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Biomedical subjects

F Kaneko

Publications and source records attributed to F Kaneko.

At least 19 recordsLinked to original sources
PubMed2006

Bullous pemphigoid antigen II (BP180) and its soluble extracellular domains are major autoantigens in mucous membrane pemphigoid: the pathogenic relevance to HLA class II alleles and disease severity.

BACKGROUND: Mucous membrane pemphigoid (MMP), a chronic autoimmune subepithelial blistering disease, is associated with circulating IgG and/or IgA autoantibodies against several basement membrane zone antigens. The heterogeneity of clinical presentation and diversity of target autoantigens have contributed to difficulties in characterizing this condition immunologically. OBJECTIVES: To analyse serum autoantibody profile and HLA class II alleles in MMP patients and to correlate this with the clinical presentation of disease. METHODS: Well-defined subgroups consisting of 124 patients with MMP were examined for IgG and IgA reactivity with immunoblotting using human epidermal, dermal and placental amnion proteins. The results were further analysed on the basis of detailed clinical (sites of involvement and disease severity) and immunopathological criteria (immunofluorescence study and HLA class II alleles). RESULTS: Immunoblot assay revealed that the majority of MMP patients had IgG (93 of 124, 75%) and/or IgA autoantibodies (63 of 124, 51%) to BP180 (including its soluble ectodomains, 120-kDa LAD-1 and 97-kDa LABD97 antigens). Other antigens targeted predominantly by IgG autoantibodies included: BP230 in 34 (27%), beta4 integrin in 26 (21%), and laminin 5 in three (2%). All the BP230+ sera and 23 (88%) beta4 integrin+ sera also reacted with at least one of the BP180 antigens. Over 85% of patients with reactivity to beta4 integrin had ocular involvement. In most cases of MMP, more severe clinical features were associated with antibody reactivity to multiple basement membrane zone antigens, as well as reactivity to multiple BP180 component antigens. Dual BP180/LAD-1 reactivity with IgG and IgA was associated with a more severe phenotype. In addition, the subset-dependent autoantibody reactivity correlated well with specific HLA class II alleles, DQB1*0301, DRB1*04 and DRB1*11. CONCLUSIONS: Our results confirmed that BP180 is a major autoantigen targeted by the sera of patients with MMP. The disease-prevalent HLA class II alleles and humoral autoimmune response against the particular subsets of antigenic epitope(s) within BP180 ectodomain may contribute to the clinicopathological significance and disease severity of MMP.

Adult↗
PubMed2004

High prevalence rate of Helicobacter pylori resistance to clarithromycin during long-term multiple antibiotic therapy for chronic respiratory disease caused by non-tuberculous mycobacteria.

BACKGROUND: Helicobacter pylori resistance to clarithromycin, probably due to the frequent use of this antibiotic for the treatment of other diseases, is the greatest obstacle against its eradication. AIM: To clarify the prevalence of clarithromycin-resistant H. pylori in patients with non-tuberculous mycobacterial lung disease receiving multiple antibiotic treatment, including clarithromycin. METHODS: We enrolled 88 patients with non-tuberculous mycobacterial lung disease; 29 underwent upper gastrointestinal endoscopy for the diagnosis of H. pylori infection prior to treatment, and 60 underwent it during treatment. The diagnosis of H. pylori infection was confirmed by histological examination, urease test and microaerobic bacterial culture. The minimum inhibitory concentration of clarithromycin was determined and the DNA was analysed for each of the isolated H. pylori strains. RESULTS: Patients during the treatment had a high prevalence rate of clarithromycin-resistant H. pylori (100%). Analysis of DNA of the clarithromycin-resistant H. pylori isolates revealed point mutations at A2142G or A2143G. Moreover, a linear correlation was found between the total cumulative dose of clarithromycin and the minimum inhibitory concentration. CONCLUSION: All patients with non-tuberculous mycobacterial lung disease being treated long-term with multiple antibiotics, including clarithromycin, harboured clarithromycin-resistant H. pylori in the stomach. Therefore, eradication of H. pylori before commencement of long-term therapy including clarithromycin should be recommended.

