A Japanese patient with a mild form of lamellar ichthyosis harbouring two missense mutations in the core domain of the transglutaminase 1 gene.
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Adult↗
Biomedical subjects
S Muramatsu
Publications and source records attributed to S Muramatsu.
Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease.
Glial cell line-derived neurotrophic factor (GDNF) is a strong candidate agent in the neuroprotective treatment of Parkinson's disease (PD). We investigated whether adeno-associated viral (AAV) vector-mediated delivery of a GDNF gene in a delayed manner could prevent progressive degeneration of dopaminergic (DA) neurons, while preserving a functional nigrostriatal pathway. Four weeks after a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), rats received injection of AAV vectors expressing GDNF tagged with FLAG peptide (AAV-GDNFflag) or beta-galactosidase (AAV-LacZ) into the lesioned striatum. Immunostaining for FLAG demonstrated retrograde transport of GDNFflag to the substantia nigra (SN). The density of tyrosine hydroxylase (TH)-positive DA fibers in the striatum and the number of TH-positive or cholera toxin subunit B (CTB, neuronal tracer)-labeled neurons in the SN were significantly greater in the AAV-GDNFflag group than in the AAV-LacZ group. Dopamine levels and those of its metabolites in the striatum were remarkably higher in the AAV-GDNFflag group compared with the control group. Consistent with anatomical and biochemical changes, significant behavioral recovery was observed from 4-20 weeks following AAV-GDNFflag injection. These data indicate that a delayed delivery of GDNF gene using AAV vector is efficacious even 4 weeks after the onset of progressive degeneration in a rat model of PD.
Animals↗
Effect of sodium thiosulfate on cisplatin removal with complete hepatic venous isolation and extracorporeal charcoal hemoperfusion: a pharmacokinetic evaluation.
BACKGROUND: Complete hepatic venous isolation and extracorporeal charcoal hemoperfusion (HVI.CHP) can limit systemic exposure to high-dose chemotherapeutic agents when given by hepatic arterial infusion (HAI). The purpose of this study was to determine if the concomitant use of sodium thiosulfate (STS) could further expand the advantages of pharmacologic delivery of HVI.CHP for cisplatin (CDDP) during HAI chemotherapy. METHODS: CDDP (4mg/kg) was administered over 20 minutes via HAI under conditions of HVI.CHP in 14 mongrel dogs. HVI.CHP was performed for 30 minutes after initiation of HAI. During CDDP infusion, 7 dogs each received 400 mg/kg STS (a 100-fold molar ratio to CDDP) over 20 minutes via the prefilter (STS group) circuit line, while the remaining 7 dogs (controls) received no STS. Blood samples were taken serially from the prefilter circuit line (hepatic venous blood), postfilter line, and the left carotid artery (systemic blood). The free and total CDDP concentrations in these samples were determined by flameless atomic absorption spectrophotometry. RESULTS: During 20 minutes HAI of CDDP, the mean CDDP extraction ratios (ER) by CHP filter were always higher in the STS group than in the control group, regardless of the form (free or total) of CDDP. The differences between the STS and control groups in the extraction ratios of free and total CDDP were significant at all time points measured (P < .05). Consequently, systemic exposure to CDDP, as assessed by area under the time-concentration curve of total CDDP, was significantly lower in the STS group than in the control group (P < .05). CONCLUSIONS: These results indicated that concomitant STS infusion could further increase the effect of HVI.CHP on CDDP removal after HAI.
Animals↗
Recombinant adeno-associated virus vector-transduced vascular endothelial cells express the thrombomodulin transgene under the regulation of enhanced plasminogen activator inhibitor-1 promoter.
We were able to facilitate plasminogen activator inhibitor 1 (PAI-1) promoter activity approximately by 14-fold using an enhancer element. This enhanced PAI-1 promoter has a strong basal activity, comparable to CAG promoter activity, and has a response similar to the PAI-1 promoter with respect to TGFbeta 1 and TNFalpha stimulation. The characteristics of the enhanced PAI-1 promoter are thought to be suited to timely and tissue-specific expression of anticoagulant molecules in the vascular cells. Thus, we developed recombinant adeno-associated virus (rAAV) vectors using the enhanced PAI-1 promoter and were successful in transducing vascular endothelial cells to express the thrombomodulin transgene under the regulation of the enhanced PAI-1 promoter in vitro. Thromobomodulin transgene expression driven by the enhanced PAI-1 promoter in rAAV vector-transduced cultured endothelial cells was between 600- and 1000-fold higher than constitutive thrombomodulin gene expression in cultured human umbilical vein endothelial cells and was up-regulated by TGFbeta1 and TNFalpha stimulation which may down-regulate endogenous thrombomodulin gene expression in endothelial cells. The brain vascular endothelial cells of Mongolian gerbils could also be transduced by the same rAAV vector in vivo. Transduction of endothelial cells by rAAV vectors to express enhanced PAI-1 promoter-driven transgenes may be a useful gene therapy approach for vascular diseases.
