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Biomedical subjects

F Gejyo

Publications and source records attributed to F Gejyo.

At least 19 recordsLinked to original sources
PubMed2001

Protection against autoimmune myocarditis by gene transfer of interleukin-10 by electroporation.

BACKGROUND: Although immunosuppressive therapy for myocarditis has attracted a great deal of attention, its effectiveness is controversial. Interleukin (IL)-10 has a variety of immunomodulatory properties. Among the nonviral techniques for gene transfer in vivo, the direct injection of plasmid DNA into muscle is simple, inexpensive, and safe. METHODS AND RESULTS: We examined the applicability of murine IL-10 (mIL-10) gene transfer to the treatment of rats with experimental autoimmune myocarditis. Nine-week-old Lewis rats were inoculated with pig myosin (day 0). A plasmid vector expressing mIL-10 cDNA (800 microgram per rat) was transferred into the tibialis anterior muscles by electroporation 3 times (5 days before immunization and at days 4 and 13); control rats received empty plasmid. Electroporation increased the serum mIL-10 levels to >250 pg/mL. The 21-day survival rate in rats treated with mIL-10 cDNA was higher (15 of 15; 100%) than that of the control group (9 of 15; 60%). Furthermore, mIL-10 treatment significantly attenuated myocardial lesions and improved hemodynamic parameters. CONCLUSIONS: These findings showed that gene transfer into muscle by electroporation in vivo is an effective means of delivery of IL-10 for the treatment of autoimmune myocarditis.

Animals↗
PubMed2001

Apolipoprotein E inhibits the depolymerization of beta 2-microglobulin-related amyloid fibrils at a neutral pH.

beta 2-Microglobulin-related (A beta 2M) amyloidosis is a common and serious complication in patients on long-term hemodialysis, and beta 2-microglobulin (beta 2-m) is a major structural component of A beta 2M amyloid fibrils. Fluorescence spectroscopic analysis with thioflavin T and electron microscopic study revealed that A beta 2M amyloid fibrils readily depolymerize into monomeric beta 2-m at a neutral to basic pH. Circular dichroism analysis revealed that soon after the initiation of the depolymerization reaction at pH 7.5, the characteristic spectrum of beta 2-m in A beta 2M amyloid fibrils changes to resemble that of monomeric beta 2-m at pH 7.5. Apolipoprotein E (apoE), a representative amyloid-associated protein, formed a stable complex with A beta 2M amyloid fibrils and inhibited the depolymerization of A beta 2M amyloid fibrils dose-dependently in a range of 0--10 microM. These results showed that apoE could enhance the deposition of amyloid fibrils in vivo, possibly by binding directly to the surface of the fibrils and stabilizing the conformation of beta 2-m in the fibrils.

Amyloid beta-Peptides↗
PubMed2001

Development of fulminant hepatitis B (precore variant mutant type) after the discontinuation of low-dose methotrexate therapy in a rheumatoid arthritis patient.

A 75-year-old female rheumatoid arthritis patient who was positive for hepatitis B surface antigen and for antibodies to hepatitis Be antigen showed liver dysfunction, and therefore methotrexate (MTX) therapy was discontinued. Her drug lymphocyte stimulation test indicated positivity for MTX. Her liver dysfunction improved briefly, but she developed fulminant hepatitis with elevated levels of hepatitis B virus (HBV)/DNA polymerase and subsequently died. HBV/DNA analysis performed with polymerase chain reaction-mutation site-specific assay revealed that the fulminant hepatitis was caused by a precore mutant virus. Sudden reactivation of the immune system by discontinuation of MTX may have led to the attack on infected cells. Even when hepatitis Be antibodies are present, MTX should not be used in patients who have chronic infection with HBV.

Arthritis, Rheumatoid↗
PubMed2001

Pneumatosis cystoides intestinalis in a patient with polymyositis.

A 29-year-old Japanese woman with polymyositis (PM) developed pneumatosis cystoides intestinalis (PCI). The patient experienced a gradual onset of mild epigastric abdominal pain and abdominal distension. Radiographs revealed pneumatosis intestinalis involving the small bowel, and colonoscopy revealed submucosal cysts. Treatment with antibiotics and high-flow oxygen resulted in remission. This is an extremely rare case of PCI in a patient with PM.

