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Biomedical subjects

Koji Hashimoto

Publications and source records attributed to Koji Hashimoto.

At least 91 records · Page 5Linked to original sources
PubMed2003

Human herpes virus 6 encephalitis in allopurinol-induced hypersensitivity syndrome.

Hypersensitivity syndrome is one of the most severe forms of drug eruption, and is characterized by a severe, potentially lethal, multiorgan involvement. Recently, reactivation of human herpesvirus 6 (HHV-6) has been suggested to be involved in this syndrome, although the exact role of HHV-6 remains elusive. In addition to exanthem subitum, neurological illnesses, such as infantile febrile illness without rash and encephalitis in immunocompromised patients have been attributed to HHV-6. A 51-year-old man developed a generalized erythematous eruption during treatment with allopurinol. Prednisolone improved his condition, but after the dose of prednisolone was reduced neurological abnormalities such as mental deterioration and positive meningeal signs developed. HHV-6 DNA in his blood by PCR analysis was positive. Furthermore, we detected HHV-6 DNA in the cerebrospinal fluid. The titers of anti-HHV-6-IgG increased during the course. His neurological symptoms gradually improved and no neurological sequelae were noted. Neurological abnormalities associated with hypersensitivity syndrome are very rare. However, the detection of HHV-6 DNA in the cerebrospinal fluid strongly indicates an involvement of reactivated HHV-6 in encephalitis.

Allopurinol↗
PubMed2003

Immunohistochemical expression of receptor-tyrosine kinase c-kit protein in invasive ductal carcinoma of the pancreas.

The expression of receptor tyrosine kinase c-kit and its biologic significance in pancreatic cancer are unclear. We studied the expression of c-kit protein (c-KIT) in resectable invasive ductal carcinomas (IDCs) of the pancreas, in order to assess whether a selective c-kit inhibitor, STI571 (Glivec), may be applied for the treatment of pancreatic IDCs. This study included 72 pancreatic IDC patients who received a pancreatectomy between 1982 and 2002. The expression of c-KIT was analyzed retrospectively by immunohistochemistry. c-KIT was expressed in 78% (56/72) of the pancreatic IDCs. c-KIT expression did not correlate with any clinicopathological factor of pancreatic IDC and c-KIT expression had no significant influence on the survival of the patients. The survival rate of the adjuvant chemotherapy (ACT) (+) group was significantly higher than that of the ACT (-) group, but c-KIT expression had no significant effects on the efficacy of the ACT. Multivariate analysis indicated that the pTNM stage, grade and ACT were all significant variables for survival in IDCs overall. As c-KIT was expressed in 78% of the pancreatic IDCs, it suggests that STI571 may be a beneficial agent for chemotherapy against human pancreatic IDCs.

Adult↗
PubMed2003

The PPARgamma ligand, 15d-PGJ2, attenuates the severity of cerulein-induced acute pancreatitis.

INTRODUCTION: The prostaglandin D2 metabolite, 15d-PGJ2, a potent natural ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), exerts antiinflammatory effects by inhibiting the induction of inflammatory response genes and NF-kappaB-dependent transcription. AIM To determine whether 15d-PGJ2 decreases the severity of secretagogue-induced acute pancreatitis (AP) and to assess cellular mechanisms contributing to these effects. METHODOLOGY Swiss Webster mice were injected with either saline or cerulein (50 microg/kg) hourly for 8 hours and received either 15d-PGJ2 (2 mg/kg) or vehicle 1 hour before and 4 hours after induction of AP. RESULTS Treatment with 15d-PGJ2 significantly attenuated AP, as determined by histologic assessment of edema, vacuolization, inflammation, and necrosis. This attenuation was associated with decreased cyclooxygenase-2 (COX-2) and intercellular adhesion molecule-1 (ICAM-1) expression and decreased serum and pancreatic IL-6 levels. Treatment with 15d-PGJ2 markedly inhibited NF-kappaB DNA-binding activity, and, moreover, this decreased activity was associated with a concomitant inhibition of IkappaB protein degradation. CONCLUSION Our findings demonstrate that 15d-PGJ2 attenuates the severity of AP most likely through the inhibition of COX-2 expression, IL-6 production, and NF-kappaB activation. Ligands specific for PPARgamma may represent novel and effective means of clinical therapy for AP.

