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Biomedical subjects

Fumitake Gejyo

Publications and source records attributed to Fumitake Gejyo.

At least 19 recordsLinked to original sources
PubMed2006

A case of mixed connective tissue disease complicated with thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare complication of mixed connective tissue disease (MCTD). In this report, we describe the case of a 73-year-old Japanese woman with MCTD who developed fever, thrombocytopenia, and microangiopathic hemolytic anemia and was diagnosed with MCTD together with TTP. The activity of von Willebrand factor (vWF) cleaving metalloprotease ADAMTS13 was low and considered to have contributed to the disease activity of TTP. The patient died despite intensive treatment of plasma exchange (PEX) and steroid pulse therapy. Autopsy results revealed that the kidneys had platelet and fibrin thrombi, which occluded capillaries and arterioles. These findings were compatible with TTP and the decreased activity of ADAMTS13 was considered to be associated with the disease activity of TTP.

ADAM Proteins↗
PubMed2006

Abeta-2M-amyloidosis and related bone diseases.

Abeta-2M-amyloidosis is a type of systemic amyloidosis that is specifically seen in patients with chronic kidney diseases. The precursor protein of Abeta-2M-amyloid fibril is beta2-microglobulin, and its elevated serum level is the main cause of Abeta-2M-amyloidosis in patients with kidney failure. However, the precise mechanism of Abeta-2M-amyloidogenesis remains unclear. In vitro analyses of Abeta-2M amyloidogenesis are still being actively conducted. Osteolytic lesions are often found around synovial membrane with Abeta-2M-amyloid deposition. Both evident osteoclastogenesis and active osteoclastic bone resorption are found, while osteoblastic bone formation is absent in the lesion most likely associated with the inflammation caused by infiltrating macrophages/monocytes into Abeta-2M-amyloid deposition. The precise cell biological mechanism of this inflammatory change is unknown. Further studies are needed to establish specific treatments against this as yet unsolved problem with long-term dialysis therapy.

Amyloid↗
PubMed2005

Long-term mortality outcome in patients with reactive amyloidosis associated with rheumatoid arthritis.

It is well established that amyloidosis is a serious clinical complication that can influence the prognosis of patients with rheumatoid arthritis (RA). The purpose of the study was to obtain information on the survival and the hemodialysis (HD) of patients with amyloidosis. Eighty patients (9 men and 71 women) who were diagnosed with amyloidosis by biopsy and definite or classical RA were studied retrospectively. The average duration of RA prior to the diagnosis of amyloidosis was 15.4+/-9.4 years. The average period from the diagnosis of amyloidosis to death was 67.4 months. Forty-nine patients died of the disease (32 cases with HD and 17 cases without HD). Thirty-one patients lived (7 cases with HD and 24 cases without HD). Regarding the survival of these patients, 49 (61.3%) of the 80 patients have died. Survival rate at 28 months was 75%; at 67 months, it was 50%; and at 111 months, it was down to 25%. Mortality rate was 11.9% per year. Survival rate in dialysis at 9.8 months was 75%; at 60.6 months, it dropped to 50%; and at 100.0 months, to 25%. As for patients' survival, high onset age of amyloidosis was the major determining factor for poor survival in these patients (p<0.001). Furthermore, male patients also had poor survival (p=0.07). The long-term results were very encouraging to initiate HD in patients with end-stage renal disease due to reactive amyloidosis associated with RA.

Age of Onset↗
PubMed2005

Both regulatory T cells and antitumor effector T cells are primed in the same draining lymph nodes during tumor progression.