Anti-Bacterial Agents↗
PubMed2003

Expression of the GLI2 oncogene and its isoforms in human basal cell carcinoma.

BACKGROUND: Mutations of the patched (Ptc) gene, a developmental regulator implicated in the signalling pathway via sonic hedgehog (Shh) and smoothened (Smo), play an essential pathogenic role in the development of basal cell carcinomas (BCCs). We previously reported the upregulation of Shh signal transducers, including Ptc, Smo and hedgehog-interacting protein, in BCCs. In vertebrates, specific downstream effectors in the Shh signalling pathway include three zinc-finger transcription factors, Gli1, Gli2 and Gli3. Gli1 possesses only an activation domain, while Gli2 and Gli3 contain both activation and repression domains. It remains unclear which of these transcription factors are responsible for the development of BCCs. OBJECTIVES: To examine the expression pattern of Gli2 mRNA by human BCCs in comparison with those by normal human skin and various skin tumours. METHODS: We performed quantitative reverse transcriptase-polymerase chain reaction analyses with a series of samples from BCCs, other skin tumours and normal skin. RESULTS: We found that Gli2 mRNA expression was enhanced in the BCCs we examined, whereas there was no significant increase in other skin tumours or normal skin. Of four spliced Gli2 isoforms designated Gli2alpha, beta, gamma and delta, the expression of Gli2beta mRNA was increased the most in BCCs. CONCLUSIONS: As Gli2beta is an isoform spliced at the first splicing site containing a repression domain and consists of an intact activation domain, its overexpression may lead to the upregulation of the Shh signalling pathway, thereby inducing BCCs.

Aged↗
PubMed2002

Expression of a sonic hedgehog signal transducer, hedgehog-interacting protein, by human basal cell carcinoma.

BACKGROUND: Aberrant activation of the hedgehog pathway has been identified in various human tumours, including familial and sporadic basal cell carcinomas (BCCs). It has been postulated that binding of sonic hedgehog protein (SHH) to its receptor, patched protein (PTC), releases the inhibitory effect of PTC against smoothened protein (SMO), another protein of the SHH signalling pathway. The positive SMO signalling is not downregulated in BCCs because of the mutational inactivation of PTC. Recently, hedgehog-interacting protein (HIP) was found to bind to SHH directly and attenuate SHH signalling like PTC, while its expression was induced by SHH signals. OBJECTIVES: To examine the expression patterns of HIP, SHH and PTC gene mRNA by human BCCs, in comparison with those by normal human skin and various skin tumours. METHODS: We performed quantitative reverse transcriptase-polymerase chain reaction analyses with a series of samples from BCCs, other skin tumours and normal skin. RESULTS: We found that the mRNA expression of both HIP and PTC genes was enhanced in all samples of BCCs, whereas none of the other skin tumours tested exhibited an increased level of such mRNAs as compared with normal skin. The transcription of the SHH gene, however, was at a baseline level in most BCCs. CONCLUSIONS: These results indicate that both HIP and PTC gene expression are specifically involved in the development of BCCs, and that the production of HIP is linked with the expression of the PTC gene but not the SHH gene.

Aged↗
PubMed2001

Characterization of a novel mammalian SUMO-1/Smt3-specific isopeptidase, a homologue of rat axam, which is an axin-binding protein promoting beta-catenin degradation.