Acute Disease↗
PubMed2003

Human herpesvirus 6 and drug allergy.

PURPOSE OF REVIEW: The similarity between viral skin eruption and drug-induced rash has inspired many researchers to seek an association between viral infection and drug allergy. Hypersensitivity syndrome (referred to in this review as drug-induced hypersensitivity syndrome) is one of the severe adverse reactions to drugs and was reported more than 50 years ago. However, the mechanism of drug-induced hypersensitivity syndrome has not been fully elucidated. Several groups reported the association between human herpesvirus 6 reactivation and drug-induced hypersensitivity syndrome 5 years ago. Recently, similar case reports have accumulated. Recent findings concerning human herpesvirus 6 and drug-induced hypersensitivity syndrome are reviewed here. RECENT FINDINGS: In drug-induced hypersensitivity syndrome, examination of serial serum samples revealed a marked and sudden increase in anti-human herpesvirus 6 IgG titers in the third or fourth week after the onset of clinical manifestations. In addition, active human herpesvirus 6 replication precedes the rise in antibody titers. Furthermore, the recurrence or worsening of signs and symptoms was observed concurrently with human herpesvirus 6 reactivation. In encephalitis associated with drug-induced hypersensitivity syndrome, human herpesvirus 6 DNA was detected in cerebrospinal fluid. This strongly indicates the involvement of reactivated human herpesvirus 6 in the pathogenesis of encephalitis. Similarly, reactivation of human herpesvirus 6 was observed in fulminant type 1 diabetes mellitus associated with drug-induced hypersensitivity syndrome caused by carbamazepine. SUMMARY: The reactivation of human herpesvirus 6 in drug-induced hypersensitivity syndrome is not a coincidental phenomenon. Human herpesvirus 6 reactivation plays an important role in the pathogenesis of drug-induced hypersensitivity syndrome, especially in the latter half of the clinical symptoms. Reactivated human herpesvirus 6 sometimes leads to the severe complications of drug-induced hypersensitivity syndrome, such as encephalitis and type 1 diabetes mellitus. In conclusion, drug-induced hypersensitivity syndrome is a complex disease composed of drug allergy and human herpesvirus 6.

Antigens, CD↗
PubMed2003

Severe palmo-plantar hyperkeratosis in Koebner epidermolysis bullosa simplex.

A 22-year-old Japanese woman with Koebner epidermolysis bullosa simplex presented with severe palmo-plantar hyperkeratosis. Skin biopsy specimens from the palm revealed hyperkeratosis and acanthosis with blistering in the basal cell layer. An electron microscopic study showed cytolysis of basal cells and clumping of tonofilaments forming thick bundles and perinuclear electron-dense bodies. Hand contractures were released and covered with full thickness autografts or split thickness autografts. The donor site was successfully treated with cultured epidermal autografts.

Adult↗
PubMed2003

Staphylococcus aureus susceptibility to innate antimicrobial peptides, beta-defensins and CAP18, expressed by human keratinocytes.

The antimicrobial peptides human beta-defensin-1 (hBD1), hBD2, hBD3, and CAP18 expressed by keratinocytes have been implicated in mediation of the innate defense against bacterial infection. To gain insight into Staphylococcus aureus infection, the susceptibility of S. aureus, including methicillin-resistant S. aureus (MRSA), to these antimicrobial peptides was examined. Based on quantitative PCR, expression of hBD2 mRNA by human keratinocytes was significantly induced by contact with S. aureus, and expression of hBD3 and CAP18 mRNA was slightly induced, while hBD1 mRNA was constitutively expressed irrespective of the presence of S. aureus. Ten clinical S. aureus isolates, including five MRSA isolates, induced various levels of expression of hBD2, hBD3, and CAP18 mRNA by human kertinocytes. The activities of hBD3 and CAP18 against S. aureus were found to be greater than those of hBD1 and hBD2. A total of 44 S. aureus clinical isolates, including 22 MRSA strains, were tested for susceptibility to hBD3 and CAP18. Twelve (55%) and 13 (59%) of the MRSA strains exhibited more than 20% survival in the presence of hBD3 (1 microg/ml) and CAP18 (0.5 microg/ml), respectively. However, only three (13%) and two (9%) of the methicillin-sensitive S. aureus isolates exhibited more than 20% survival with hBD3 and CAP18, respectively, suggesting that MRSA is more resistant to these peptides. A synergistic antimicrobial effect between suboptimal doses of methicillin and either hBD3 or CAP18 was observed with 10 MRSA strains. Furthermore, of several genes associated with methicillin resistance, inactivation of the fmtC gene in MRSA strain COL increased susceptibility to the antimicrobial effect mediated by hBD3 or CAP18.

