Can nafamostat mesilate be used for temporary management of hemodialysis in a patient with heparin-induced thrombocytopenia (HIT)?
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Anticoagulants↗
Biomedical subjects
M Matsuo
Publications and source records attributed to M Matsuo.
Purine-rich exon sequences are not necessarily splicing enhancer sequence in the dystrophin gene.
Purine-rich sequences within exons are proposed to promote proper splicing as splicing enhancers. In order to test this supposition in the dystrophin gene, which is characterized by the large size of its introns, purine-rich sequences from three exons (exons 43, 46 and 53) were examined for their splicing enhancer activity by using a Drosophila doublesex pre-mRNA. The most powerful activating effect on upstream intron splicing was seen with a sequence from exon 43. A sequence from exon 53 showed relatively low activity, whilst that from exon 46 had little effect. To characterize the splicing enhancer sequences in exons 53 and 46 further, entire exons were divided into 30nt fragments that were examined separately for their splicing enhancer activity. In exon 53, two fragments located at the 5' and 3' ends, respectively, had strong splicing enhancer activity, although they were not the most purine-rich regions of the exon. In contrast, all of the fragments derived from exon 46 had little activity. These results suggest that different exons in the dystrophin transcript are subject to different mechanisms of control by the splicing machinery.
Animals↗
[Current practice in MR imaging of the liver].
MR imaging, which is able to evaluate T1- and T2-relaxation time, fat, hemorrhage, metal deposition, blood flow, perfusion, diffusion, and so on, has offered more information for the diagnosis of diffuse and focal hepatic diseases than CT. The spoiled-GRE sequence with high contrast resolution and ease of the aimed contrast capture derived from the k-space property, with the use of a phased-array multicoil, have remarkably increased the value of gadolinium-enhanced dynamic MR diagnosis of the liver. In recent years, the clinical use of ferumoxide has begun, and issues concerning the superiority or inferiority and combination of contrast media are being debated. This paper describes the value, role, and clinical practice of unenhanced, gadolinium-enhanced, and ferumoxide-enhanced MR imaging of the liver based on knowledge obtained in our institution, with some reference to the literature.
Carcinoma, Hepatocellular↗
Functional analysis of a mutant sulfonylurea receptor, SUR1-R1420C, that is responsible for persistent hyperinsulinemic hypoglycemia of infancy.
The ATP-sensitive potassium (K(ATP)(+)) channel is crucial for the regulation of insulin secretion from the pancreatic beta-cell, and mutations in either the sulfonylurea receptor type 1 (SUR1) or Kir6. 2 subunit of this channel can cause persistent hyperinsulinemic hypoglycemia of infancy (PHHI). We analyzed the functional consequences of the PHHI missense mutation R1420C, which lies in the second nucleotide-binding fold (NBF2) of SUR1. Mild tryptic digestion of SUR1 after photoaffinity labeling allowed analysis of the nucleotide-binding properties of NBF1 and NBF2. Labeling of NBF1 with 8-azido-[alpha-(32)P]ATP was inhibited by MgATP and MgADP with similar K(i) for wild-type SUR1 and SUR1-R1420C. However, the MgATP and MgADP affinities of NBF2 of SUR1-R1420C were about 5-fold lower than those of wild-type SUR1. MgATP and MgADP stabilized 8-azido-ATP binding at NBF1 of wild-type SUR1 by interacting with NBF2, but this cooperative nucleotide binding was not observed for SUR1-R1420C. Studies on macroscopic currents recorded in inside-out membrane patches revealed that the SUR1-R1420C mutation exhibits reduced expression but does not affect inhibition by ATP or tolbutamide or activation by diazoxide. However, co-expression with Kir6.2-R50G, which renders the channel less sensitive to ATP inhibition, revealed that the SUR1-R1420C mutation increases the EC(50) for MgADP activation from 74 to 197 microm. We suggest that the lower expression of the mutant channel and the reduced affinity of NBF2 for MgADP may lead to a smaller K(ATP)(+) current in R1420C-PHHI beta-cells and thereby to the enhanced insulin secretion. We also propose a new model for nucleotide activation of K(ATP)(+) channels.
ATP-Binding Cassette Transporters↗
Different binding properties and affinities for ATP and ADP among sulfonylurea receptor subtypes, SUR1, SUR2A, and SUR2B.
