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Biomedical subjects

T Fukazawa

Publications and source records attributed to T Fukazawa.

At least 37 records · Page 2Linked to original sources
PubMed2000

Vitamin D receptor gene polymorphism in multiple sclerosis and the association with HLA class II alleles.

We have previously reported that the association between Bsm I polymorphism, one of the vitamin D receptor genes (VDRG) polymorphism, and multiple sclerosis (MS). In this report, we investigated the further possible role or relevance of VDRG in the pathogenesis of MS. Apa I polymorphism was detected by PCR-RFLP from the DNA of 77 conventional MS patients and 95 healthy controls. The study of the Bsm I and Apa I haplotypes was carried out by employing previously reported Bsm I data. The AA genotype and the [A] allele in the profiles were significantly more prevalent in MS patients than in controls (P=0.0070 and P=0.0321, respectively). In the [A] allele-positive MS patients, the positive rate of DPB1*0501 in HLA was significantly higher than that of the [A] allele-positive controls and that of the [A] allele-negative MS patients even when the corrected P value (P(corr)) was applied (P(corr)=0.0220 and P(corr)=0.0077, respectively). The frequency of DRB1*1501 was higher in the [A] allele-positive patients than in the [A] allele-positive controls and the [A] allele-negative patients (P(uncorr)=0.0431 and P(uncorr)=0.0089, respectively), but the P values did not reach statistical significance after P corrections. The rate of Bsm I and Apa I haplotypes was much higher in bA/bA-positive MS patients than in the controls (P=0.0003), and in the bA positive MS patients, the positive rate of DPB1*0501 was higher than that of the bA-positive controls and that of the bA-negative MS patients (P(corr)=0.0308 and P(corr)=0.0033, respectively). These results indicate that VDRG polymorphism may be associated with susceptibility to MS, and HLA alleles may correlate with risk for MS together with VDRG.

Adult↗
PubMed2000

Overexpression of the wild-type p53 gene inhibits NF-kappaB activity and synergizes with aspirin to induce apoptosis in human colon cancer cells.

The tumor suppressor gene p53 is a potent transcriptional regulator of genes which are involved in many cellular activities including cell cycle arrest, apoptosis, and angiogenesis. Recent studies have demonstrated that the activation of the transcriptional factor nuclear factor kappaB (NF-kappaB) plays an essential role in preventing apoptotic cell death. In this study, to better understand the mechanism responsible for the p53-mediated apoptosis, the effect of wild-type p53 (wt-p53) gene transfer on nuclear expression of NF-kappaB was determined in human colon cancer cell lines. A Western blot analysis of nuclear extracts demonstrated that NF-kappaB protein levels in the nuclei were suppressed by the transient expression of the wt-p53 in a dose-dependent manner. Transduced wt-p53 expression increased the cytoplasmic expression of I kappaB alpha as well as its binding ability to NF-kappaB, thus markedly reducing the amount of NF-kappaB that translocated to the nucleus. The decrease in nuclear NF-kappaB protein correlated with the decreased NF-kappaB constitutive activity measured by electrophoretic mobility shift assay. Furthermore, parental cells transfected with NF-kappaB were better protected from cell death induced by the wt-p53 gene transfer. We also found that the wt-p53 gene transfer was synergistic with aspirin (acetylsalicylic acid) in inhibiting NF-kappaB constitutive activity, resulting in enhanced apoptotic cell death. These results suggest that the inhibition of NF-kappaB activity is a plausible mechanism for apoptosis induced by the wt-p53 gene transfer in human colon cancer cells and that anti-NF-kappaB reagent aspirin could make these cells more susceptible to apoptosis.

Adenocarcinoma↗
PubMed2000

A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter.