Animals↗
Inhibition of the light-independent synthesis of chlorophyll in pine cotyledons at low temperature.
Cotyledons of Japanese black pine (Pinus thunbergii) were yellow when they developed in darkness at 8 degrees C since the light-independent synthesis of chlorophyll was almost completely inhibited in these cotyledons. The level of chlorophyll in dark-grown cotyledons was less than one-twentieth of that in light-grown cotyledons at the same temperature. In the yellow cotyledons, levels of transcripts of cab, rbcS, rbcL and psbA genes were quite high. The large and small subunits of ribulose-1,5-bisphosphate carboxylase/oxygenase were also detected at relatively high levels in yellow cotyledons. However, the accumulation of the two apoproteins of the light-harvesting chlorophyll a/b-binding protein of PSII was limited because of the limited supply of chlorophyll.
Chlorophyll↗
[Gene therapy for Parkinson's disease: studies in animal models].
Recent developments in viral vectors capable of providing high levels of long-term transgene expression in the brain have led to the pursuit of two strategies in gene therapy for the treatment of Parkinson's disease (PD). One is the local production of dopamine in the striatum achieved by inducing the expression of dopamine-synthesizing enzymes. Three enzymes are necessary for efficient dopamine synthesis: tyrosine hydroxylase (TH) converts tyrosine to L-DOPA, aromatic L-amino acid decarboxylase (AADC) then converts L-DOPA to dopamine, and guanosine triphosphate cyclohydrolase I (GCH) is the rate-limiting enzyme for the synthesis of TH co-factor tetrahydrobiopterine. We have previously demonstrated that transduction with separate adeno-associated virus (AAV) vectors expressing TH, AADC, and GCH is effective in reducing motor abnormalities in 6-hydroxydopamine-lesioned rats and in MPTP-treated monkeys. Behavioral recovery persisted for at least 18 months after intrastriatal injection in parkinsonian rats. In MPTP monkeys, the amelioration of motor abnormalities was remarkable on the contralateral side, accompanied by robust transgene expression and elevated dopamine synthesis in the AAV-injected putamen. The second strategy entails the expression of neurotrophic factors or brain vesicular monoamine transporter in the striatum or the substantia nigra to slow the degeneration of dopamine neurons. Gene therapy using viral vectors offers a promising approach in the treatment of PD patients.
Animals↗
Successful rescue of severe recurrent hepatitis C with interferon and ribavirin in a liver transplant patient.
BACKGROUND: Rapid graft dysfunction caused by hepatitis C virus (HCV) reinfection, although uncommon, is a disastrous complication in liver transplant patients. Finding an effective therapy for this subgroup of patients with severe recurrent HCV is a priority. METHOD: We describe a successful rescue of a 46-year-old man with recurrent hepatitis C (HCV genotype 1b) using long-term interferon (IFN) and ribavirin. The patient had a very aggressive type of posttransplantation HCV infection, as judged by biochemical and histologic findings. RESULTS: Despite high pretreatment values of serum alanine aminotransferase (ALT; peak value of 901 IU/L) and HCV-RNA (2.3 x 10(6) copies/ml), the combination therapy with IFN and ribavirin produced a rapid normalization of the serum ALT values, accompanied by the clearance of serum HCV-RNA. Although HCV-RNA reappeared in the serum at 3 months, the patient had continued ALT normalization and histological improvement with follow-up of over 26 months to date after the initiation of the combination therapy. CONCLUSION: This observation suggests that IFN in combination with ribavirin may offer an effective therapeutic option for liver transplant patients with severe recurrent hepatitis C.
Alanine Transaminase↗
Gene therapy of Parkinson's disease using adeno-associated virus (AAV) vectors.