A novel SUMO-1/Smt3-specific isopeptidase, SMT3IP2/Axam2 (Smt3-specific isopeptidase 2), was cloned and characterized. The catalytic domains in the carboxyl-terminal region were very much similar to those of other SUMO-1/Smt3-specific proteases, but the amino-terminal part was quite different. The enzyme specifically bound to Smt3a and Smt3b but not to SUMO-1. The SMT3IP2 expressed by Escherichia coli could cleave SUMO-1, Smt3a, or Smt3b from a SUMO-1/RanGAP1, Smt3a/RanGAP1, or Smt3b/RanGAP1 conjugate, respectively, and had the activity of a carboxyl-terminal hydrolase to produce a glycine residue in the carboxyl terminus of these ubiquitin-like proteins. The sequence data indicated that the amino acid sequence of SMT3IP2 was mostly identical to that of rat Axam, which binds to Axin and promotes the degradation of beta-catenin, although its amino-terminal region was much shorter than that of Axam. Therefore, we designated this isopeptidase SMT3IP2/Axam2. When human SW480 cells were transfected with wild-type SMT3IP2/Axam2, the beta-catenin disappeared. When the cells were transfected with the SMT3IP2/Axam2 C500A mutant, which had neither isopeptidase nor carboxyl-terminal hydrolase activity, or with the 1-352 mutant, which lacked the catalytic domain of the enzyme, again the beta-catenin disappeared, indicating that the enzyme activities were not necessary for the instability of beta-catenin in this transfection assay system and that its competition with Dvl for binding to Axin may be important for the instability of beta-catenin as suggested previously for Axam (Kadoya, T., Kishida, S., Fukui, A., Hinoi, T., Michiue, T., Asashima, M., and Kikuchi, A. (2000) J. Biol. Chem. 275, 37030-37037). The involvement of its enzyme activities in the Wnt signaling pathway remains to be elucidated.

Adaptor Proteins, Signal Transducing↗
PubMed2001

The latency pattern of Epstein-Barr virus infection and viral IL-10 expression in cutaneous natural killer/T-cell lymphomas.

The nasal type, extranodal natural killer or T(NK/T)-cell lymphoma is usually associated with latent Epstein-Barr virus (EBV) infection. In order to elucidate the EBV gene expression patterns in vivo, we examined eight patients with cutaneous EBV-related NK/T-cell lymphomas, including six patients with a NK-cell phenotype and two patients with a T-cell phenotype. The implication of EBV in the skin lesions was determined by the presence of EBV-DNA, EBV-encoded nuclear RNA (EBER) and a clonality of EBV-DNA fragments containing the terminal repeats. Transcripts of EBV-encoded genes were screened by reverse transcription- polymerase chain reaction (RT-PCR), and confirmed by Southern blot hybridization. The expression of EBV-related antigens was examined by immunostaining using paraffin-embedded tissue sections and cell pellets of EBV-positive cell lines. Our study demonstrated that all samples from the patients contained EBV nuclear antigen (EBNA)-1 mRNA which was transcribed using the Q promoter, whereas both the Q promoter and another upstream promoter (Cp/Wp) were used in EBV-positive cell lines, B95.8, Raji and Jiyoye. Latent membrane protein-1 (LMP-1) mRNA was detected in seven of eight patients and all cell lines, whereas EBNA-2 transcripts were found only in the cell lines. Immunostaining showed no LMP-1, EBNA-2 or ZEBRA antigens in the paraffin-embedded tissue sections, although they were positive in the cell line cells. Latent BHRF1 transcripts encoding bcl-2 homologue and BCRF1 transcripts encoding viral interleukin (vIL)-10 were detected in one and two of eight patients, respectively. A patient with NK-cell lymphoma expressing both transcripts died of rapid progression of the illness. Our results indicate that the restricted expression of the latency-associated EBV genes and the production of vIL-10 and bcl-2 homologue may favour tumour growth, evading the host immune surveillance.

Adolescent↗
PubMed2001

Effects of collagen matrix containing transforming growth factor (TGF)-beta(1) on wound contraction.

We evaluated the effectiveness of transforming growth factor (TGF)-beta(1) on wound contraction, both alone and in combination with collagen matrix, using an in vivo delayed wound healing type model. To clarify the mechanisms involved in the effectiveness of TGF-beta(1), we also used a fibroblast-populated collagen gel contraction in vitro model. Although we found that TGF-beta(1) significantly accelerated contraction of the fibroblast-populated collagen gel in vitro, we demonstrated that both collagen matrix alone and 1.0 microg of TGF-beta(1) alone significantly inhibited wound contraction in the in vivo model. In addition, the combination of TGF-beta(1) and collagen matrix was much more effective than TGF-beta(1) alone, a finding which was supported by histopathological examination. Wounds treated with collagen matrix containing TGF-beta(1) showed horizontal rearrangement of collagen fibers in the dermal part as well as evidence of active fibroblast proliferation, which was not observed in the scar regions of controls. These results show that the application of TGF-beta(1) treated collagen matrix is effective for preventing contraction producing so called "neodermis" in treating a delayed healing type model and may be highly beneficial for treating chronic wounds.