Dominantly inherited, late-onset pure cerebellar ataxia is a group of genetically heterogeneous neurodegenerative disorders. Approximately half of these disorders in the Japanese population are caused by moderate expansion of a CAG repeat in the coding region of the CACNA1A gene on chromosome 19p13 (SCA6). However, neither the loci nor the specific mutations for the remaining disorders have been determined. We performed systematic linkage analysis in a three-generation Japanese family with a locus or mutation that differed from those of known spinocerebellar ataxias. The family members with a late onset (> or =39 years old) exhibited pure cerebellar ataxia, whereas those with an early onset (< or =27 years old) first showed intermittent axial myoclonus followed by ataxia. Other neurological signs were sparse, and neuroimaging studies revealed that atrophy was confined to the cerebellum. Multipoint analysis and haplotype reconstruction ultimately traced this novel spinocerebellar ataxia locus (SCA14) to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter (Zmax = 4.08, corrected for age-dependent penetrance).

Adolescent↗
PubMed2000

Genomic HLA profiles of MS in Hokkaido, Japan: important role of DPB1*0501 allele.

The polymorphism of the HLA class II genes was investigated in 97 patients with multiple sclerosis (MS) in Hokkaido, the northernmost main island of Japan. Of these, 80 patients were classified as having conventional MS and 17 as having opticospinal MS (OS-MS). Our findings confirmed a previous report that the DPB 1*0501 allele is positively associated with OS-MS (P = 0.0043). The frequency of DPB 1*0501 was also found to be higher in conventional MS patients than in controls (79% vs. 58%, P = 0.0084), although the differences were not statistically significant. Our results indicate that OS-MS is a DPB 1*0501-associated subgroup of MS, and that DPB1*0501 is also correlated with risk of conventional MS in Japanese.

Adolescent↗
PubMed2000

Genetics of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Although environmental risk factors are clearly involved in MS, the importance of genetic factors has been strongly supported by the results of studies on multiplex families, though a weak association with major histocompatibility complex (MHC) has been the only genetic feature of MS consistently observed to date. Other candidates genes have been pointed out, but none has been confirmed. Recent genome scans suggest that no single MS susceptibility locus is necessary or sufficient to cause MS, and this finding is compatible with a polygenic etiology. Furthermore, MS is a heterogeneous disorder, and thus different genes may influence its course or presentation. Actually, some candidate genes have been proposed, which contribute to the genotype-phenotype interactions in MS.

Cytokines↗
PubMed2000

Both the HLA-CPB1 and -DRB1 alleles correlate with risk for multiple sclerosis in Japanese: clinical phenotypes and gender as important factors.

The purpose of this study was to clarify the association of HLA-DRB1 and -DPB1 alleles with multiple sclerosis (MS) in Japanese, to determine whether optico-spinal MS (OS-MS) and conventional MS are immunogenetically distinct, and to verify the role of gender difference in HLA associations of MS. We studied HLA-DRB1 and -DPB1 polymorphisms in 166 Japanese patients with MS. Forty-seven patients were classified as having the optico-spinal MS (OS-MS) and 119 as having conventional MS. A lack of DPB1*0301 and a higher frequency of DPB1*0501 compared with controls (corrected P<0.0074; odds ratio=9.48) were found in OS-MS. By contrast, we found for the first time an association of DPB1*0301 with conventional MS in Japanese (corrected P=0.0444; odds ratio=3.28). Logistic analysis, adjusted for sex and age, revealed independent associations of DPB1*0301 (P=0.0004, adjusted odds ratio (aOR)=4.70), DPB1*0501 (P=0.0081, aOR= 2.50) and DRB1*1501 (P=0.0252, aOR=2.21) with conventional MS. However, the frequencies of DRB1*1501 and DPB1*0501 in male patients with conventional MS were equal to those in male controls while the DPB1*0301 frequency was increased in both male and female patients. We did not find any association of these HLA alleles with disease course and severity. In conclusion, OS-MS is a DPB1*0501-associated distinct subtype of MS, and DPB1*0301 is the most strongly associated allele with conventional MS in Japanese. In addition, gender plays an important role in HLA association with MS.

Alleles↗
PubMed2000

Recessively inherited spastic paraplegia associated with ataxia, congenital cataracts, thin corpus callosum and axonal neuropathy.

