Biomedical subjects
Publications and source records attributed to T Yoshikawa.
Glycyrrhiza pallidiflora hairy roots were induced from axenic young plants by direct infection with Agrobacterium rhizogenes. The chemical constituents were then investigated after mass culture. The isoflavone, licoagroisoflavone and the coumestan, licoagroside C, were isolated along with seven known flavonoids. Their structures were determined on the basis of spectroscopic evidence.
OBJECTIVE: The aim of this study was to evaluate whether the method of light curing could influence: (a) marginal sealing and resin composite adaptation to the cavity wall; (b) polymerization contraction rate; and (c) the hardness at the top and bottom surfaces of a body of resin composite. METHODS: Standard cylindrical cavities, 1mm deep and 3mm in diameter were prepared on flat superficial dentin surfaces in bovine teeth. The teeth were bonded with one of two adhesive systems (Clearfil Photo Bond, and Super-Bond D Liner) and filled with a hybrid resin composite. The resins were cured using three light intensities of 600, 270 and 20mW/cm(2), and various curing times. After thermal cycling, the specimens were subjected to a dye penetration test to evaluate marginal sealing and adaptation of the resin composite to the cavity walls. In addition, using the same curing conditions, the rate of polymerization contraction was measured. The difference of hardness over time of composite specimens was measured using Knoop hardness measurements taken at the top and bottom surfaces of resin specimens made in a Teflon mold the same dimensions as the cavity prepared in dentin. RESULTS: When the composite was light cured with an initial light intensity of 270mW/cm(2) for 10s, a 5s interval then a light intensity of 600mW/cm(2) for 50s, the best marginal sealing and cavity wall adaptation was observed compared with the other curing modes. Earlier hardening occurred at the resin composite base compared with the top surface of the composite, and most of the polymerization contraction was completed during the initial flowable stage of the resin composite. All other methods demonstrated results with some degree of marginal opening and cavity wall gap formation, the worst being 600mW/s for 60s. SIGNIFICANCE: The use of a low initial light intensity (270mW/cm(2)) for 10s followed by high intensity light (600mW/cm(2)) for 50s provides the best adaptation of resin composite to cavity walls and possibly the least polymerization contraction stress.
OBJECTIVES: We sought to define the clinical and long-term prognostic implications of autoantibodies that act against the second extracellular loop of beta1-adrenergic receptors (ARs) in patients with idiopathic dilated cardiomyopathy (IDC). BACKGROUND: Although autoantibodies directed against various domains of beta-ARs are found in patients with IDC, only a subgroup against the second extracellular domain of beta1-ARs exerts intrinsic sympathomimetic-like actions on human beta-ARs. It is suggested that the autoantibodies take part in the pathophysiology of IDC and may affect long-term prognosis of patients with this disorder. METHODS: Sera from 104 patients with IDC were screened for autoantibodies that act against the second extracellular loop of beta1-ARs by enzyme-linked immunosorbent assay, using a synthetic peptide corresponding to the domain. Relations of the autoantibodies to clinical variables and long-term prognosis were assessed by multivariate analysis. RESULTS: Autoantibodies were detected in 40 patients (38%). Multifocal ventricular premature contractions (p < 0.01) and ventricular tachycardia (VT; p < 0.01) were more common in autoantibody-positive than in autoantibody-negative patients, although no differences in cardiac function or neurohormonal levels were demonstrated. The presence of autoantibodies (p = 0.001) and a low left ventricular ejection fraction (LVEF <30%; p = 0.02) were independent predictors of VT. Sudden death was independently predicted by the presence of autoantibodies (p = 0.03), as well as by LVEF <30% (p = 0.01), whereas total mortality was predicted only by LVEF <30% (p = 0.001). CONCLUSIONS: Autoantibodies directed against the second extracellular loop of beta1-ARs were closely related to serious ventricular arrhythmias in patients with IDC, and the presence of autoantibodies independently predicted sudden death. These autoantibodies may contribute to electrical instability in patients with IDC.