Adult↗
PubMed2001

Inhibitory role of eosinophils on cell surface plasmin generation by bronchial epithelial cells: inhibitory effects of transforming growth factor beta.

Eosinophilic bronchitis is an essential component of bronchial asthma, and eosinophils play an important role. We studied the effect of eosinophils on cell surface plasmin generation by bronchial epithelial cells, because plasmin is thought to be involved in bronchial tissue repair/remodeling by means of fibrinolysis and the activation of proteases such as matrix metalloproteases. Plasmin was generated from exogenous plasminogen on the cell surface of cultured bronchial epithelial cells, NCI-H292. Transforming growth factor beta (TGF-beta) treatment resulted in reduced cell surface plasmin generation and a large increase in plasminogen activator inhibitor-type 1 (PAI-1) antigen production in NCI-H292 cells, whereas no conspicuous effects were observed with IL-1 beta and TNF alpha treatment (regulators in pulmonary epithelial cells). On the other hand, this cell surface plasmin generation was reduced by co-incubation with Eol-1, an eosinophil cell line. The addition of TGF-beta antisense and anti-TGF-beta antibodies attenuated this adverse effect of Eol-1 cell co-incubation. These data suggest that eosinophils play an inhibitory role on cell surface plasmin generation by bronchial epithelial cells by means of the up-regulation of PAI-1 expression induced by TGF-beta. Therefore, the accumulation of eosinophils in bronchial walls is thought to be involved in bronchial tissue repair/remodeling in asthma through this protease network.

Asthma↗
PubMed2001

Role of macrophage scavenger receptors in response to Listeria monocytogenes infection in mice.

Type I and type II macrophage scavenger receptors (SR-A I/II) recognize a variety of polyanions including bacterial cell-wall products such as lipopolysaccharide, suggesting a role for SR-A I/II in immunity against bacterial infection. SR-A I/II-deficient (MSR-A-/-) mice were more susceptible to infection with listeriolysin-O (LLO)-producing Listeria monocytogenes. After infection, Kupffer cells in wild-type (MSR-A+/+) mice phagocytized larger numbers of Listeria than those in MSR-A-/- mice. The number and the diameter of hepatic granulomas were larger in MSR-A-/- mice than MSR-A+/+ mice. L. monocytogenes replicated at higher levels in the liver of MSR-A-/- mice compared with MSR-A+/+ mice, and macrophages from MSR-A-/- mice showed impaired ability to kill Listeria in vitro. However, macrophages from MSR-A+/+ and MSR-A-/- mice showed similar levels of listericidal activity against isogenic mutant L. monocytogenes with an inactivated LLO gene. The listerial phagocytic activities of MSR-A+/+ macrophages treated with an anti-SR-A I/II antibody (2F8) and MSR-A-/- macrophages were significantly impaired compared with untreated MSR-A+/+ macrophages, indicating that SR-A I/II function as a receptor for L. monocytogenes. Electron microscopy revealed that most L. monocytogenes had been eliminated from the lysosomes of MSR-A+/+ macrophages in vivo and in vitro. In contrast, L. monocytogenes rapidly lysed the phagosomal membrane and escaped to the cytosol in MSR-A-/- macrophages and in MSR-A+/+ macrophages treated with 2F8 before phagosome-lysosome fusion. These findings imply that SR-A I/II plays a crucial role in host defense against listerial infection not only by functioning as a receptor but also by mediating listericidal mechanisms through the regulation of LLO-dependent listerial escape from the macrophages.

Animals↗
PubMed2001

Long-term production of erythropoietin after electroporation-mediated transfer of plasmid DNA into the muscles of normal and uremic rats.