ATP-sensitive potassium (K(ATP)) channels, composed of sulfonylurea receptor (SURx) and Kir6.x, play important roles by linking cellular metabolic state to membrane potential in various tissues. Pancreatic, cardiac, and vascular smooth muscle K(ATP) channels, which consist of different subtypes of SURx, differ in their responses to cellular metabolic state. To explore the possibility that different interactions of SURx with nucleotides cause differential regulation of K(ATP) channels, we analyzed the properties of nucleotide-binding folds (NBFs) of SUR1, SUR2A, and SUR2B. SURx in crude membrane fractions was incubated with 8-azido-[alpha-(32)P]ATP or 8-azido-[gamma-(32)P]ATP under various conditions and was photoaffinity-labeled. Then, SURx was digested mildly with trypsin, and partial tryptic fragments were immunoprecipitated with antibodies against NBF1 and NBF2. Some nucleotide-binding properties were different among SUR subtypes as follows. 1) Mg(2+) dependence of nucleotide binding of NBF2 of SUR1 was high, whereas those of SUR2A and SUR2B were low. 2) The affinities of NBF1 of SUR1 for ATP and ADP, especially for ATP, were significantly higher than those of SUR2A and SUR2B. 3) The affinities of NBF2 of SUR2B for ATP and ADP were significantly higher than those of SUR2A. This is the first biochemical study to analyze and compare the nucleotide-binding properties of NBFs of three SUR subtypes, and our results suggest that their different properties may explain, in part, the differential regulation of K(ATP) channel subtypes. The high nucleotide-binding affinities of SUR1 may explain the high ability of SUR1 to stimulate pancreatic K(ATP) channels. It is also suggested that the C-terminal 42 amino acids affect the physiological roles of SUR2A and SUR2B by changing the nucleotide-binding properties of their NBFs.
ATP-Binding Cassette Transporters↗
Lesser reduction in bone mineral density by the immunosuppressant, FK506, compared with cyclosporine in rats.
BACKGROUND: Posttransplantation osteopenia leading to osteoporosis induced commonly by treatment with immunosuppressants including cyclosporine (CsA) is a severe complication and results in lowering the quality of life in patients receiving organ transplantation. FK506 is a newly developed immunosuppressant and is currently being used for the prevention of rejection after organ transplantation. In this study, to investigate whether FK506 as well as CsA would cause osteopenia or not, we evaluated the effect of FK506 on bone mineral density and several parameters relevant to bone metabolism in comparison with that of CsA using normal rats. METHODS: Ten-week-old male Sprague-Dawley rats were treated with FK506 (vehicle, 1 mg/kg, and 3.2 mg/kg) or CsA (vehicle, 10 mg/kg, and 32 mg/kg) by daily oral gavage for 28 days. Bone mineral density of the femur, plasma insulin-like growth factor I (IGF-I), and urinary deoxypyridinoline were determined by peripheral quantitative computerized tomography, radioimmunoassay, and enzyme-linked immunosorbent assay, respectively. RESULTS: The reduction in bone mineral density of the femur was observed in both FK506- and CsA-treated rats. The reduction in CsA-treated rats, however, was statistically significant and strikingly severe, whereas that in FK506-treated rats was much less severe than CsA. Plasma IGF-I levels were significantly elevated in FK506-treated rats but not in CsAtreated rats. Urinary deoxypyridinoline levels were unchanged in FK506-treated rats but elevated in CsA-treated rats. CONCLUSIONS: Compared with CsA, FK506 does not appear to induce severe osteopenia by high-turnover bone metabolism in the rat by mediating via IGF-I induction in part. The results suggest that FK506 may exert favorable effects on bone metabolism in patients with organ transplantation compared with CsA. To assess this idea, further clinical investigations focused on bone metabolism will be required.
Amino Acids↗
New induction of leukotriene A(4) hydrolase by interleukin-4 and interleukin-13 in human polymorphonuclear leukocytes.