Amino Acid Sequence↗
PubMed2002

Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the Asp814Val mutation.

Substitution of valine (Val) for aspartic acid (Asp) at codon 814 constitutively activates murine c-kit receptor tyrosine kinase (KIT), and Asp816Val mutation, corresponding to murine Asp814Val mutation, is found in patients with mastocytosis and acute myelocytic leukemia. However, the signal transduction pathways responsible for oncogenesis by the Asp814Val mutant (KIT(Val814)) are not fully understood. To examine the oncogenic signal transduction of KIT(Val814), we converted 20 tyrosine (Tyr) residues to phenylalanine (Phe) in the cytoplasmic domain of KIT(Val814) or deleted the C-terminal region containing 2 other tyrosine residues (Del). Among various KIT(Val814)- derived mutants, KIT(Val814-Tyr719Phe) and KIT(Val814-Del) severely impaired receptor tyrosine phosphorylation and association with the p85 subunit of phosphatidylinositol 3'-kinase (p85 (PI3-K)). Moreover, KIT(Val814-Tyr719Phe) and KIT(Val814-Del) failed to induce ligand-independent growth in Ba/F3 cells, indicating that Tyr719, the binding site for p85(PI3-K), and the C-terminal region are indispensable for factor-independent growth by KIT(Val814). Although the C-terminal region was also required for ligand-dependent growth by wild-type KIT (KIT(WT)), the Tyr719Phe substitution had negligible effects on ligand-dependent growth by KIT(WT). Furthermore, dominant-negative PI3-K significantly inhibited ligand-independent growth by KIT(Val814). These results demonstrate that Tyr719 is crucial for constitutive activation of KIT(Val814), but not for the ligand-induced activation of KIT(WT), and that the downstream signaling of PI3-K plays an important role in ligand-independent growth and tumorigenicity by KIT(Val814), thereby suggesting that KIT(Val814) is a unique activating mutation that leads to a distinguishable function from the effects of KIT(WT).

Animals↗
PubMed2002

Phosphatidylinositol 3-kinase is a key regulator of early phase differentiation in keratinocytes.

The survival and growth of epithelial cells depend on adhesion to the extracellular matrix. Because epidermal keratinocytes differentiate as they leave the basement membrane, an adhesion signal may regulate the initiation of differentiation. Phosphatidylinositol 3-kinase (PI3K) is a fundamental signaling molecule that regulates the adhesion signal. Transfection of a dominant negative form of PI3K into keratinocytes using an adenovirus vector resulted in significant morphological changes comparable to differentiation and the induction of differentiation markers, keratin (K) 1 and K10. In turn, transfection with the constitutively active form of PI3K almost completely abolished the induction of K1 and K10 by differentiation in suspension cultures using polyhydroxyethylmethacrylate-coated dishes. PI3K activity was lost in suspension culture, except by cells bearing the constitutively active form of PI3K. These data demonstrate that blockade of PI3K results in differentiation and that activation of PI3K prevents differentiation. Furthermore, expression of the dominant negative form of PI3K significantly inhibited keratinocyte adhesion to the extracellular matrix and reduced the surface expression of alpha(6) and beta(1) integrins in suspension culture. Moreover, expression of the active form of PI3K restored the mRNA levels of adhesion molecules that were reduced in suspension culture, including alpha(3), alpha(6), and beta(1) integrins, BP180, and BP230. In conclusion, loss of PI3K activity results in keratinocytes leaving the basement membrane and the initiation of a "default" differentiation mechanism.