The peripheral tolerance mechanism prevents effective antitumor immunity, even though tumor cells possess recognizable tumor-associated Ags. Recently, it has been elucidated that regulatory T cells (Treg) play a critical role in maintaining not only self-tolerance, but also tolerance of tumor cells. However, because the Treg that maintain self-tolerance arise naturally in the thymus and are thought to be anergic in peripheral, it is still unclear where and when Treg for tumor cells are generated. In this study we analyze tumor-draining lymph nodes (LNs) and demonstrate that both antitumor effector T cells and Treg capable of abrogating the antitumor reactivity of the effector T cells are primed in the same LNs during tumor progression. The regulatory activity generated in tumor-draining LNs exclusively belonged to the CD4(+) T cell subpopulation that expresses both CD25 and a high level of CD62L. Forkhead/winged helix transcription factor gene expression was detected only in the CD62L(high)CD4(+)CD25(+) T cells. CD62L(high)CD4(+)CD25(+) Treg and CD62L(low)CD4(+)CD25(+) T cells, which possess effector T cell functions, had comparable expression of LFA-1, VLA-4, CTLA-4, lymphocyte activation gene-3, and glucocorticoid-induced TNFR. Thus, only CD62L expression could distinguish regulatory CD4(+)CD25(+) cells from effector CD4(+)CD25(+) cells in draining LNs as a surface marker. The Treg generated in tumor-draining LNs possess the same functional properties as the Treg that arise naturally in the thymus but recognize tumor-associated Ag. CD62L(high)CD4(+)CD25(+) Treg contained a subpopulation that expressed CD86. Blocking experiments revealed that ligation of CTLA-4 on effector T cells by CD86 on Treg plays a pivotal role in regulating CD4(+) effector T cells.

Animals↗
PubMed2005

Historical background and clinical treatment of dialysis-related amyloidosis.

Dialysis-related amyloidosis (DRA) is a frequent and serious complication in patients on long-term dialysis. The amyloid has a marked affinity for joint tissues, and carpal tunnel syndrome, polyarthralgia, destructive spondyloarthropathy, and bone cysts are the major clinical manifestations of DRA. beta(2)-Microglobulin (beta(2)-m) was identified as the major protein constituent of the amyloid fibrils. Risk factors for the development of DRA include age, duration of dialysis treatment, use of low-flux dialysis membrane, use of low purity dialysate, monocyte chemoattractant protein-1 GG genotype, and apolipoprotein E4 allele, although the retention of beta(2)-m in the plasma appears to be prerequisite. Clinical therapeutic strategies for DRA include dialysis, medical or surgical therapy, and renal transplantation. Preventive measures have attempted to remove beta(2)-m from the serum by using high-flux membranes and a beta(2)-m adsorption column in hemodialysis. Renal transplantation is a radical approach to treating the arthralgias attributed to the amyloid deposits while the regression of dialysi-related amyloid deposits is not identified after successful renal transplantation in many studies. It is necessary to elucidate the pathogenesis of DRA and to establish more effective prevention and therapy in the future.

Aged↗
PubMed2005

Kinetic analysis of the polymerization and depolymerization of beta(2)-microglobulin-related amyloid fibrils in vitro.

beta(2)-Microglobulin-related (Abeta(2)M) amyloidosis is a serious complication in patients on long-term dialysis, and partial unfolding of beta(2)-microglobulin (beta(2)-m) is believed to be prerequisite to its assembly into Abeta(2)M amyloid fibrils. Many kinds of amyloid-associated molecules (e.g., apolipoprotein E (apoE), glycosaminoglycans (GAGs), proteoglycans (PGs)) may contribute to the development of Abeta(2)M amyloidosis. The formation of Abeta(2)M amyloid fibrils in vitro was first observed at low pH (2.0-3.0). Very recently, low concentrations of 2,2,2-trifluoroethanol (TFE) and the sub-micellar concentration of sodium dodecyl sulfate, a model for anionic phospholipids, have been reported to cause the extension of Abeta(2)M amyloid fibrils at a neutral pH, inducing partial unfolding of beta(2)-m and stabilization of the fibrils. Moreover, apoE, GAGs and PGs were found to stabilize Abeta(2)M amyloid fibrils at a neutral pH, forming a stable complex with the fibrils. Some GAGs, especially heparin enhanced the fibril extension in the presence of TFE at a neutral pH. Some PGs, especially biglycan also induced the polymerization of acid-denatured beta(2)-m. These findings are consistent with the hypothesis that in vivo, specific molecules that affect the conformation and stability of beta(2)-m and amyloid fibrils will have significant effects on the deposition of Abeta(2)M amyloid fibrils.

Amyloid↗
PubMed2005

PDZ domain-binding motif of human T-cell leukemia virus type 1 Tax oncoprotein is essential for the interleukin 2 independent growth induction of a T-cell line.