Parkinson's disease (PD) is characterized by the progressive loss of the dopaminergic neurons in the substantia nigra and a severe decrease in dopamine in the striatum. A promising approach to the gene therapy of PD is intrastriatal expression of dopamine-synthesizing enzymes [tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC)]. The most appropriate gene-delivery vehicles for neurons are adeno-associated virus (AAV) vectors, which are derived from non-pathogenic virus. Therefore, TH and AADC genes were introduced into the striatum in the lesioned side using separate AAV vectors in parkinsonian rats, and the coexpression of TH and AADC resulted in better behavioral recovery compared with TH alone. Another strategy for gene therapy of PD is the protection of dopaminergic neurons in the substantia nigra using an AAV vector containing a glial cell line-derived neurotrophic factor (GDNF) gene. Combination of dopamine-supplement gene therapy and GDNF gene therapy would be a logical approach to the treatment of PD.
Animals↗
Intestinal absorption and excretion of troglitazone sulphate, a major biliary metabolite of troglitazone.
1. Deconjugation by sulphate transfer and intestinal absorption of troglitazone sulphate (M1), the major metabolite of a thiazolidinedione antidiabetic drug, troglitazone, were studied in the male F344 rat using 14C-troglitazone, 4C-M1 and 35S-M1. 2. Some part of M1, produced in the liver and excreted mostly in the bile, was deconjugated in the intestine to the parent compound, troglitazone, by arylsulphate sulphotransferase originated from intestinal flora. However, deconjugation of M1 was not catalyzed by arylsulphatases. Caecal injection of M1 led to the appearance of troglitazone and M1 in plasma. 3. Biliary excretion mostly as M1, and, following absorption, as M1 and troglitazone after deconjugation, were indicated as the basis for the enterohepatic circulation of troglitazone. 4. Enterohepatic circulation may prolong the pharmacological effects of troglitazone.
Animals↗
Evidence of protein synthesis during resuscitation of ischemically damaged canine pancreas by the two-layer method.
The two-layer method, which supplies sufficient oxygen to the canine pancreas graft and allows adenotriphosphate synthesis within the graft, resuscitates the ischemically damaged pancreas graft during mild hypothermic (20 degrees C) preservation, but the mechanisms are unknown. The purpose of this study was to determine whether protein synthesis was performed on ischemically damaged pancreas graft during preservation by the two-layer method in a canine autotransplantation model. The pancreas grafts subjected to 90 minutes of warm ischemia were preserved by the two-layer method (perfluorochemical/University of Wisconsin solution) at 20 degrees C for 5 hours. Graft viability was judged from graft survival after autotransplantation. DNA, RNA, and protein synthesis was quantitated by determining incorporation of tritiated thymidine, tritiated uridine, and tritiated leucine, respectively, during preservation. Significant increases in RNA and subsequent protein syntheses were observed during preservation by the two-layer method. In contrast, DNA synthesis did not follow RNA and protein synthesis. We conclude that protein is synthesized in the process of postischemic cellular recovery of the pancreas graft during mild hypothermic preservation by the two-layer method.
Animals↗
Chromosomal diagnosis in each individual blastomere of 5- to 10-cell bovine embryos derived from in vitro fertilization.
Chromosomal normality and sex were diagnosed in each blastomere of bovine embryos derived from in vitro fertilization (IVF). Bovine embryos developing to the 5- to 10-cell stage were separated into individual blastomeres with 0.5% protease. After treatment with 100 ng/mL vinblastine sulfate for 8 to 10 h, they were prepared for chromosome samples. In total, 33 bovine embryos and 185 blastomeres were examined. Chromosomal normality was analyzed in 43.8% (81/185) of the blastomeres and 60.6% (20/33) of the embryos; while chromosomal anomalies were found in 16 (80%, 16/20) of the embryos, 5 haploid embryos and 11 mosaic (n/2n) embryos. Mosaicism characteristic of the opposite sex in X-and Y-chromosomes was found in 2 haploid embryos, and that of a Y-chromosome and of XX chromosomes in 1 n/2n embryo. Various sex-chromosome compositions were also observed in the other 10 chromosomal mosaic n/2n embryos.
Animals↗
Postprandial normal saline intake delays gastric emptying of solids in conscious dogs: partial involvement of CCK in its mechanism.