We investigated a consanguineous Japanese family with a complicated form of familial spastic paraplegia (FSP). Three siblings were affected, probably by autosomal recessive inheritance. All showed ataxia, subnormal mentality, congenital cataracts, and slight cerebellar atrophy on CT scans. Spastic paraplegia was predominant in 2 siblings, while ataxia was more marked in the other. Slight but definite atrophy of the corpus callosum and axonal neuropathy were demonstrated in 1 sibling who underwent detailed investigation. Review of similar cases reported in the literature indicates that this recessively inherited disorder probably represents a homogeneous group within the heterogeneous cluster of complicated FSP.

Adult↗
PubMed2000

Fulminant hepatic failure in the elderly: a clinicopathological study of autopsy cases aged over 65 years.

The pathology of fulminant hepatic failure (FHF) in the elderly is little known because of its very low frequency. Thirteen autopsy cases, all above 65 years of age (mean +/- SD, 72 +/- 6 years), and 10 younger control cases, all below 40 years of age (30 +/- 7 years), were analyzed. The elderly group comprised 10 cases with subacute FHF and three cases with acute FHF, while the younger group comprised seven cases with subacute FHF and three cases with acute FHF. The most predominant pathological type in the elderly group was submassive hepatic necrosis (10 cases), followed by acute hepatitis with bridging hepatic necrosis (AH-BHN; two cases) and massive hepatic necrosis (one case). In two cases of submassive hepatic necrosis, hepatic regeneration seemed to be insufficient for the suggested history. The underlying diseases and terminal complications were significantly more frequent in the elderly group than in the younger group. In conclusion, the immune response in the elderly group is found to be strong enough to cause massive or submassive hepatic necrosis. However, impaired hepatic regeneration is occasionally observed in the elderly cases and AH-BHN is often lethal because of frequent underlying diseases and severe complications.

Acute Disease↗
PubMed2000

Hepatocellular carcinoma arising in an elderly male with primary biliary cirrhosis.

We report the case of an elderly male with asymptomatic primary biliary cirrhosis (PBC) who developed a hepatocellular carcinoma (HCC). The 89-year-old man, who was otherwise healthy, was admitted for investigation of mild hepatic dysfunction, which had been detected during a routine physical check-up. Serum chemistry, positive anti-mitochondrial antibody (M2) and liver biopsy results led to a diagnosis of PBC. Three years later, at age 92, computed tomography (CT) and ultrasound scans of his abdomen revealed a large hepatic tumour, which was confirmed on liver biopsy to be HCC. The tumour ruptured 3 months after diagnosis and the patient was successfully stabilized by coil embolization of his right hepatic artery. We believe that, to date, this is the oldest reported patient to have had interventional radiology for the management of HCC.

Aged↗
PubMed2000

Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere.

We designed and synthesized a new class of peptidomimetic human immunodeficiency virus protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl isostere as the active moiety. From a structure-activity relationship study of HIV-1 protease inhibition, enzyme selectivity for other aspartyl proteases, the antiviral activity and pharmacokinetics in rats, 24c (KNI-227) and 24d (KNI-272, our first clinical candidate) were found to be selective and orally potent HIV protease inhibitors. Moreover, an improvement of the pharmacokinetic features of KNI-272 provided two long-lasting and highly bioavailable compounds (24g: JE-2178, 24h: JE-2179).

Animals↗
PubMed1999

CTLA-4 gene polymorphism may modulate disease in Japanese multiple sclerosis patients.