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL), whereas HTLV type 2 (HTLV-2), is not associated with ATL or any other leukemia. HTLV-1 encodes the transforming gene tax1, whose expression in an interleukin (IL)-2-dependent T-cell line (CTLL-2) induces IL-2-independent growth. RESULTS: In this study, we demonstrated that IL-2-independent growth induction by Tax1 was abrogated by mutations of the PDZ domain-binding motif (PBM) at the Tax1 C-terminus. HTLV-2 Tax2, which shares 75% amino acid identity with Tax1 but does not have a PBM, was not able to induce IL-2-independent growth of CTLL-2. CONCLUSION: Our results suggest that Tax1, through interaction with PDZ domain protein(s) induces IL-2-independent growth, which may be a factor in multi-step leukemogenesis caused by HTLV-1.

Binding Sites↗
PubMed2005

Examination of the molecular diversity of alpha1 antitrypsin in urine: deficit of an alpha1 globulin fraction on cellulose acetate membrane electrophoresis.

In the clinical field of nephrology, a noninvasive approach employing the analysis of electrophoretic patterns in urinary protein has been established. In this study a total of 52 urine samples with IgA nephropathy (IgAN), anti-neutrophil cytoplasmic antigen-associated crescentic glomerulonephritis (GN), and other types of GN were analyzed. Patients with high alpha1 globulin (alpha1G) fractions, which contained alpha1AT in cellulose acetate membrane electrophoresis (CAE), tended to have alpha1 antitrypsin (alpha1AT) of normal molecular weight (57 kDa and 49 kDa), while patients with a deficit alpha1G fraction tended to have alpha1AT of low molecular weight (<49 kDa) (P < 0.01). The alpha1G fraction was significantly higher in patients with IgAN, and there were significantly more patients with normal molecular weight alpha1AT compared to patients with other diseases (P < 0.01). The isoelectric point of alpha1AT with lower-weight molecules was more on the alkali side compared to higher-weight molecules in two-dimensional electrophoresis. Detecting changes in alpha1G fractions in CAE may support the differential diagnosis of IgAN from other types of GN.

Alpha-Globulins↗
PubMed2005

Inhibitory effect of antimicrobial agents and anisodamine on the staphylococcal superantigenic toxin-induced overproduction of proinflammatory cytokines by human peripheral blood mononuclear cells.

Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), produces superantigenictoxins, such as toxic shock syndrome toxin-1 (TSST-1). TSST-1 abnormally activates T cells to overproduce inflammatory cytokines (such as tumor necrosis factor-alpha, interleukin-2, and interferon-gamma) leading to shock. In this study, we investigated the inhibitory effect of antimicrobial agents and anisodamine (a Chinese herbal extract) on TSST-1-induced cytokine production. Among the macrolides and related agents examined, azithromycin and rokitamycin showed the greatest inhibitory activity against the TSST-1-induced cytokine production. This inhibitory effect was similar to that of anisodamine, which, however, had no inhibitory activity against bacterial growth. Vancomycin, teicoplanin, arbekacin, and linezolid (anti-MRSA and related agents) had no significant inhibitory effect on cytokine production. The inhibitory effect of the drugs on cell proliferation was not significant. These data indicate that some antimicrobial agents, e.g., azithromycin and rokitamycin, manifest anti-superantigenic toxin activity through the inhibition of cytokine production, just like anisodamine.

Adult↗
PubMed2005

Pretreatment plasma intact parathyroid hormone and serum calcium levels, but not serum phosphate levels, predict the response to maxacalcitol therapy in dialysis patients with secondary hyperparathyroidism.

BACKGROUND: The treatment strategy for secondary hyperparathyroidism is generally determined empirically with regards to present parathyroid function and serum calcium (Ca) and inorganic phosphate (Pi) levels. More evidence is needed to avoid the aimless continuation of active vitamin D therapy. METHODS: Nondiabetic dialysis patients whose plasma intact parathyroid hormone (iPTH) levels were greater than 300 pg/ml were included in the study. Maxacalcitol was intravenously injected three times a week. The treatment was continued for 48 weeks, unless the iPTH level was reduced to less than 300 pg/ml or unfavorable events occurred. The patients whose plasma iPTH levels were below 300 pg/ml within 48 weeks were defined as those who had been successfully treated. RESULTS: Findings for 146 patients were analyzed, and 96 patients were successfully treated. Serum Pi levels did not significantly increase during the therapy. The pretreatment plasma iPTH levels and serum Ca levels were lower in the patients who were successfully treated with maxacalcitol. A logistic regression study and classifying by stratum analyses revealed that the pretreatment serum Ca levels and plasma iPTH levels were significantly related to the result of maxacalcitol therapy, while the serum Pi levels were not. Analyses using a receiver-operating characteristic curve revealed that the areas under curves obtained for iPTH and Ca were significantly greater than those obtained for Pi (P < 0.0001). CONCLUSIONS: Serum Ca levels and parathyroid function were correlated with the results of maxacalcitol therapy. Pretreatment serum Pi levels could not predict the result.