Although it is known that a caloric liquid meal given after food intake delays solid gastric emptying, the effect of a noncaloric liquid is not known. The aims of this study were to determine the effect of normal saline given at 3 hr after feeding on gastric antral motor activity and gastric emptying and to evaluate the role of endogenous cholecystokinin in the changes in gastric function induced by postprandial saline intake in conscious dogs. Two cannulas were implanted in each of five mongrel dogs for infusion of phenolsulfonphthalein into the proximal duodenum and for aspiration of luminal samples from the distal duodenum. Gastric contractile and emptying activity were measured by the force transducer method and a freeze-drying method newly developed by our group, respectively. Postprandial pancreaticobiliary secretion was assessed from amylase and bile acid outputs into the duodenum. One hundred grams of freeze-dried dog food was given as a solid meal after mixing it with 100 ml of normal saline. The dogs were given 100 ml of normal saline per os at 3 hr after feeding. In another study, intravenous administration of devazepide, a specific cholecystokinin-A receptor antagonist, at a dose of 0.1 mg/kg/hr was begun 15 min before postprandial saline intake and continued for 1 hr. Gastric antral motility was significantly (P < 0.01) inhibited for 30 min after the dogs had drunk saline at 3 hr after feeding. The mean fractional emptying rate of gastric solids in percentage per 30 min after postprandial saline intake was significantly (P < 0.05) slower than that in the control study without saline intake at 3 hr after feeding. Amylase output into the duodenum after postprandial saline intake showed a gradual increase lasting for about 1 hr, whereas that of bile acid increased transiently but markedly 15 min after saline intake, in comparison with the control study. Pretreatment with devazepide partially ameliorated the suppression of gastric antral motility. Postprandial intake of saline inhibited gastric motor activity and delayed solid gastric emptying, whereas it increased the outputs of amylase and bile acid. Endogenous cholecystokinin may be partially involved in these phenomena caused by saline intake at 3 hr after feeding.
Administration, Oral↗
Effects of inflammatory cytokines induced by Helicobacter pylori infection on aminopyrine accumulation in parietal cells isolated from guinea pigs.
The effects of inflammatory cytokines induced by Helicobacter pylori infection on acid secretion have not been well defined. The purpose of this study was to investigate the direct effects of these cytokines on parietal cells isolated from guinea pigs. We examined the effects of human recombinant IL-1beta (0.05-100 ng/ml), IL-8 (2-256 ng/ml), and TNF-alpha (0.625-80 ng/ml) on acid secretion stimulated by three secretagogues (10(-4) M histamine, 10(-4) M carbachol, and 10(-5) M tetragastrin) and on basal acid secretion from isolated parietal cells, which was measured by the aminopyrine accumulation method. None of three cytokines showed any significant effects on stimulated or basal acid secretion from isolated guinea pig parietal cells. We concluded that inflammatory cytokines induced by Helicobacter pylori infection may affect acid secretion through mechanisms other than direct actions on parietal cells.
Aminopyrine↗
Effect of truncal vagotomy on gallbladder bile kinetics in conscious dogs.
Previous studies on the effects of vagotomy on gallbladder (GB) motility have yielded conflicting results. The aim of this study was to evaluate the effects of vagotomy on GB motility and bile kinetics using a new method. Twelve dogs were divided into two groups of six (control and pyloroplasty) and, 4 weeks later, underwent truncal vagotomy. A catheter secured in the GB fundus was used to monitor GB volume. After injecting polyethylene glycol (PEG) into the GB, combined measurements of GB volume and PEG concentration enabled GB emptying and bile kinetics to be estimated. Seven and five of the 12 vagotomized dogs were classified as having large and normal fasting GB volumes, respectively. Postprandial GB emptying was impaired when the fasting GB volume was enlarged. In the fasting state, bile kinetics of vagotomized dogs were significantly smaller than the control values. The emptying ability of the GB of vagotomized dogs with large fasting GB volumes was reduced considerably both in the postprandial and the fasting states. Such retention of bile in the GB after vagotomy may facilitate cholesterol crystal nucleation and stone growth.
Animals↗
A new type of Ser substitution for gamma Arg-275 in fibrinogen Kamogawa I characterized by impaired fibrin assembly.
A new type of substitution, Arg to Ser at gamma275, has been found in a heterozygous dysfibrinogen derived from a 23-year-old woman with no major bleeding or thrombosis. By sequence analyses of the affected gamma-chain and its gene. we found a single amino acid substitution of gamma Arg-275 to Ser in an aberrant gamma (274-302) residue peptide isolated from lysyl endopeptidase-digests of the patient's fibrinogen. In agreement with this amino acid substitution, we identified a single nucleotide exchange of A for C at position 5728 in the gamma-chain gene creating a codon (AGC) encoding Ser instead of the codon (CGC) encoding Arg at position gamma 275. Like two other known types of mutants with a His or Cys substitution at this position, the functional abnormality was characterized by delayed fibrin polymerization, most likely due to impaired abutting of two D domains of adjacent fibrin monomers in the same strand of fibrin protofibrils. The structural derangement that affects the D:D association may not be so severe as compared with those of Cys and His mutants, possessing an additional disulfide-linked Cys molecule and an imidazole ring at the mutation site, respectively.