The anemia associated with chronic renal failure is one of the best target diseases for erythropoietin (Epo) gene transfer. We previously reported a short-term (1 month) study of continuous rat Epo delivery by muscle-targeted gene transfer of plasmid DNA expressing rat Epo (pCAGGS-Epo) using in vivo electroporation in normal rats. Here, we performed a long-term pharmacokinetic study of continuous Epo delivery by this method in normal rats and uremic five-sixths nephrectomized rats. In normal rats, Epo gene expression and sufficient erythropoiesis occurred with Epo gene transfer in a dose-dependent manner, and persisted for at least 11 weeks. Repeated administration of the plasmid DNA effectively produced erythropoiesis. Similar erythropoiesis was observed in the uremic rats, and persisted for more than 15 weeks. Both normal and uremic rats showed a significant decrease in platelet count. Moreover, the uremic rats showed Epo-induced hypertension, which is the major side-effect of recombinant human Epo. These results demonstrate that muscle-targeted pCAGGS-Epo transfer by in vivo electroporation is a useful procedure for the long-term continuous delivery of Epo in both normal and uremic rats.

Animals↗
PubMed2001

Real-time observation of hemodynamic changes in glomerular aneurysms induced by anti-Thy-1 antibody.

BACKGROUND: Blood flow in the microvasculature plays a pivotal role in determining the outcome of injury and repair in inflamed tissue. Real-time observation of the kidney microvasculature, including the glomerular capillary tufts, is extremely difficult because of the methodological limitations of currently available microscope optics. In the present study, we attempted to analyze hemodynamic events that occurred in vivo during microvascular regeneration following destruction of the glomerular capillary tuft, functionally and quantitatively by the use of a real-time confocal laser-scanning microscope (CLSM) system. METHODS: A polyethylene catheter was inserted into the carotid artery to allow blood pressure measurement. Mesangiolytic lesions producing microaneurysms were induced by the injection of anti-Thy-1.1 antibody. On days 3 and 7 after antibody injection, we examined hemodynamic changes under an intravital microscope equipped with real-time CLSM in combination with a high-speed CCD video camera. To measure vessel diameter and erythrocyte velocity, rats were injected with fluorescein isothiocyanate (FITC)-labeled dextran and FITC-labeled red blood cells (RBCs). RESULTS: On day 3 of the disease, mean arterial blood pressure was 112 +/- 5 mm Hg, which was significantly higher than that of normal rat or of rats on day 7 (93 +/- 1 and 101 +/- 9 mm Hg, respectively). Within mircroaneurysms on day 3, RBC velocity was greatly suppressed. By day 7, RBC velocity, in glomeruli with normal appearances, recovered to about half of the level seen in normal controls (430.6 +/- 284.7 microm/sec), while in narrowed glomerular tufts, it was still only 104.6 +/- 35.1 microm/sec. CONCLUSIONS: The noninvasive procedure, using CLSM in combination with a high-speed video camera, allowed us to examine hemodynamic events quantitatively and to analyze microvascular architecture three dimensionally in the kidney. It is useful for estimating hemodynamic response and vascular regeneration in vivo and may be promising for clinical application.

Aneurysm↗
PubMed2001

Expression of osteopontin in gentamicin-induced acute tubular necrosis and its recovery process.

BACKGROUND: There is controversy regarding the exact localization and roles of osteopontin (OPN), a multipotential chemokine, in renal injury. There is little information on the expression and role of OPN in gentamicin-induced acute tubular necrosis (ATN) and its recovery process. METHODS: A severe ATN model was made using male Wistar rats by injecting gentamicin (150 mg/kg/day) for five days and limiting the provision of water. The expression and localization of OPN mRNA and protein, ED1 as a macrophage marker, proliferating cellular nuclear antigen (PCNA), CD44 as an OPN receptor, megalin as a proximal tubule marker, and their relationships to each other were examined from the early tubular necrotic period to the late recovery period by Northern blotting, in situ hybridization, and double immunohistochemical staining. RESULTS: In the gentamicin group, OPN mRNA and protein were expressed in only the PCNA-positive proliferating cortical distal tubules, not in the necrotic proximal tubules, until day 6 after the first administration, but were found markedly in PCNA-positive regenerative proximal and distal tubules on days 10, 15, and 30. The localization of PCNA-positive cells was almost always accompanied with the up-regulated expression of OPN using quantitative analysis (P < 0.01). CD44 expression was markedly up-regulated in the renal cortical tubular epithelium from days 6 to 30. In the control group, no expression of OPN and CD44 in the cortical area was found throughout the experimental period. CONCLUSIONS: These results suggested that OPN is related to the proliferation and regeneration of tubular epithelial cells after tubular damage.