We examined the roles of lipid peroxidation, neutrophil accumulation, and inflammatory cytokines in the protective effect of polaprezinc against aspirin-induced gastric mucosal injury in rats. The intragastric administration of acidified aspirin induced hyperemia and hemorrhagic erosions in rat stomachs. The increase in the total gastric erosive area after aspirin administration was significantly inhibited in a dose-dependent manner by treatment with polaprezinc. The increases in thiobarbituric acid-reactive substances and tissue-associated myeloperoxidase activity 3 hr after aspirin administration were significantly inhibited by pretreatment with polaprezinc. The gastric concentration of TNF-alpha increased after aspirin administration, and the increase was also inhibited in a dose-dependent manner by treatment with polaprezinc. The peak expression of TNF-alpha mRNA 1 hr after aspirin administration was inhibited by 30 mg/kg of polaprezinc. Based on these data, the beneficial effects of polaprezinc on aspirin-induced gastric mucosal injury may be attributed to its antioxidative and antiinflammatory properties.
The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation.
We investigated whether a causal relationship exists between human herpesvirus 6 (HHV-6) and skin rash resembling acute graft-versus-host disease (GVHD) following bone marrow transplantation (BMT). Isolation of HHV-6 was used to monitor active HHV-6 infection in this study. We analyzed 25 episodes of skin rash in 22 recipients. All recipients were seropositive for HHV-6 before BMT. The onset of skin rash started prior to 30 days post transplantation (group A) in 15 of 25 cases, but after that (group B) in the remaining 10 cases. Twenty-five skin tissue samples were obtained from 22 recipients. The HHV-6 genome was detected in four of 15 skin samples from group A, but not detected in those from group B. HHV-6 was isolated from 11 of 22 recipients around 2 to 3 weeks after BMT (range 14 to 28 days after BMT). HHV-6 was isolated at a time between 10 days before and after the onset of skin rash (skin rash-related viremia) in nine cases in group A. Meanwhile, no skin rash-related viremia was observed in group B. Of the four recipients with positive detection of HHV-6 genome in their skin tissue (group A), two had HHV-6 viremia at the same time. The association between the timing of HHV-6 infection and the onset of skin rash was analyzed statistically. HHV-6 viremia (skin rash-related viremia) was found in nine of 15 (60%) cases in group A, compared with none of 10 (0%) cases in group B. This difference was statistically significant (P = 0.008). Moreover, HHV-6 infection (skin rash-related viremia and/or positive detection of HHV-6 DNA in skin tissue) was demonstrated in 11 of 15 (73.3%) cases in group A, compared with none of 10 (0%) cases in group B (P = 0.001). Thus, this study suggests that HHV-6 may be involved in the development of skin rash in the first month after allogeneic BMT.
In our search for candidate genes for affective disorder on the short arm of chromosome 18, we cloned IMPA2, a previously unreported myo-inositol monophosphatase gene, that maps to 18p11.2. We determined its genomic structure and detected three new single nucleotide polymorphisms (SNPs). In the present study, we screened the gene further to search for additional polymorphisms in Japanese samples and identified seven other SNPs, including a novel missense mutation. These polymorphisms clustered into three regions of the gene. Three relatively informative SNPs, 58G>A, IVS1--15G>A and 800C>T from clusters 1, 2 and 3, respectively, were selected for association tests using a case-control design. The Japanese cohort included 302 schizophrenics, 205 patients with affective disorder and 308 controls. Genotyping was done either by melting curve analysis on the LightCycler or by sequencing. All three SNPs showed significant genotypic association (nominal P = 0.031--0.0001) with schizophrenia, but not with affective disorder. These findings increase the relevance of 18p11.2 to schizophrenia susceptibility because GNAL, which has been shown previously to be implicated in schizophrenia in an independent study, is in close physical proximity to IMPA2. Our findings suggest that IMPA2 or a gene nearby may contribute to the overall genetic risk for schizophrenia among Japanese.