Cell Differentiation↗
PubMed2002

Occlusion and subsequent re-canalization in early duodenal development of human embryos: integrated organogenesis and histogenesis through a possible epithelial-mesenchymal interaction.

Histogenesis of the duodenum, especially changes in the epithelium in relation to temporal occlusion and re-canalization of the lumen, was investigated by light microscopy together with morphometric analysis, as well as by scanning and transmission electron microscopy of 133 externally normal human embryos ranging from Carnegie stage 12 to 23. A series of morphogenetic events passed the duodenum in a cranio-caudal (proximo-distal) wave like fashion during the period examined. They included: (1) a decrease in the caliber and area of the lumen, (2) 'occlusion' of the lumen, (3) vacuole formation, (4) 're-canalization' and villi formation. The only exemption to this rule was that, in the upper part of the duodenum, the lumen was not obliterated in the embryos examined. Morphometric analyses revealed that both the area of the epithelium and the number of epithelial cells decreased during the 'occlusion' phase. This result suggests that, unlike the classical view, epithelial cell proliferation does not play an important role in occluding the lumen, but the predominant morphogenetic event during this phase is convergence of the epithelial cells to elongate the duodenum. Apoptosis, contrary to some classical views, decreased during the 're-canalization' phase, and it appeared to be involved in the formation of the small lumens in the epithelial 'plug' and in villi formation, but not in enlarging the secondary lumens. The secondary small lumens in the occluded lumen were frequently formed near the border between the central 'plug' and peripheral basal cells on the basement membrane. This and other findings of concentric differentiation in both the epithelial and mesenchymal layers suggested a possible control mechanism by the epithelium-mesenchymal interaction on human duodenal morphogenesis and histogenesis. The present electron microscopic observations also provided details on the mechanisms involved in the enlargement of the secondary lumen and differentiation of villi. The implications of these findings to duodenal anomalies are also discussed.

Duodenum↗
PubMed2002

BP180 ELISA using bacterial recombinant NC16a protein as a diagnostic and monitoring tool for bullous pemphigoid.

Bullous pemphigoid (BP) is an acquired autoimmune subepidermal blistering disease against hemidesmosomal cytoplasmic BP230 and transmembrane BP180 proteins. Epitope mapping studies have shown that the membrane-proximal noncollagenous (NC) 16a domain of BP180 harbors clusters of antigenic sites recognized by the vast majority of BP sera. In this study, we developed an enzyme-linked immunosorbent assay (ELISA) using bacterial recombinant NC16a protein and evaluated its clinical benefit for diagnosis and monitoring disease activity. Fifty four (84.4%) of 64 sera from BP patients were positive, while only one (1.1%) of 91 sera from collagen disease patients and five (1.5%) of 336 sera from normal control barely exceeded the cut-off value. None of 69 pemphigus vulgaris sera and none of 42 pemphigus foliaceus sera exceeded the cut-off value. Thus, the sensitivity and specificity of NC16a ELISA were 84.4 and 98.9%, respectively. The correlation between ELISA scores and disease activity along the time course was examined using seven BP patients. NC16a ELISA scores tended to fluctuate in parallel with the disease activity along the time course and reflected the disease activity much better than indirect immunofluorescence. These findings indicate that NC16a ELISA will be a valuable tool not only for the diagnosis of patients with BP but also for the monitoring of the disease activity.