Animals↗
PubMed2001

Treatment of recurrent auricle pseudocyst with intralesional injection of minocycline: a report of two cases.

Pseudocyst of the auricle (PCA) is characterized by asymptomatic and fluctuant swelling of the external ear and frequent relapses despite various therapeutic approaches. We describe two patients with recurrent PCA who were successfully treated with intralesional injection of 1 mg/mL of minocycline hydrochloride (minocycline), 2 or 3 times at 2-week intervals. Intralesional injection of minocycline may be a new therapeutic choice for conservative management of PCA, especially in recurrent cases. The mechanisms of minocycline action that may have led to reduction of the cystic lesions are discussed.

Adolescent↗
PubMed2001

Biphasic cytokine expression by T cell clones from patients with atopic dermatitis with different incubation periods and strengths of stimuli.

It has been proposed that T helper (Th) 2 cells play a key role in the pathogenesis of atopic dermatitis (AD) because of clinical and experimental findings including hyper IgE, eosinophilia and Th2 type cytokine overexpression, etc. In contrast, several observations such as Th1 type cytokine detection in chronic lesions and histological features resembling allergic contact dermatitis suggest that Th1 rather than Th2 cells are important for the pathogenesis of skin lesions. In order to clarify this paradox, we investigated the function of T cell clones established from AD patients. Most T cell clones induced by house dust mite antigen and interleukin (IL)-2 from peripheral blood mononuclear cells of two AD patients exhibited CD4+/ CD8-, CD45RO+/ CD45RA-, and produced high levels of IL-4 and low levels of interferon-gamma (IFN-gamma) after phytohemagglutinin (PHA) (1 microg/ml) stimulation, suggesting a Th2 subtype. When stimulated with a high dose of concanavalin A (conA) (10 microg/ml), however, these clones produced high amounts of IFN-gamma. IL-4 production reached a peak 24 hours after conA (10 ,g/ml) stimulation, whereas IFN-gamma production was increased up to 48 hours after stimulation. The findings of T cell receptor (TCR) stimulation with immobilized anti-CD3 monoclonal antibody (mAb) showed that the suitable strength of TCR stimulation for IFN-y production was higher than for IL-4. Also, in the TCR stimulated condition, the peak of IFN-gamma production was later than that of IL-4. These results indicate that T cell clones which exhibited a Th2 profile under weak stimulation can produce IFN-y in the late phase of stimulation when strong stimuli are used. The results are consistent with the previous observation that IFN-gamma production prominently appears in the chronic and late phase lesions of AD.

Adolescent↗
PubMed2000

Transcriptional factor AP-2gamma increases human cystatin A gene transcription of keratinocytes.

The transcriptional activator protein-2 (AP-2) has been suggested to participate in keratinocyte gene regulation. Cystatin A, a cysteine proteinase inhibitor, is one of the cornified cell envelope constituents and is expressed in the upper epidermis. We report AP-2-dependent transcriptional regulation of cystatin A gene expression of keratinocytes. At least three isoforms of AP-2 (AP-2 alpha, beta, gamma) have been described. Transfection of AP-2alpha, beta and gamma expression vectors into cultured normal human keratinocytes (NHK) resulted in increased cystatin A expression in both mRNA and protein levels. Among the three isoforms AP-2gamma was most potent in inducing cystatin A expression. In contrast, transfection of antisense oriented AP-2gamma expression vector decreased basal AP-2 expression, accompanied by decreased cystatin A mRNA. The fragment, +77 to -478 of 5'-flanking region of human cystatin A gene, was subcloned into chloramphenicol acetyltransferase (CAT) reporter vector (p478CAT). Cotransfection of p478CAT vector with AP-2alpha, beta, and gamma expression vectors resulted in three-, three-, and sixfold increase in the CAT activity, respectively. Transfection of the deleted construct (p478DeltaAP-2CAT, devoid of AP-2-like binding site (-75 to -84)) decreased CAT activity by one-third compared to p478CAT promoter activity. Cotransfection of p478DeltaAP-2CAT with AP-2alpha, beta, and gamma expression vectors had no effect on the decreased promoter activity. Immunohistochemical analysis of human skin showed that AP-2alpha is exclusively expressed in the nuclei of basal cell layer. AP-2gamma is expressed in the nuclei of basal, spinous, and granular cell layers. AP-2beta expression was not observed in the epidermis. Gel mobility shift assay revealed that the AP-2gamma protein specifically binds to oligonucleotides containing AP-2-like binding site of cystatin A gene. These results indicate that AP-2gamma regulates the cystatin A gene expression of epidermal keratinocytes at the transcriptional level.