Multiple sclerosis (MS) is widely believed to have a T-cell-mediated autoimmune etiology. The CTLA-4 gene is a strong candidate for involvement in autoimmune diseases because it plays an important role in the termination of T-cell activation. To examine the genetic association of the CTLA-4 gene locus with MS, we analyzed the CTLA-4 gene exon 1 A/G polymorphism in 74 Japanese MS patients and 93 controls. We also investigated the possible interactions of the CTLA-4 gene polymorphism with clinical course and severity, with MRI findings, with another genetic marker-HLA antigens, and with oligoclonal bands (OCB) in the cerebrospinal fluid (CSF). The CTLA-4 exon 1 polymorphism was similar between MS patients and controls. Conversely, clinical disability was significantly more severe in AA homozygous patients than in the other patients, and the allele frequency and the phenotype frequency of the A allele were significantly higher in patients with severe-grade MRI findings of cerebral white matter than in patients with mild-grade MRI findings. The allele frequency and the phenotype frequency of the A allele were significantly higher in patients with OCB than in patients without. This CTLA-4 polymorphism may modulate the prognosis of patients with MS and may be relevant to generation of OCB in the CSF.

Abatacept↗
PubMed1999

Association of vitamin D receptor gene polymorphism with multiple sclerosis in Japanese.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active form of vitamin D, exerts an immunosuppressive effect and can completely prevent experimental autoimmune encephalomyelitis (EAE). 1,25(OH)2D3 exerts most of its actions only after it has bound to its specific nuclear receptors. To investigate the possible role of vitamin D receptor gene (VDRG) polymorphism in susceptibility to or disease-modulation of MS, we evaluated 77 Japanese patients with 'conventional' MS and 95 controls. A VDRG allelic polymorphism was assessed by Bsm1 endonuclease restriction after specific PCR amplification. Genotypic polymorphism was clearly defined as BB (absence of restriction site on both alleles), bb (presence of restriction site on both alleles), or Bb (heterozygous). We found overexpression of the b allele (92.9 vs. 84.2%: P=0.0138) and homozygote bb (85.7 vs. 71.6%; P=0.0263) in MS patients compared with controls. The results indicate for the first time an association of MS with VDRG polymorphism, which may be involved in pathogenesis of MS, or in the linkage disequilibrium of VDRG to another pathogenic gene loci. The role of VDR gene polymorphism should be further studied in other populations, and the distribution of other polymorphism, such as Apa I, Taq I, should be also analyzed to confirm another susceptibility gene for MS and to obtain more adequate strategies for treatment of MS.

Adolescent↗
PubMed1999

Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine.

We designed and synthesized a new class of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl (HMC) isostere as the active moiety. A systematic evaluation of structure-activity relationships for HIV protease inhibition, anti-HIV activities, and pharmacokinetic profiles has led to the delineation of a set of structural charateristics that appear to afford an orally available HIV protease inhibitor. Optimum structures, exemplified by 21f (JE-2147), incorporated 3-hydroxy-2-methylbenzoyl groups as the P2 ligand, (R)-5,5-dimethyl-1,3-thiazolidine-4-carbonyl (Dmt) residue at the P1' site, and 2-methylbenzylcarboxamide group as the P2' ligand. The present study demonstrated that JE-2147 has potent antiviral activities in vitro and exhibits good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals.

Administration, Oral↗
PubMed1999

Differential involvement of the CD95 (Fas/APO-1) receptor/ligand system on apoptosis induced by the wild-type p53 gene transfer in human cancer cells.