Adult↗
PubMed2002

Selective inhibition of NF-kappaB attenuates the severity of cerulein-induced acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is associated with increased cytokine production, which can ultimately produce deleterious local and systemic effects. The transcription factor NF-kappaB is activated by degradation of its inhibitory factor, IkappaB, and can stimulate various cytokines. The purpose of this study was to determine whether the inhibition of NF-kappaB binding activity with a novel peptide that binds to the NF-kappaB essential modifier binding domain (NBD) could attenuate the severity of AP. STUDY DESIGN: AP was induced in Swiss Webster mice by hourly injections of the cholecystokinin analogue cerulein (50 microg/kg). Mice were injected with either the wild-type or control (mutated) NBD peptide at the time of the first cerulein injection; they were then sacrificed over a time course, and pancreata and lungs were harvested for histologic analysis and scoring. Myeloperoxidase activity was measured to assess neutrophil sequestration as an indicator of inflammation. NF-kappaB binding activity and steady-state levels of IkappaB and NF-kappaB subunits were determined by gel shift and Western blot, respectively. RESULTS: AP resulted in increased NF-kappaB DNA-binding activity and decreased steady-state levels of IkappaB. Treatment with NBD peptide decreased inflammation in the pancreas, decreased hemorrhage in the lungs, and decreased myeloperoxidase activity in both pancreas and lung. CONCLUSIONS: The marked induction of NF-kappaB binding activity suggests a role for this transcription factor in the early inflammatory changes associated with AP. Treatment with the NBD peptide attenuated the severity of injury associated with AP. Novel compounds that selectively target NF-kappaB may prove to be useful treatment of AP and AP-associated lung injury.

Acute Disease↗
PubMed2002

Crucial Fas-Fas ligand interaction in spontaneous acceptance of hepatic allografts in mice.

The Fas/Fas ligand (FasL) system plays important roles in the immune system, including host immunoregulation and cytotoxicity. In this study, we investigated the involvement of Fas-FasL interactions in spontaneous acceptance of hepatic allografts in murine orthotopic liver transplantation. Liver transplantation between the C57BL/6 (B6, H-2b) donor and the MRL/Mp (MRL, H-2k) recipient was performed in various combinations of donor and recipient mice with wild type (+/+), Fas-mutant (lpr) or FasL-mutant (gld) genotypes. The prolongation and spontaneous acceptance of the fully allogeneic grafts in recipients was not observed in either MRL-lpr recipients with B6+/+ livers or MRL+/+ recipients with B6-gld livers. Moreover, the serum alanine aminotransferase (ALT) levels and the degree of cell infiltration into hepatic allografts on day 7 after transplantation were inversely correlated with the recipient survival time (in days). The donor-specific cytotoxic T-lymphocyte (CTL) activities of the graft-infiltrating cells (GICs) from MRL-gld recipients with B6+/+ livers were much lower than those from MRL+/+ or -lpr recipients on days 5 and 10 after transplantation. However, the CTL activities of the GICs from MRL+/+ and -gld recipients predominantly disappeared by day 15 after transplantation. Furthermore, the anti-donor CTL activities induced in MRL+/+ recipients were ascribed to CD8+ cells, and were not mediated by Fas-FasL interactions. These results strongly suggest that the Fas/FasL system plays a critical role for recipient immunoregulation, enabling recipients in accepting hepatic allografts by deletion of the donor-specific T cells, but not for CTL/target cell interaction in MRL+/+ recipients.

Alanine Transaminase↗
PubMed2002

Interferon-gamma, a strong suppressor of cell proliferation, induces upregulation of keratin K6, one of the inflammatory- and proliferation-associated keratins.

Keratin K6 is known as an inflammatory and hyperproliferative keratin, and is induced by an inflammatory and hyperproliferative agent. In this study, we demonstrated that interferon-gamma, an antiproliferative agent, also induces keratin K6. We used normal human ex vivo skin, normal human cultured keratinocytes, HaCaT keratinocytes, and DJM cells to examine the induction of K6 by interferon-gamma, by immunohistochemical staining, Western blot analysis, promoter chloramphenicol acetyl transferase assay, and reverse transcriptase polymerase chain reaction of mRNA. We succeeded in demonstrating the induction of keratin K6 by interferon-gamma in ex vivo human skin and HaCaT keratinocytes at the protein and message level, and in cultured normal human keratinocytes at the promoter level. The inhibition of the signal transducing activator of transcription 1 pathway by a dominant-negative transfer gene caused the inhibition of K6 induction by interferon-gamma, and the blocking of nuclear factor kappaB using antisense oligonucleotides also inhibited the K6 induction. We also blocked the released interleukin-1alpha from keratinocytes after stimulation with interferon-gamma by neutralizing antibodies, which showed a decrease in the K6 induction. Our results suggest that a small amount of interleukin-1alpha, which cannot induce K6 by itself, is secreted upon stimulation by interferon-gamma, and that the induction of K6 occurs through the synergistic effect of the interferon-gamma/signal transducing activator of transcription 1 and interleukin-1alpha/nuclear factor kappaB pathways. This is the first report to describe K6 induction in epidermal keratinocytes by interferon-gamma and indicate a probable signal transduction pathway, and demonstrates that K6 is a possible partner of K17 in the inflammatory process.