Adult↗
PubMed2005

Monocyte chemoattractant protein-1 A-2518G gene polymorphism and renal survival of Japanese patients with immunoglobulin A nephropathy.

BACKGROUND: Monocyte chemoattractant protein (MCP)-1 is closely related to the pathogenesis of the progression of various chronic renal diseases, including IgA nephropathy (IgAN), through its chemoattractant effect on macrophages. However, the correlation of MCP-1 gene polymorphism with the long-term prognosis of Japanese patients with IgAN has not been clearly determined yet. METHODS: We investigated 277 Japanese patients diagnosed with IgAN based on renal biopsy to clarify the association between the progression of IgAN and MCP-1 gene polymorphism at position A-2518G, which regulates the transcription of the MCP-1 gene. RESULTS: The incidence of endstage renal disease was significantly higher in patients with the AA genotype (47.1%) compared to those with the AG (24.1%) or GG (27.4%) genotype (P = 0.024). Moreover, Kaplan-Meier analysis revealed that the AA genotype significantly facilitated the progression of renal disease (log rank; P = 0.0029), and Cox proportional hazards regression model analysis showed that the AA genotype represented a 2.058-fold risk for the progression of renal disease (P = 0.026) compared to the AG/GG genotype. However, when the patients were treated with angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker, or corticosteroid, homozygosity for the -2518A allele was not associated with a higher rate of incidence of endstage renal disease. Serum MCP-1 levels were higher although not significantly so, in the patients with IgAN possessing the AA genotype. CONCLUSIONS: The AA genotype at MCP-1 -2518 was an independent risk factor for the progression of renal disease in Japanese patients with IgAN, and was closely associated with renal survival.

Adult↗
PubMed2005

Evidence for megalin-mediated proximal tubular uptake of L-FABP, a carrier of potentially nephrotoxic molecules.

Liver-type fatty acid binding protein (L-FABP) binds with high affinity to hydrophobic molecules including free fatty acid, bile acid and bilirubin, which are potentially nephrotoxic, and is involved in their metabolism mainly in hepatocytes. L-FABP is released into the circulation, and patients with liver damage have an elevated plasma L-FABP level. L-FABP is also present in renal tubules; however, the precise localization of L-FABP and its potential role in the renal tubules are not known. In this study, we examined the cellular and subcellular localization of L-FABP in the rat kidney and tried to determine from where the L-FABP in kidney tissues had originated. Immunohistochemical studies of kidney sections localized L-FABP in the lysosomes of proximal tubule cells (PTC). In rats with carbon tetrachloride (CCl4)-induced acute liver injury, we detected high levels of L-FABP in the circulation and in the kidney compared with those in the control rat by immunoblotting, while reverse transcription-polymerase chain reaction showed that the level of L-FABP mRNA expression in the kidney of CCl4-treated rats was low and did not differ from that in the control rat. When 35S-L-FABP was intravenously administered to rats, the kidneys took up 35S-L-FABP more preferentially than the liver and heart, and histoautoradiography of kidney sections revealed that 35S-L-FABP was internalized via the apical domains of PTC. Quartz-crystal microbalance analysis revealed that L-FABP bound to megalin, a multiligand endocytotic receptor on PTC, in a Ca2+-dependent manner. Degradation assays using megalin-expressing rat yolk sac tumor-derived L2 cells demonstrated that megalin mediated the cellular uptake and catabolism of 125I-L-FABP. In conclusion, circulatory L-FABP was found to be filtered by glomeruli and internalized by PTC probably via megalin-mediated endocytosis. These results suggest a novel renal uptake pathway for L-FABP, a carrier of hydrophobic molecules, some of which may exert nephrotoxic effects.