Interleukin (IL)-4, IL-10, and IL-13, Th2 cell-derived cytokines, play major roles in the pathophysiology of allergic diseases. These cytokines up-regulate or down-regulate the production of arachidonic acid metabolites. In this study, we have investigated the effect of IL-4, IL-10, IL-13, and other cytokines on A23187-stimulated synthesis of leukotriene (LT) B(4) in human polymorphonuclear leukocytes (PMNs). Production of LTB(4) was measured by specific radioimmunoassay and high performance liquid chromatography. Messenger RNA (mRNA) expression of cytosolic phospholipase A(2) (cPLA(2)), 5-lipoxygenase (5-LO), and LTA(4) hydrolase, which were involved in the synthesis of LTB(4), was determined by reverse transcription-polymerase chain reaction and Northern blot analysis. Protein synthesis of their enzymes was determined by Western blot analysis. IL-4 and IL-13 enhanced A23187-stimulated LTB(4) synthesis and increased mRNA expression and protein synthesis of LTA(4) hydrolase, but not those of cPLA(2) or 5-LO. These results indicate that IL-4 and IL-13 transcriptionally or post-transcriptionally up-regulate the synthesis of LTB(4), a potent chemotactic factor to PMNs, at the enzyme level of LTA(4) hydrolase, and this up-regulation mechanism may participate in the development of allergic inflammation. (Blood. 2000;96:601-609)
Arachidonate 5-Lipoxygenase↗
Nonequivalent nucleotide trapping in the two nucleotide binding folds of the human multidrug resistance protein MRP1.
Multidrug resistance protein 1 (MRP1) and P-glycoprotein, which are ATP-dependent multidrug efflux pumps and involved in multidrug resistance of tumor cells, are members of the ATP binding cassette proteins and contain two nucleotide-binding folds (NBFs). P-glycoprotein hydrolyzes ATP at both NBFs, and vanadate-induced nucleotide trapping occurs at both NBFs. We examined vanadate-induced nucleotide trapping in MRP1 stably expressed in KB cell membrane by using 8-azido-[alpha-(32)P]ATP. Vanadate-induced nucleotide trapping in MRP1 was found to be stimulated by reduced glutathione, glutathione disulfide, and etoposide and to be synergistically stimulated by the presence of etoposide and either glutathione. These results suggest that glutathione and etoposide interact with MRP1 at different sites and that those bindings cooperatively stimulate the nucleotide trapping. Mild trypsin digestion of MRP1 revealed that vanadate-induced nucleotide trapping mainly occurs at NBF2. Our results suggest that the two NBFs of MRP1 might be functionally nonequivalent.
ATP-Binding Cassette Transporters↗
Molecular evidence of complex tissue- and sex-specific mRNA expression of the rat alpha(2u)-globulin multigene family.
alpha(2u)-Globulin is well known to be a rat protein encoded by a highly homologous multigene family with more than twenty members. We report here the cloning and identification of major alpha(2u)-globulin mRNA species expressed in various tissues. Initially, eight individual clones (PGCL1-8) were obtained from a male preputial gland cDNA library. Data base analysis with BLAST demonstrated six mRNAs to be novel, all clones being characterized by highly conserved sequence motifs as lipocalins. All cDNAs contained an open reading frame of 543 nucleotides and encode 181 amino acid proteins showing 92.5-98.7% and 87.3-98.3% nucleic and amino acid identity, respectively. Denaturing gradient gel electrophoresis (DGGE) with sequence analysis showed that PGCL4 is a major member in the female mammary gland, and in the submaxillary and lachrymal glands of both sexes, while the counterpart in male liver and the coagulate glands was found to be PGCL1. Numbers of cDNA species including PGCL1 and PGCL4 were found in preputial glands, no sex-related difference being observed. These results directly demonstrate complex tissue- and sex-specific expression of alpha(2u)-globulins in terms of mRNA species, providing useful information for understanding regulation of the alpha(2u)-globulin multigene family.
Alpha-Globulins↗
Antithrombotic treatment (argatroban vs. heparin) in coronary angioplasty in angina pectoris: effects on inflammatory, hemostatic, and endothelium-derived parameters.