5' Untranslated Regions↗
PubMed2000

Polymorphism analysis of Epstein-Barr virus isolates from patients with cutaneous natural killer/T-cell lymphoproliferative disorders: A possible relation to the endemic occurrence of these diseases in Japan.

Certain forms of cutaneous lymphomas in Asia are associated frequently with Epstein-Barr virus (EBV) infection, whereas such cases are less common in western countries. The virus-related peptides, EBV-determined nuclear antigen (EBNA)-2 and the latent membrane protein (LMP)-1, play an essential role in cell transformation. The polymorphisms of these EBV genes may be related to their transforming abilities. In order to clarify the viral subtype that may be involved in the incidence of EBV-associated lymphomas, we analyzed the EBNA-2 and LMP-1 gene polymorphisms and mutations in healthy adults and in patients with EBV-associated cutaneous natural killer(NK)/T-cell lymphoproliferative disorders in Japan. In EBV-related cutaneous lymphoproliferative disorders, EBV subtype 1 was found in all 15 cases, and 1 sample contained a dual infection with subtypes 1 and 2. All EBV isolates from our patients lost a Xho-1 site in exon 1 of the LMP-1 gene, and 7 of 13 cases had a Nco-1 site within the promoter region. All isolates without the LMP-1-Xho-1 site had a 30 bp deletion in the carboxy terminus of the LMP-1 gene, except for the isolate from a patient with angioimmunoblastic lymphadenophathy-like T-cell lymphoma in which a novel Nco-1 site was present in exon 1. Eleven of fourteen throat washings from healthy adults which contained EBV-DNA harbored EBV subtype 1, and the EBNA2 region was not amplified in the other 3 samples. The Xho-1 site was lost in 12 (86%) of 14 isolates and the 30 bp deletion was present in 11 (78%) of 14 isolates from the throat washings. The findings indicate that the predominant EBV isolate from Japanese healthy adults and patients with cutaneous NK/T-cell lymphoproliferative disorders is subtype 1 with a 30 bp deletion and loss of a Xho-1 site in the LMP-1 gene. Since previous data indicated that either subtype 1 or the 30 bp deletion variant possesses high tumorigenic activity, the prevalence of subtype 1 containing these mutations might be responsible for the high incidence of EBV-associated lymphoproliferative disorders in Japan.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Boomerang deformity of cervical spinal cord migrating between split laminae after laminoplasty.

Patients with cervical compression myelopathy were studied to elucidate the mechanism underlying boomerang deformity, which results from the migration of the cervical spinal cord between split laminae after laminoplasty with median splitting of the spinous processes (boomerang sign). Thirty-nine cases, comprising 25 patients with cervical spondylotic myelopathy, 8 patients with ossification of the posterior longitudinal ligament, and 6 patients with cervical disc herniation with developmental canal stenosis, were examined. The clinical and radiological findings were retrospectively compared between patients with (B group, 8 cases) and without (C group, 31 cases) boomerang sign. Moderate increase of the grade of this deformity resulted in no clinical recovery, although there was no difference in clinical recovery between the two groups. Most boomerang signs developed at the C4/5 and/or C5/6 level, where maximal posterior movement of the spinal cord was achieved. Widths between lateral hinges and between split laminae in the B group were smaller than in the C group. Flatness of the spinal cord in the B group was more severe than in the C group. In conclusion, the boomerang sign was caused by posterior movement of the spinal cord, narrower enlargement of the spinal canal and flatness of the spinal cord.