The cholecystokinin gene (CCK) is thought to play a role in the pathogenesis of both panic disorder and schizophrenia. In this study, we have extended the 5'-upstream sequence of the CCK gene, and identified a compound short tandem repeat (STR), located approximately -2.2 to -1.8 kb from the cap site. This STR was found to be polymorphic with ten different allele lengths. Case-control studies using 73 panic patients, 305 schizophrenics and 252 controls showed a significant allelic association with panic disorder (P = 0.025), but not with schizophrenia. Dividing the STR alleles into three classes according to length, Long (L), Medium (M) and Short (S), produced strong genotypic (MM) (nominal P = 0.0014) and allelic (M) (nominal P = 0.0079) associations with panic disorder. screening the newly extended promoter region detected not only the previously identified -36c>t and -188a>g single nucleotide polymorphisms (SNPs) but a new rare snp, -345g>C. Neither of the former two SNPs showed significant association with either panic disorder or schizophrenia. Haplotypic distributions of the STR and SNPs -188 and -36 were significantly different between panic samples and controls (P = 0.0003). These findings suggest that the novel STR or a nearby variant may confer susceptibility to the development of panic disorder.
BACKGROUND: The expression of tissue inhibitor of matrix metalloproteinase (TIMP) 1 in tumour tissue from patients with colorectal carcinoma has been reported to be related to disease progression. However, the clinical significance of plasma TIMP-1 has not been fully elucidated. METHODS: The plasma level of TIMP-1 protein was determined by enzyme-linked immunosorbent assay in samples from 54 patients who underwent resection of the primary tumour. RESULTS: Plasma TIMP-1 levels were associated significantly with depth of invasion and metastasis to lymph nodes and liver. Circulating TIMP-1 levels were significantly higher in patients with serosal invasion, liver metastases and Dukes' stage C tumours. Using a cut-off value of 160 ng/ml, serosal invasion and Dukes' C stage could be predicted with an accuracy of 68.5 per cent. With a cut-off value of 170 ng/ml, metastasis to the lymph node and liver could be predicted with an accuracy of 66.7 and 70.4 per cent respectively. These values were greater than those for carcinoembryonic antigen and CA19-9. CONCLUSION: These data suggest that the plasma concentration of TIMP-1 correlates with both invasion and metastasis in patients with colorectal carcinoma.
BACKGROUND: Neutrophils activation and tumour necrosis factor-alpha (TNF-alpha) induction play a critical role in aspirin-induced gastric mucosal injury. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, has recently been implicated as a regulator of inflammatory responses. The aim of the present study was to determine whether pioglitazone, a specific PPAR-gamma ligand, can ameliorate aspirin-induced gastric mucosal injury in rats, and whether the agent can inhibit the increase in neutrophil accumulation associated with TNF-alpha expression. METHODS: Aspirin-induced injury was produced by the intragastric administration of aspirin (200 mg/kg) and HCl (0.15 N, 8.0 mL/kg). Pioglitazone was given to the rats by gastric intubation 1 h before the aspirin administration. Thiobarbituric acid-reactive substances and tissue-associated myeloperoxidase activity were measured in gastric mucosa as indices of lipid peroxidation and neutrophil infiltration. The gastric concentration of TNF-alpha and the expression of TNF-alpha mRNA was determined by ELISA and reverse transcriptase-polymerase chain reaction. RESULTS: The intragastric administration of acidified aspirin induced hyperemia and haemorrhagic erosions in rat stomachs. The increase in the total gastric erosive area after aspirin administration was significantly inhibited by treatment with pioglitazone in a dose-dependent manner. The increases in thiobarbituric acid-reactive substances and myeloperoxidase activity after aspirin administration were both significantly inhibited by pre-treatment with pioglitazone (10 mg/kg). The gastric content of TNF-alpha increased and the expression of TNF-alpha mRNA was up-regulated after aspirin treatment. However, the peak TNF-alpha mRNA expression 1 h after aspirin administration was inhibited by pioglitazone. CONCLUSION: Based on these data, the beneficial effects of pioglitazone on aspirin-induced gastric mucosal injury may be attributed to its anti-inflammatory properties.