Animals↗
PubMed2005

Molecular interactions in the formation and deposition of beta2-microglobulin-related amyloid fibrils.

In beta2-microglobulin-related (A beta2M) amyloidosis, a serious complication in patients on long-term dialysis, partial unfolding of beta2-microglobulin (beta2-m) is believed to be prerequisite to its assembly into A beta2M amyloid fibrils. Many kinds of amyloid-associated molecules, (e.g., apolipoprotein E (apoE), glycosaminoglycans (GAGs), proteoglycans (PGs)) may contribute to the development of A beta2M amyloidosis. In 1990s, the formation of A beta2M amyloid fibrils in vitro was first observed at low pH (2.0-3.0). Very recently, low concentrations of 2,2,2-trifluoroethanol (TFE) and the sub-micellar concentration of sodium dodecyl sulfate, a model for anionic phospholipids, have been reported to cause the extension of A beta2M amyloid fibrils at a neutral pH, inducing partial unfolding of beta2-m and stabilization of the fibrils. Moreover, apoE, GAGs, and PGs were found to stabilize A beta2M amyloid fibrils at a neutral pH, forming a stable complex with the fibrils. Some GAGs, especially heparin, enhanced the fibril extension in the presence of TFE at a neutral pH. Some PGs, especially biglycan also induced the polymerization of acid-denatured beta2-m. These findings are consistent with the hypothesis that in vivo, specific molecules that affect the conformation and stability of beta2-m and amyloid fibrils will have significant effects on the deposition of A beta2M amyloid fibrils.

Amyloid↗
PubMed2005

Antibody response to influenza vaccination in nursing home residents and healthcare workers during four successive seasons in Niigata, Japan.

OBJECTIVE: To evaluate the antibody response to influenza vaccines in nursing home residents and healthcare workers (HCWs) and its relation to residents' functional and chronic disease status during four successive seasons. DESIGN: Before-after study. SETTING: Nine nursing homes during the 1998-1999 season and two during the 1999-2000, 2000-2001, and 2001-2002 seasons. PARTICIPANTS: Two hundred fifty-nine residents and 79 HCWs during the 1998-1999 season; 180 and 71, respectively, during the 1999-2000 season; 162 and 71, respectively, during the 2000-2001 season; and 153 and 79, respectively, during the 2001-2002 season. RESULTS: Multivariate analysis indicated that the mean fold increase in the geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibodies and the response rate (the proportion of vaccinees resulting in a significant, at least fourfold increase in antibody titer) were good and no significant differences occurred for almost all strains in both residents and HCWs. The GMTs of HI antibodies and the protection rate (the proportion of participants with HI antibody titers > or = 40) were increased in both residents and HCWs, but were significantly lower for almost all strains in residents than in HCWs. Furthermore, multivariate analysis indicated that subdivision of residents into three groups by level of daily activities and into four groups according to underlying diseases revealed only minor differences in immune responses. CONCLUSIONS: Antibody responses to the influenza vaccine were lower in residents than in HCWs. However, residents showed similar antibody responses regardless of their level of daily activity or underlying diseases.

Aged↗
PubMed2005

Sustained transgene expression in rat kidney with naked plasmid DNA and PCR-amplified DNA fragments.

Recently, we developed a kidney-targeted gene transfer technique, in which naked DNA was injected into the renal vein while the renal vein and artery were clamped. Kidney-targeted DNA transfer with only the renal vein clamped is an important modification that may permit less invasive catheter-based gene transfer in future clinical applications. The preparation of PCR-amplified DNA fragments is less time-consuming than that of naked plasmid DNA. We examined rat erythropoietin (Epo) plasmid, pCAGGS-Epo, or PCR-amplified DNA fragment, fCAGGS-Epo, transfer into the rat kidney with only the renal vein clamped. The Epo level peaked at week 3 and then was sustained for 24 weeks, which resulted in significant erythropoiesis. This modified technique, allowing long-term expression of both PCR-amplified DNA fragments and naked plasmid DNA, could potentially be used for catheter-based gene transfer in humans, and could help determine the physiological functions of putative genes.

Animals↗