To evaluate the suitability of two anticoagulants (heparin vs. argatroban) as adjunctive drugs during and after elective conventional percutaneous transluminal coronary angioplasty, we compared the changes in inflammatory, hemostatic, and endothelium-derived markers in groups of patients with stable angina treated with the two drugs during percutaneous transluminal coronary angioplasty. Twenty-seven patients were randomly allocated to either group 1 (15 patients who received an empiric dose of heparin and aspirin as anticoagulant), or group 2 (12 patients who received an alternative regimen of argatroban and aspirin). Both drugs were administered as a bolus followed by continuous infusion for 96 hours during and after percutaneous transluminal coronary angioplasty. There were no differences in the inflammatory response induced by percutaneous transluminal coronary angioplasty in both groups, but the fibrinogen concentration significantly decreased during percutaneous transluminal coronary angioplasty in group 2. Decreased platelet counts and increased mean platelet volume were observed during percutaneous transluminal coronary angioplasty in both groups. The levels of prothrombin fragment 1+2 and thrombin antithrombin III complex increased markedly during percutaneous transluminal coronary angioplasty. Group 2 showed a more rapid return to the baseline levels of these two markers than group 1. Secondary fibrinolysis was evidenced by a steep increase of D-dimer after percutaneous transluminal coronary angioplasty in both groups. In contrast to the significant decrease in antithrombin activities during percutaneous transluminal coronary angioplasty in group 1, no marked change in these markers was found in group 2. Although the levels of von Willebrand factor and plasminogen activator inhibitor-1 showed essentially the same changes in both groups during and after percutaneous transluminal coronary angioplasty, more markedly increased levels of tissue type plasminogen activator and type plasminogen activator-plasminogen activator inhibitor-1 complex after percutaneous transluminal coronary angioplasty were found in group 1 than in group 2. While neither drug had any effect on the percutaneous transluminal coronary angioplasty-induced inflammatory response, argatroban may more effectively inhibit the generated thrombin and prevent antithrombin consumption during and after percutaneous transluminal coronary angioplasty.
Aged↗
Nonsense mutation of the alpha-actinin-3 gene is not associated with dystrophinopathy.
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Actinin↗
Mother and daughter with 45,X/46,X,r(X)(p22.3q28) and mental retardation: analysis of the X-inactivation patterns.
We report on a mother and daughter both with a 45,X/46,X,r(X)(p22. 3q28) karyotype and mental retardation. Fluorescence in situ hybridization (FISH) and microsatellite analyses for 14 loci/region at Xp22.3 and seven loci/region at Xq28 indicated that the ring X chromosome was missing a roughly 12-Mb region from Xp22.3 with the breakpoint between DXS85 and DXS9972, and another region of less than 100 kb from Xq28 with the breakpoint distal to the region defined by the FISH probe c8.2/1. X-inactivation analysis, using the methylation status of the AR gene (exon 1) as an indicator, showed that the normal and ring X chromosomes in the X,r(X)(p22.3q28) cell lineage were randomly inactivated. The Xp22.3 deleted region partially overlaps with the regional intervals of MRX19, MRX21, MRX24, MRX37, MRX43, and MRX49 associated with heterozygote manifestation. Therefore, it is likely that one or more of these MRX genes, subject to X-inactivation, are lost from the ring X chromosome, and that reduced expression of the MRX gene(s) caused by random X-inactivation has resulted in mental retardation in the mother and daughter.
Adult↗
Are there any associations among coagulation factor VII gene polymorphism, plasma activated factor VII levels, and cerebrovascular disease?
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Asian People↗
A novel cryptic exon in intron 2 of the human dystrophin gene evolved from an intron by acquiring consensus sequences for splicing at different stages of anthropoid evolution.
The dystrophin gene, which is mutated in Duchenne muscular dystrophy, is thus the largest human gene. A full spectrum of splicing of the dystrophin transcript has not been elucidated yet, though more than 10 alternative splicings have been identified in the 5' region of the dystrophin gene. In this study, two novel dystrophin transcripts containing a 140-nucleotide insertion precisely between exons 2 and 8 or between exons 2 and 18 were identified in skeletal muscle. The genomic region corresponding to and surrounding this 140-nucleotide sequence was sequenced to reveal that the insertion possessed a branch point and both acceptor and donor splice site consensus sequences perfectly. Therefore, the 140-bp insertion sequence was considered to be a novel exon. The novel exon was mapped to intron 2 and was designated exon 2a. Reverse-transcription PCR screening for transcripts containing exon 2a in 12 human tissues revealed its presence in 3 of them, including skeletal muscle. Phylogenetic studies disclosed that exon 2a evolved from intron DNA by the progressive acquisition of nucleotide substitutions in ancestral hominoids.
Animals↗
T2-weighted MR imaging for focal hepatic lesion detection: supplementary value of breath-hold imaging with half-Fourier single-shot fast spin-echo and multishot spin-echo echoplanar sequences.
