenal involvement. Computed tomography (CT) of the abdomen showed transient hepatic portal venous gas in the right lobe of the liver, which had probably been induced by obstruction of the bilioenteric anastomosis by the biliary drain. The gas and bacteria, both of which are commonly observed in cases of bilioenteric anastomosis, may have been diffused through the sinusoid into the portal venous system. Thus, hepatic portal venous gas could be a serious sign when it develops in patients with cholangitis following bilioenteric anastomosis.

Cholangitis↗
PubMed1994

Absence of association of TAP and LMP genes with type 1 (insulin-dependent) diabetes mellitus.

Although one of the major genes which cause type 1 (insulin-dependent) diabetes mellitus is located in the class II HLA region in humans, its precise location is still unknown. In order to investigate whether TAP (Transporter associated with Antigen Processing) and LMP (Low Molecular Weight Polypeptide) genes, which are located in the class II HLA region, are HLA-linked diabetogenic genes, the association of TAP1, TAP2 and LMP2 genes with type 1 diabetes was analyzed in the Japanese population. No difference in allele frequencies of these genes was detected between diabetic patients and control subjects. On the other hand, DQA1 and DQB1 genes showed significant association with type 1 diabetes. These data suggest that the diabetogenic gene in the class II HLA region may be located near the DQA1 and DQB1 loci, rather than the TAP and LMP loci.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

The role of insulin in coronary atherosclerosis.

In 197 patients with coronary artery disease (CAD) who underwent coronary angiography, 75 g oral glucose tolerance test (OGTT) was performed, measuring plasma glucose(PG) and plasma insulin (IRI) at 4 time points (0, 30, 60 and 120 min). Subjects were separated into two groups by their insulinogenic index (I.I. = delta IRI/delta PG from 0 up to 30 min), 99 cases with good insulin response (I.I. > or = 0.4) and 98 cases with poor insulin response (I.I. < 0.4). Only two subjects were diabetic in good insulin response, while 37 were diabetic in poor insulin response. The severity of coronary atherosclerosis was expressed as a coronary index (CI), calculated according to Balcon's method. Fasting PG and the sum of PG were significantly higher in the latter group, while the sum of IRI was significantly lower. CI was not significantly different, however. In the group with good insulin response, the severity of CAD was significantly correlated to fasting IRI (n = 99, r = -0.387, P < 0.02), but, there was no such relationship in the other group. We conclude that hyperinsulinemia might be a risk factor for ischemic heart disease, but in diabetics it is difficult to link the relationship between fasting IRI and CI.

Adult↗
PubMed1994

Early-onset type 2 (non-insulin-dependent) diabetes mellitus is associated with glucokinase locus, but not with adenosine deaminase locus, in the Japanese population.

To investigate the possible contribution of glucokinase (GCK) and adenosine deaminase (ADA) loci to the genetic susceptibility to type 2 (non-insulin-dependent) diabetes mellitus, we studied the association of these loci with type 2 diabetes in the Japanese population. Fifty patients with type 2 diabetes and 50 control subjects were analyzed for microsatellite polymorphism 3' to the GCK gene and PstI polymorphism in the ADA gene by polymerase chain reaction. The frequency of the most common GCK allele (Z) was significantly lower in type 2 diabetic patients than that in control subjects and a longer Z + 2 allele was more common in type 2 diabetic patients (26% vs. 15%, P = 0.053), particularly in those with younger age of onset (33% vs. 15%, younger onset type 2 diabetes vs. control, P = 0.014). The frequency of genotypes containing at least one Z + 2 allele was significantly more common in type 2 diabetic patients (46% vs. 28%, P < 0.05), particularly in those with younger age of onset (61% vs. 28%, relative risk 4.00, P < 0.01). In contrast, there was no difference in allelic or genotypic frequencies of PstI polymorphism in the ADA gene between the two groups. Despite the association between the GCK locus and type 2 diabetes, none of the patients had known mutations (Glu265-->AM265, Glu279-->AM279, Gly299-->Arg299, Glu300-->Gln300, Leu309-->Pro309). These results suggest that the GCK locus, but not the ADA locus, contributes to the genetic susceptibility to type 2 diabetes in Japanese.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Deaminase↗
PubMed1994

Classification and treatment of diabetic retinopathy.

Diabetic retinopathy is the leading cause of blindness. In Japan about 45% of diabetic patients under medical care have retinopathy and 10% have proliferative retinopathy. Until recently, Scott's classification (1953, 1957) of retinopathy was commonly used in Japan. As there are several problems with this classification, I proposed a new classification in 1983. It aims to separate benign and malignant types and to be more useful clinically so that each stage corresponds better to the indication of specific treatment. Diabetic retinopathy is divided into benign (type A) and malignant (type B) retinopathy, and each type is subdivided into 5 stages. Benign retinopathy is unlikely to cause blindness unless maculopathy is present. It includes background retinopathy (A1 and A2) and interrupted proliferative retinopathy (A3, A4 and A5) after photocoagulation or vitrectomy. Malignant retinopathy is likely to get worse and may lead to blindness if left without specific treatment. It includes preproliferative retinopathy (B1), early (B2), advanced (B3) and end-stage (B4 and B5) proliferative retinopathy. The presence of specific findings is described by the addition of letters: maculopathy (M), tractional retinal detachment (D), neovascular glaucoma (G), and ischemic optic neuropathy (N). Systemic metabolic control of diabetes is the best means of treatment for benign retinopathy, but malignant retinopathy should immediately be seen by ophthalmologists for specific treatment: focal photocoagulation for B1, focal or panretinal photocoagulation for B2 and panretinal photocoagulation for B3-B5. Vitrectomy is indicated in B4 or more severe stages.

Diabetic Retinopathy↗