Mast cell chymase plays important roles in inflammation and tissue remodeling. Here we show that mast cell chymase also functions as an enhancer of immunoglobulin production. In the culture of murine spleen cells stimulated with lipopolysaccharide and interleukin-4, purified rat chymase (rat mast cell protease-I; RMCP-I), at physiological concentrations, enhanced immunoglobulin E (IgE) and IgG1 syntheses but not IgG3 synthesis. The enhancement was also evident when spleen cells depleted of T cells and macrophages were employed as responding cells. Enzymatic activity of RMCP-I was required to enhance IgE and IgG1, because two inhibitors for chymotryptic enzymes, chymostatin and Y-40613, a novel chymase inhibitor, suppressed the enhanced immunoglobulin production, and phenylmethylsulphonyl fluoride, an irreversible inhibitor for serine proteases, totally abolished the enhancing effect. Furthermore, a specific inhibitor for Zn2+-dependent metalloproteases, GI 129471, could also completely inhibit the production of IgE and IgG1 that was enhanced by RMCP-I, suggesting that a metalloprotease also played an essential role in the immunoglobulin production. Our results together with others show that proteases from mast cell granules have important function not only in the efferent phase but also in the afferent phase of immune responses.
BACKGROUND: Quantitative analysis of human herpesvirus 6 (HHV-6) genome is important for monitoring active virus infection. The purpose of our study is to evaluate the reliability of a hybridization-based microtiter plate assay (polymerase chain reaction enzyme-linked immunosorbent assay (PCR ELISA)) for quantifying the virus genome. METHODS: Semiquantitative analysis of the virus genome was carried out in 31 (18 male and 13 female) infants with primary HHV-6 infection. If the HHV-6 virus could be isolated from the peripheral blood mononuclear cells (PBMC), the infants were defined as being infected with HHV-6. The PCR ELISA method was used to determine the virus load. A titration of the virus was also carried out in the samples obtained during the acute phase of exanthem subitum. RESULTS: Specificity of the method was demonstrated by a lack of amplification of human herpesvirus 7 and cytomegalovirus DNA. The upper and lower detection limits of the method were 58 and 5800 copies of the virus genome, respectively. The quantity of HHV-6 DNA in the PBMC during the acute phase (879 +/- 975 copies/10(4) PBMC) was significantly higher than during the convalescent phase (54 +/- 76 copies/10(4) PBMC). Furthermore, the virus load in acute phase plasma (53 +/- 75 copies/microL) was also significantly higher than in the convalescent phase samples (2 +/- 9 copies/microL). Virus load in both PBMC and plasma gradually increased after the onset of exanthem subitum until about day 3 to 4 of the illness, but then decreased quickly. However, there was no significant association between virus load and the numbers of infected cells. CONCLUSION: Virus load in both PBMC and plasma gradually increased after the onset of exanthem subitum until about day 3 and day 4 of the illness, respectively, then it decreased quickly. These results indicate that our PCR ELISA system is reliable for monitoring active HHV-6 infection in vivo.
A composite of marrow mesenchymal stem cells (MSCs) and porous hydroxyapatite (HA) has bone-forming capability. To promote the capability, we added recombinant human bone morphogenetic protein-2 (BMP) to the composite. The bone formation was assessed by rat subcutaneous implantation of 4 different kinds of implants, i.e., HA alone, BMP/HA composites, MSCs/HA composites, and the composites containing BMP (MSCs/BMP/HA). Both HA and the BMP/HA composites did not show bone formation at any time after implantation. The MSCs/HA composites showed moderate bone formation at 4 weeks and extensive bone formation at 8 weeks. The MSCs/BMP/HA composites showed obvious bone formation together with active osteoblasts at 2 weeks and more bone formation at 4 and 8 weeks. The MSCs/BMP/HA composites demonstrated high alkaline phosphatase and osteocalcin expression at both the protein and gene levels. These results indicate that the combination of MSCs, porous HA, and BMP synergistically enhances osteogenic potential and provides a rational basis for their clinical application in bone reconstruction surgery.