Animals↗
PubMed2001

Novel glomerular lipoprotein deposits associated with apolipoprotein E2 homozygosity.

BACKGROUND: Hyperlipoproteinemia is occasionally associated with severe glomerular injury caused by abnormal accumulation of lipid in glomeruli, which occurs in conditions such as lipoprotein glomerulopathy (LPG). This study investigates the cases of two siblings with homozygous apolipoprotein (apo) E2 who show unique histologic features, massive proteinuria, and dysbetalipoproteinemia. METHODS: Histologic studies were performed using renal biopsy specimens. Plasma lipoproteins were extensively characterized. The exons of the apo E genes were sequenced to avoid missing any mutations. RESULTS: Histologically, the siblings' condition resembled LPG by light microscopy studies. Electron microscopy studies revealed large lipoid deposits in the paramesangium, subendothelium, and subepithelium of the glomeruli, which were different from LPG in terms of not forming the layered structure resembling a fingerprint even in large lipoprotein thrombi, and mesangial foam cells. Immunohistochemically, the lipoid deposits contained apo E and apo B. These patients did not have either diabetic nephropathy or other known forms of glomerulonephritis. The sequence of exons of the apo E genes revealed homozygosity for apo E2 in both cases. CONCLUSION: The extensive lipoprotein deposition in glomeruli, which resembles LPG, can also occur in apo E2 homozygous individuals, but in a distinct fashion. Because the two cases were siblings, they may have other shared alleles, in addition to the apo E2 allele, that negatively affect processing of lipoproteins and lead to abnormal accumulation of lipoprotein deposits in glomeruli.

Amino Acid Sequence↗
PubMed2001

Cholesteryl ester transfer protein as a protective factor against vascular disease in hemodialysis patients.

Cholesteryl ester transfer protein (CETP) may promote reverse cholesterol transport. An elevated concentration of high-density lipoprotein cholesterol (HDL-C) is a protective factor against atherosclerosis. However, the effects of CETP itself and its interaction with HDL-C have not been investigated in hemodialysis patients, who are at high risk for atherosclerosis and generally considered to have decreased reverse cholesterol transport. We investigated the independent or synergistic influence of postprandial serum CETP and HDL-C concentrations on apparent atherosclerotic complications in 202 hemodialysis patients aged 40 to 80 years. Patients with vascular disease (n = 39) had significantly lower concentrations of CETP than those without vascular disease (n = 163). When all study subjects were divided into four groups according to CETP and HDL-C concentrations based on median values, we found significant differences in the prevalence of vascular disease (test for trend, P < 0.005): 28.8% in group I (HDL-C < 48 mg/dL; CETP < 2.2 microgram/mL); 25.0% in group II (HDL-C < 48 mg/dL; CETP >/= 2.2 microgram/mL); 17.8% in group III (HDL-C >/= 48 mg/dL; CETP < 2.2 microgram/mL); and 6.9% in group IV (HDL-C >/= 48 mg/dL; CETP >/= 2.2 microgram/mL). Multiple logistic regression analysis retained the interaction term between HDL-C (in milligrams per deciliter) and CETP (in micrograms per milliliter), but not HDL-C or CETP itself, as inversely associated with vascular disease in the entire patient group. In patients with HDL-C levels at the median value or greater, CETP had an independent odds ratio of 0.31 (95% confidence interval, 0.1 to 0.97; P < 0.05) after adjusting for age. These results suggest that CETP may serve as a protective factor against vascular disease in hemodialysis patients, especially those with normal or elevated HDL-C concentrations.

Adult↗
PubMed2001

Reduction of circulating beta2-microglobulin level for the treatment of dialysis-related amyloidosis.

Dialysis-related amyloidosis (DRA) is a common complication associated with long-term haemodialysis therapy. The elimination of beta2-microglobulin (beta2m), the major constituent of the amyloid fibrils in DRA, from circulation has been expected to bring some clinical benefit. Recently, a direct haemoperfusion method using selective beta2m absorption column to eliminate circulating beta2m has been introduced into clinical practice. According to a recently performed, prospective, multicentre study, joint pain, stiffness and daily activities were significantly improved in patients with established DRA after the introduction of selective beta2m absorption therapy. Meanwhile, although osteoarticular lesions progressed in the control group, there was no significant progression in the selective beta2m absorption therapy group. The absorptive affinity of the column for beta2m is not quite specific and therefore some other unknown uraemic toxins might be removed also. However, the improvement of joint pain and the ability to undertake daily activities showed reversed correlations against plasma beta2m clearance. Symptoms associated with the increased amount of extracorporeal circulation and increased economical burden are areas of concern for this therapy. In conclusion, selective beta2m absorption therapy was suggested to have the potential to ameliorate established DRA symptoms and simultaneously prevent its local development. The mechanism by which DRA symptoms are ameliorated remains obscure.