Adult↗
Regional pharmacokinetics of doxorubicin following hepatic arterial and portal venous administration: evaluation with hepatic venous isolation and charcoal hemoperfusion.
We evaluated the regional pharmacokinetics of doxorubicin after hepatic arterial infusion (HAI) and portal venous infusion (PVI) using a novel system for hepatic venous isolation and charcoal hemoperfusion (HVI-CHP). The HVI-CHP system was used to determine directly the doxorubicin plasma concentration in the hepatic vein and the hepatic venous flow rate, and simultaneously, to eliminate hepatic re-entry of the drug. Beagles received doxorubicin (1 mg/kg) through either the hepatic artery (HAI group, n = 6) or the portal vein (PVI group, n = 6). In both groups, hepatic venous blood was completely isolated and directed to the CHP filter. The filtered blood was returned through the left jugular vein. During HVI-CHP, the hepatic venous flow rate was monitored and plasma doxorubicin concentrations were serially measured in prefilter (= hepatic venous), postfilter, and systemic blood. The hepatic tissue uptake of doxorubicin was determined based on the blood flow rate and doxorubicin level in the hepatic vein. The hepatic extraction ratio of doxorubicin was defined as the percentage hepatic tissue uptake to the amount of drug administered. During drug infusion, similarly in either group, HVI-CHP produced a 66-87% reduction of the postfilter doxorubicin level as compared with the prefilter level. The prefilter drug level was significantly lower in HAI group than in PVI group (P < 0.01). Thus, the area under the time concentration curve for the prefilter drug level in the HAI group (6.90+/-0.96 microg min/ml) was significantly lower than that in the PVI group (18.10+/-2.90 microg min/ml, P < 0.01). Conversely, the hepatic extraction ratio in the HAI group (84.6+/-2.9%) was significantly higher than that in the PVI group (58.1+/-3.4%, P < 0.01). We conclude that in the beagle, doxorubicin is more effectively extracted by the liver when administered via the hepatic artery than when administered via the portal vein. These results indicate that HAI of doxorubicin is superior to PVI in terms of reduction of systemic drug exposure and systemic toxicity.
Animals↗
Maternal anticipation in Machado-Joseph disease (MJD): some maternal factors independent of the number of CAG repeat units may play a role in genetic anticipation in a Japanese MJD family.
We studied the relationship between the number of CAG repeat units in the MJD1 gene and clinical features of Machado-Joseph disease (MJD) in eight patients from two generations of a Japanese MJD family. Because of lack of characteristic clinical signs of MJD such as dystonia, bulging eyes or facial myokymia, clinical diagnosis of MJD in this family was difficult to make prior to molecular testing for the CAG repeat expansion in the MJD1 gene. All the patients exhibited maternal transmission of MJD, and the intergenerational change in the number of CAG repeat units in the MJD1 gene was very small (+0.5+/-0.3, mean+/-S.E.M., n=4) in spite of marked genetic anticipation (-17.0 years/generation). In the present family, the degree of anticipation per repeat unit in maternal transmissions was much larger than that in maternal transmissions in the other six MJD families. This indicates that some maternal factors other than the increase of the number of CAG repeat units, which is known to be the basis of anticipation, may play a role in genetic anticipation in this MJD family.
Adult↗
Resection of pheochromocytoma under inferior vena caval isolation and extracorporeal charcoal hemoperfusion.
Resection of pheochromocytoma is associated with potential risks of hypertensive crises and serious arrhythmias due to massive release of catecholamines from the tumor. We report our surgical experience with complete inferior vena caval isolation and extracorporeal charcoal hemoperfusion (IVCI-CHP), which were performed to prevent systemic exposure to catecholamines during surgical manipulation. The IVCI-CHP significantly reduced the postfilter and systemic catecholamine levels compared with the prefilter levels (P<.01), indicating substantial catecholamine extraction (>90%) by the CHP filter. Reflecting the reduction of systemic exposure to catecholamines during IVCI-CHP, the patient's blood pressures were markedly stable. Our findings suggest that IVCI-CHP may be useful to minimize the risk of hypertensive crises during surgical manipulation of pheochromocytoma, by preventing systemic exposure to high levels of circulatory catecholamines.
Adrenal Gland Neoplasms↗