The CD95 (Fas/APO-1) system regulates a number of physiological and pathological processes of cell death. The ligand for CD95 induces apoptosis in sensitive target cells by interacting with a transmembrane cell surface CD95 receptor. We previously reported that the recombinant adenovirus-mediated transfer of the wild-type p53 gene caused apoptotic cell death in a variety of human cancer cells. To better understand the mechanism responsible for this cell death signaling, we have investigated the potential involvement of the CD95 receptor/ligand system in p53-mediated apoptosis. The transient expression of the wild-type p53 gene upregulated the CD95 ligand mRNA as well as protein expression in H1299 human lung cancer cells deficient for p53 and in DLD-1 and SW620 human colon cancer cells with mutated p53, all of which constitutively expressed CD95 receptor as shown by a flow cytometric analysis, and induced rapid apoptotic cell death as early as 24 h after gene transfer. However, the sensitivity to the cytolytic effect of agonistic anti-CD95 antibody (CH11) varied among these cell lines: CH11 induced apoptosis in H1299 cells, but not in DLD-1 and SW620 cells despite their abundant CD95 receptor expression, suggesting that the CD95 receptors on DLD-1 and SW620 cells might be inactivated. In addition, an antagonistic anti-CD95 ligand antibody (4H9) that interfered with the CD95-receptor-ligand interaction partially reduced the apoptosis induced by the wild-type p53 gene transfer in H1299 cells, whereas apoptosis of DLD-1 and SW620 cells occurred in the presence of 4H9. Taken together, these findings led us to conclude that the CD95 receptor/ligand system is differentially involved in p53-mediated apoptosis, suggesting that the restoration of the wild-type p53 function may mediate apoptosis through CD95 receptor/ligand interactions as well as an alternative pathway.

Adenocarcinoma↗
PubMed1999

Combined NK1 and NK2 tachykinin receptor antagonists: synthesis and structure-activity relationships of novel oxazolidine analogues.

We report herein the synthesis and structure-activity relationships of a series of novel oxazolidine analogues with regards to NK1 and NK2 tachykinin receptor binding affinity. Among this series of oxazolidine analogues, some compounds exhibited excellent high binding affinities for both NK1 and NK2 receptors. In addition, we describe the inhibitory effect in vivo on SP-induced airway vascular hyperpermeability and NKA-induced bronchoconstriction in guinea pigs.

Animals↗
PubMed1999

Allosteric effects of four stereoisomers of a fused indole ring system with 3H-N-methylscopolamine and acetylcholine at M1-M4 muscarinic receptors.

We previously demonstrated that brucine and some analogues allosterically enhance the affinity of ACh at muscarinic receptor subtypes M1, M3 or M4. Here we describe allosteric effects at human M1-M4 receptors of four stereoisomers of a pentacyclic structure containing features of the ring structure of brucine. All compounds inhibited 3H-NMS dissociation almost completely at all subtypes with slopes of 1, with similar affinity values at the 3H-NMS-occupied receptor to those estimated from equilibrium assays, consistent with the ternary complex allosteric model. Compound 1a showed positive cooperativity with H-NMS and small negative or neutral cooperativity with ACh at all subtypes. Its stereoisomer, 1b, showed strong negative cooperativity with both 3H-NMS and ACh across the subtypes. Compound 2a was positive with 3H-NMS at M2 and M4 receptors, neutral at M3 and negative at M1 receptors; it was negatively cooperative with ACh at all subtypes. Its stereoisomer, 2b, was neutral with 3H-NMS at M1 receptors and positive at the other subtypes; 2b was negatively cooperative with ACh at M1, M3 and M4 receptors but showed 3-fold positive cooperativity with ACh at M2 receptors. This latter result was confirmed with further 3H-NMS and 3H-ACh radioligand binding assays and with functional assays of ACh-stimulated 35S-GTPgammaS binding. These results provide the first well characterised instance of a positive enhancer of ACh at M2 receptors, and illustrate the difficulty of predicting such an effect.

Acetylcholine↗
PubMed1999

A micromechanical model of the cochlea with radial movement of the tectorial membrane.

The function of the tectorial membrane in the cochlear micromechanics is uncertain. In modeling approaches some models have assumed it to be a resonator that participates in the sharp tuning mechanisms of the cochlea with its mass coupled to the ciliary stiffness of outer hair cells, being driven by the shear force between the reticular lamina and itself. This paper presents a different type of micromechanical model which assumes that the tectorial membrane is driven by a lymphatic fluid flow that can be shown to have a substantial radial component. It also assumes that the reticular lamina is relatively stiff and thereby restrains the top end of outer hair cells that exert a force to the basilar membrane via Deiters cells. When combined with a three-dimensional block model, it can simulate the sharp tuning mechanisms of the cochlea well.

Acoustic Stimulation↗