Absorption↗
PubMed2001

The circadian blood pressure rhythm in non-diabetic hemodialysis patients.

This study investigates the circadian blood pressure variation of non-diabetic chronic hemodialysis (HD) patients on both HD and non-HD days as well as the factors affecting diurnal BP variation. Forty-nine HD patients aged 61.8 +/- 12.9 years who were on daytime HD for 97 +/- 68 months were studied. No significant difference was found in every daytime and nighttime BP between the first (HD) and the second (non-HD) day. However, the ratio nighttime/daytime BP was significantly higher on the second day. Each BP diurnal variability pattern was classified as either Dipper (D: the ratio nighttime/daytime mean BP 0.8-0.9), non-dipper (0.9 < ND < 1.0), or inverted dipper (ID > 1.0). More than 75% of the cases were classified as ND (26 cases) or ID (11 cases). The ultrafiltration rate in D was significantly less than that in ND and ID. The difference of plasma renin activity between pre- and post-HD (dRen) was significantly higher in ID than in D and ND. The amount of dialysis (Kt/V) was found to be significantly correlated with nighttime BP fall. Ultrafiltration, dRen and Kt/V were independent factors for the abnormal BP diurnal variability. In conclusion, the decreased nocturnal BP fall seen in non-diabetic HD patients is associated with increased extracellular fluid even in the patients without overt overhydration, whereas relatively insufficient amount of dialysis (low Kt/V) may be another possible cause. The increased dRen observed only in ID patients may reflect occult cardiovascular damage or functional disturbances in aortic and carotid baroreflexes caused by arterial structural changes.

Adult↗
PubMed2001

Determination of optimal blood pressure for patients with IgA nephropathy based on renal histology.

To evaluate the optimal BP control for patients with IgA nephropathy (IgAN) based on the histologic severity of the nephropathy and the degree of renal dysfunction. We analyzed 332 consecutive renal biopsy specimens and clinical data from patients with IgAN. Patients were divided into three groups based on their BP at the time of biopsy: an optimal BP (SBP<120 mmHg and DBP<80 mmHg), a hypertensive BP (SBP > or = 140 mmHg and/or DBP > or = 90 mmHg), and an intermediate BP group. Each biopsy specimen was evaluated for mesangial proliferation, degree of sclerosis and/or hyalinosis of the arterioles and the interlobular artery using a semiquantitative method. Creatinine clearance and the percentage of sclerosed glomeruli were also determined. Both the degree of renal dysfunction and the histologic changes correlated significantly with BP, even in patients with a BP <140/90 mmHg. The patients with an optimal BP at the time of biopsy had significantly less histologic damage with respect to mesangial proliferation and vessel changes than those with an intermediate or hypertensive BP. In the patients with a hypertensive BP, the percentage of sclerotic glomeruli was significantly higher and the creatinine clearance was significantly lower. The optimal BP proposed by the WHO in 1999 prevents histologic evidence of renal damage for patients with IgAN.

Adult↗
PubMed2001

Three-dimensional analysis of nephrogenesis in the neonatal rat kidney: light and scanning electron microscopic studies.