Blotting, Western↗
PubMed2002

Differential effects of desmoglein 1 and desmoglein 3 on desmosome formation.

The desmoglein plays an important part in the formation of desmosomes. We constructed recombinant adenoviruses containing desmoglein 1 and desmoglein 3 derivatives partly lacking the extracellular domain (desmoglein 1DeltaEC and desmoglein 3DeltaEC, respectively), and full-length desmoglein 1 and desmoglein 3 and studied the involvement of desmoglein 1 and desmoglein 3 in desmosome formation. During low-level expression of desmoglein 3DeltaEC in transduced HaCaT cells, keratin insertion at cell-cell contact sites was only partially inhibited and desmoplakin was partially stained at cell-cell contact sites. Low-level expression of desmoglein 1DeltaEC, however, resulted in complete inhibition of keratin insertion at the cell-cell contact sites, and desmoplakin was stained in perinuclear dots. These results indicate the dominant-negative effect of desmoglein 1DeltaEC on desmosome formation was stronger than that of desmoglein 3DeltaEC. Desmoglein 1DeltaEC coprecipitated plakoglobin to approximately the same extent as desmoglein 3DeltaEC. Therefore, we conclude that the dominant-negative effect of desmoglein 1DeltaEC is not simply due to plakoglobin sequestration. On the other hand, during low-level expression of full-length desmoglein 3 and desmoglein 1, they both colocalized with desmoplakin. During high-level expression, however, keratin insertion at cell-cell contact sites was inhibited in desmoglein 1 but not in desmoglein 3, and desmoplakin was stained at cell-cell contact sites in desmoglein 3 but not in desmoglein 1. These data suggest desmoglein 1 and desmoglein 3 expressed at low level were incorporated into desmosome but at high-level expression, desmoglein 1 disrupted desmosomes but desmoglein 3 did not. Our findings provide biologic evidence that desmoglein 1 and desmoglein 3 play a different functional role in cell-cell adhesion of keratinocytes.

Cadherins↗
PubMed2002

Living-donor liver transplantation for fulminant hepatic failure in adult patients with a left-lobe graft.

BACKGROUND: Living donors are practically the only source of organs in countries where the availability of cadaveric donors is severely restricted, such as Japan. A left-lobe graft, in which one third of the liver is donated, is therefore used for adult-to-adult living-donor liver transplantation (LDLT) in patients with fulminant hepatic failure (FHF). METHODS: Fifteen adult patients with FHF, ranging from 22 to 59 years of age, were treated with LDLT with a left-lobe graft. Preoperative encephalopathy was grade II in 2 patients, grade III in 4 patients, and grade IV in 9 patients. The graft volume (GV) ranged from 260 to 570 mL, thus corresponding to 23% to 54% of the recipients' standard liver volume (SLV). The patients were divided into 2 groups according to their GV/SLV: a medium-size graft group (GV/SLV > or =30%; group M, n = 11) and a small-size graft group (GV/SLV <30%; group S, n = 4). The effects of GV/SLV on graft function and survival were compared. Postoperative neurologic complications were also evaluated. RESULTS: The donors are all doing well. Twelve (80%) of the 15 recipients are still alive, with a follow-up period of from 3 to 43 months. No statistically significant differences were observed in the postoperative serum levels of bilirubin and alanine aminotransferase, prothrombin time, or frequency of postoperative complications between the 2 groups. The graft and patient survival rates were 75% (3/4) and 75% (3/4) in group S and 73% (8/11) and 82% (9/11) in group M, respectively. All patients who survived the perioperative period recovered without any neurologic sequelae. CONCLUSIONS: The high success rate and low donor risk of LDLT may therefore justify its use for adult patients with FHF using a left-lobe graft.

Adult↗