Adult↗
PubMed2000

Cutaneous lymphoproliferative disorders associated with Epstein-Barr virus infection: a clinical overview.

Epstein Barr virus (EBV) infection is implicated in various kinds of neoplasms including certain types of cutaneous T or natural killer (NK) cell proliferative disorders. Although a pathogenic role of EBV infection is not clear, some EBV gene products expressed during a latency phase were found to have biological properties leading to cellular gene expression and immortalization. Furthermore, EBV can use an array of strategies to evade host immune responses, and maintain the latent infection. EBV-associated cutaneous lymphoproliferative disorders are prevalent in Asia, and less frequent in western countries where infectious mononucleosis is common in adolescents and young adults. This review introduces recent advances on the mechanism of EBV infection, highlighting unique clinicopathologic manifestations of EBV-associated cutaneous lymphoproliferative disorders.

Adolescent↗
PubMed2000

Dermal fibroblasts are one of the therapeutic targets for topical application of 1alpha,25-dihydroxyvitamin D3: the possible involvement of transforming growth factor-beta induction.

BACKGROUND: Transforming growth factor (TGF) -beta has been suggested to be an effective inhibitor for abnormal keratinocyte growth in psoriasis. As a majority of the secreted TGF-beta are biologically latent complexes, activation is essential for TGF-beta-mediated cellular responses in vitro and in vivo. Objectives Here we report the response of the TGF-beta regulation system to 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], an active vitamin D3 analogue Patients/methods We studied two types of fibroblasts derived from normal and psoriatic lesional skin, using an enzyme-linked immunosorbent assay and Northern blotting techniques. RESULTS: 1,25(OH)2D3 caused a dose-dependent induction of latent and active TGF-beta1 proteins in both cell cultures. The increases were significant over 72 h, but not within 48 h after stimulation. The time course of TGF-beta1 mRNA expression showed a biphasic response consisting of early ( approximately 1 h) and late phases ( approximately 96 h) of induction. Concomitant increases of TGF-beta2 and -beta3, other mammalian isoforms, were observed in the 1,25(OH)2D3-treated cells, but the kinetics were all different. Co-incubation with metabolic inhibitors, actinomycin D and cycloheximide, revealed that the early induction of TGF-beta1 mRNA by 1,25(OH)2D3 is dependent on de novo RNA synthesis, but not on RNA stabilization or protein synthesis. It seems likely to be a transient and negligible response given the absence of TGF-beta1 protein production. The late induction of TGF-beta1 mRNA was partially blocked by adding isoform-specific antibodies to TGF-beta1, -beta2 and -beta3, indicating TGF-beta autoregulation. Despite these marked responses, there were no significant differences in the TGF-beta expression between normal and psoriatic fibroblasts. CONCLUSIONS: These results suggest that antiproliferative and anti-inflammatory effects of 1,25(OH)2D3 on psoriatic lesional skin may be mediated, at least in part, by a complex TGF-beta regulation in local dermal fibroblasts.

Administration, Topical↗
PubMed2000

Novel point mutations in the steroid sulfatase gene in patients with X-linked ichthyosis: transfection analysis using the mutated genes.

X-linked ichthyosis is caused by steroid sulfatase deficiency which results from abnormalities in its coding gene. The majority of X-linked ichthyosis patients ( approximately 90%) have complete or partial deletions of the steroid sulfatase gene. In this study, we examined the mutations of the steroid sulfatase gene in two unrelated X-linked ichthyosis patients without complete deletion of the gene. Polymerase chain reaction-single-strand conformation polymorphism and direct sequencing analyses showed that each patient has a different single base pair substitution within exon 8 encoding the C-terminal half of the steroid sulfatase polypeptide. Both mutations resulted in the transversion of functional amino acids: a G-->C substitution at nucleotide 1344, causing a predicted change of a glycine to an arginine, and a C-->T substitution at nucleotide 1371, causing a change from a glutamine to a stop codon. In vitro steroid sulfatase cDNA expression using site-directed mutagenesis revealed that these mutations are in fact pathogenic and reflect the levels of steroid sulfatase enzyme activities in each of the X-linked ichthyosis patients.

Adult↗