In order to clarify the process of renal development more precisely than previously, the present study observed the rat neonatal kidney by scanning electron microscopy (SEM) of KOH digested tissue as well as by light microscopy of plastic sections. In the subcapsular region, aggregation of the mesenchymal cells was closely associated with the upper side of the ureteric duct ampulla. These mesenchymal cells projected a number of fine irregular processes at the basal portion facing the ureteric duct. A spherical cluster transformed from the mesenchymal cell aggregation was found on the lower side of the terminal ampulla, and was differentiated into the renal vesicle. Some cells at the top of the renal vesicle formed a cone-shaped projection and invaded the ureteric duct ampulla, forming a connection with it. In the advanced stage, a shallow transverse cleft appeared on the outer lateral side of the renal vesicle, and a second cleft was formed on the opposite side close to the junction between the renal vesicle and the ampulla. As the two clefts deepened, the vesicle assumed the well-known S-shaped body. In the advanced S-shaped body, the lower limb became cup-shaped, while the segment between the middle and lower limbs of the "S" elongated to form a tubular structure (i.e., the prospective proximal tubule and Henle's loop). The upper limb of the "S" also increased its length to form a distal tubule. The middle limb of the "S", however, was attached firmly to the cup-shaped lower limb (i.e., the prospective renal corpuscle) and was considered to become the macula densa of the mature nephron. In the maturing renal corpuscle, irregularly shaped cells were observed as a sheet-like aggregation at its vascular pole and were continuous with the vascular smooth muscle cells. These findings will help toward a better understanding of the morphological complexities of nephrogenesis.

Animals↗
PubMed2001

Extension of A beta2M amyloid fibrils with recombinant human beta2-microglobulin.

In order to elucidate the pathogenesis of A beta2M amyloidosis, we established an experimental system to study the mechanism of amyloid fibril formation or degradation in vitro. We compared the kinetics of A beta2M amyloid fibril (fA beta2M) extension with native beta2microglobulin (n-beta2M) purified from the urine of a patient suffering from renal insufficiency, with that with recombinant beta2M (r-beta2M) in vitro. n-Beta2M and r-beta2M were incubated with fA beta2M purified from synovial tissues excised from A beta2M amyloidosis patients. The fA beta2M extension reaction could be explained by a first-order kinetic model in both beta2Ms. The extension reaction was greatly dependent on the pH of the reaction mixture and maximum around pH 2.5-3.0 in both beta2Ms. The fA beta2M extended with both beta2Ms assumed the similar helical filament structure, although the fibrils extended with r-beta2M were slightly wider than those extended with n-beta2M and the former fibrils assumed a helical structure more clearly as compared to the latter. In order to obtain pure, unmodified fA beta2M, we next extended fA beta2M repeatedly by the algorithmic protocol with r-beta2M. As the generation of the extended fibrils proceeded, the initial rate of the extension reaction increased The ultrastructure of fibrils was completely preserved throughout the repeated extension steps. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunoblotting revealed that fA beta2M extended repeatedly with r-beta2M were composed solely of r-beta2M. The use of these r-beta2M and fA beta2M will be advantageous to assess the effects of several amyloid-associated molecules in the formation or degradation of fA beta2M in vitro.

Amyloid↗
PubMed2001

[Beta 2-microglobulin and dialysis-related amyloidosis].

Dialysis-related amyloidosis is a common complication encountered in patients receiving chronic hemodialysis. beta 2-microglobulin(beta 2-m) constitutes the causative protein of amyloidosis, and its deposition in tissues has been proven to be a primary cause of the onset. However, many other risk factors are also associated including (1) prolonged duration of dialysis, (2) advanced age, (3) dialysate of low purity, and (4) the use of a dialysis membrane with poor biocompatibility. Recently we confirmed that apolipoprotein E is a risk factor for the onset of carpal tunnel syndrome associated with dialysis-related amyloidosis. Dialysis using high-flux membranes and the clinical application of a column that selectively adsorbs beta 2-m are currently being assessed interms of the ability to remove as much beta 2-m from the blood as possible. Drug therapy may also be useful at present in symptomatic treatment; a low dose of adrenocorticosteroids has recently been demonstrated as extremely effective for joint pain associated with beta 2-m amyloid deposits. The long-term use of drugs, however, carries a risk of side effects. As a therapeutic approach to dialysis-related amyloidosis, high-flux dialysis membranes permitting the elimination of beta 2-m with satisfactory biocompatibility have been developed and positive clinical effects have been observed both in the retrospective and prospective studies in the use of high-flux membranes together with a decrease in the serum beta 2-m level. However, there is no evidence yet of the long term reduction of amyloid deposits when the elimination of beta 2-m is maintained using a high-flux membrane.

Amyloid beta-Protein Precursor↗