An 8-month-old boy was admitted to a neighboring hospital for severe liver dysfunction and drowsiness 4 days after a diagnosis of exanthem subitum. A diagnosis of fulminant hepatic failure was made, and liver biopsy was performed during the acute stage. The presence of human herpesvirus-6 variant B (HHV-6B) DNA was shown in liver tissue by polymerase chain reaction (PCR) and in the endothelium of the portal vein by in situ hybridization (ISH). Histologic examination showed microvesicular steatosis resembling that of Reye's syndrome, even though aspirin had not been prescribed. We considered HHV-6 to be the causative agent in this case and report what is perhaps the first precise histologic description of fulminant hepatic failure caused by HHV-6.
The effect of probucol on atheroma formation was evaluated using mouse models for atherosclerosis with different diet protocols. Dietary administration of probucol (0.5 %, wt/wt) for 12 weeks reduced total plasma cholesterol levels in both apolipoprotein E (apoE)-deficient mice fed a western diet and in low-density lipoprotein receptor (LDLR)-deficient mice fed a Paigen diet by 60 % and 30 % to 60 %, respectively. Probucol treatment also significantly reduced high-density lipoprotein (HDL) levels in apoE-deficient mice, but not in LDLR-deficient mice. Atherosclerotic plaques in the aortic sinus of probucol-treated apoE-deficient mice were two-fold larger than those in untreated apoE-deficient mice, while the lesions in probucol-treated LDLR-deficient mice were similar to those in untreated LDLR-deficient mice. A strong negative correlation between HDL cholesterol levels and lesion sizes at the aortic sinus was observed in apoE-deficient mice, but not in LDLR-deficient mice. Thus, in contrast to LDLR-deficient mice, probucol had a strong proatherogenic effect in the aortic sinus of apoE-deficient mice associated with the reduction of HDL levels in spite of the reduction of total plasma cholesterol levels. The varying effects of probucol on atherogenesis depend upon the portion of aorta and which animal model is evaluated, implicating that complex cellular events are involved in the effect of probucol.
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OBJECTIVE: The purpose of this study was to evaluate various oral antimicrobial agent levels in tooth extraction sites. STUDY DESIGN: The concentration of dental alveolar blood in extraction wounds after the oral administration of talampicillin (500 mg), cefaclor (500 mg), cefteram pivoxil (200 mg), cefuroxime axetil (250 mg), cefdinir (200 mg), and ofloxacin (100 mg) was determined in 338 patients and was assessed on the basis of its antimicrobial activity against Streptococcus isolated in odontogenic infections. RESULTS: The percentage of patients whose concentrations exceeded the minimum inhibitory concentration for 90% of Streptococcus was 62.5% to 100% for talampicillin at 30 to 360 minutes, 0% to 12.5% for cefaclor at 30 to 360 minutes, 18.2% to 100% for cefteram pivoxil at 30 to 480 minutes, 50% to 100% for cefuroxime axetil at 30 to 480 minutes, 0% to 50% for cefdinir at 16 to 290 minutes, and 0% to 40% for ofloxacin at 30 to 480 minutes. CONCLUSION: These results indicate that talampicillin, cefteram pivoxil, and cefuroxime axetil have minimum inhibitory concentration levels for 90% of Streptococcus in tooth sockets.
We detected primary human herpesvirus 6 (HHV-6) infection in 5 infants who received living related liver transplantation from their HHV-6 seropositive mothers. Primary HHV-6 infection was confirmed by demonstrating the seroconversion of HHV-6 antibodies with an immunofluorescence assay, by the isolation of the virus, or both. Seroconversion of HHV-6 immunoglobulin G antibody was demonstrated in all 5 recipients. HHV-6 was isolated from 3 of the 5 recipients between 2 and 3 weeks after transplantation. Moreover, the virus genome was detected in plasma by polymerase chain reaction in 4 of the 5 recipients during the same period. Although the 5 recipients had pyrexia at the time of primary HHV-6 infection, none of the recipients had a skin rash after defervescence. Clinical symptoms disappeared without specific antiviral treatment in all but 1 of the recipients.