The purpose of our study was to evaluate the supplementary value of breath-hold fat-suppressed T2-weighted magnetic resonance (MR) imaging with half-Fourier single-shot fast spin-echo (SE) or multishot SE echoplanar (EP) sequences combined with respiratory-triggered fat-suppressed fast SE T2-weighted MR imaging for detection and characterization of focal hepatic lesions. MR images in 42 patients with 82 solid, malignant and 77 nonsolid, benign lesions were analyzed. Image review was conducted on a segment-by-segment basis; in all, 333 liver segments were reviewed separately for solid and nonsolid lesions by three independent radiologists. For solid lesions, observer performance with receiver-operating-characteristic (ROC) analysis in one radiologist and specificity in another significantly improved after adding single-shot fast SE images. For nonsolid lesions, observer performance with ROC analysis in one radiologist and specificity in another significantly improved after adding single-shot fast SE images. Combining breath-hold half-Fourier single-shot fast SE imaging with respiratory-triggered fast SE imaging may be recommended for improved detection and characterization of focal hepatic lesions. J. Magn. Reson. Imaging 2000;12:444-452.
Adipose Tissue↗
Pseudothrombosis in the portal venous system: a potential pitfall with gadolinium-enhanced dynamic gradient-recalled echo imaging of the liver.
Gadolinium-enhanced dynamic magnetic resonance (MR) images in 90 patients were reviewed to assess the artifacts mimicking portal venous thrombosis. The incidence of definite signal-intensity decrease mimicking pathologic condition was higher (P < 0.01) in the right (8%) and left (9%) portal vein branches and portal trunk (6%) than in the splenic (0%) or superior mesenteric (1%) vein with equilibrium-phase images. Radiologists should remember that dynamic MR images occasionally show signal-intensity decrease mimicking portal venous thrombosis due to flow artifact.
Adult↗
Clinical and molecular studies in 15 females with ring X chromosomes: implications for r(X) formation and mental development.
We report clinical and molecular findings in 15 Japanese mosaic females with r(X) chromosomes, 45,X/46,X,r(X), confirmed by fluorescence in situ hybridization (FISH) analysis for DXZ1 and whole X chromosome painting. Cases 1-3, 5-7, and 11-13 had mental retardation (MR), the remaining cases being free from MR. FISH analysis showed that XIST was absent from the r(X) chromosomes in cases 1-4 and was present on the r(X) chromosomes in cases 5-15. X-inactivation analysis for the methylation status of the AR gene indicated that, of eight cases with XIST-positive r(X) chromosomes in more than 10% (23%-62%) of lymphocytes (cases 5-12), cases 5-10 had selective X-inactivation, whereas cases 11 and 12 had active X disomy. Microsatellite analysis for multiple loci on the pericentromeric region revealed that, of 11 cases with r(X) chromosomes in more than 10% (13%-62%) of lymphocytes (cases 1, 2, and 4-12), cases 1, 2, and 5-10 had heterozygous alleles for at least one locus, whereas cases 4, 11, and 12 had single alleles for all the loci examined. The results suggest that the r(X) and normal X chromosomes could be of biparental or uniparental origin, and that mental status in females with r(X) chromosomes is determined by multiple factors, including the presence or absence of XIST on the r(X) chromosomes and the size and frequency of active r(X) chromosomes, in addition to co-incidental genetic and environmental factors.
Adolescent↗
Non-homologous recombination between Alu and LINE-1 repeats caused a 430-kb deletion in the dystrophin gene: a novel source of genomic instability.
Although large deletions in the dystrophin gene have been identified in more than two-thirds of Duchenne and Becker muscular dystrophy patients, the molecular mechanisms that lead to the generation of these deletions are largely unknown. Here, Alu and LINE-1 (L1) repetitive elements were shown to be present at one or other of the two ends, respectively, of a 430-kb deletion in the dystrophin gene. The breakpoint of the deletion, which stretches from exons 2 to 7, was defined more precisely by polymerase chain reaction (PCR) walking on introns 1 and 7. Finally, the region containing the breakpoint was amplified as a fragment of more than 10kb. Sequencing of the deletion endpoint revealed the presence of an Alu sequence in intron 1, 25 kb downstream from the 3' end of exon 1 that was joined directly to an L1 sequence in intron 7, 4.5kb downstream from the 3' end of exon 7. The deletion was calculated to be 430kb. To our knowledge, this is a novel recombination event joining non-homologous Alu and L1 repeats, and is the largest known intrachromosomal deletion that is thought to involve repetitive genetic elements. Sequence characteristics around the breakpoint are discussed.
Alu Elements↗