[Acquired coagulation abnormality due to factor V inhibitor].
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Blood Coagulation Disorders↗
Biomedical subjects
Fumitake Gejyo
Publications and source records attributed to Fumitake Gejyo.
Identification of genes regulating colorectal carcinogenesis by using the algorithm for diagnosing malignant state method.
We studied the expression profiles of various stages of colorectal tumors (adenoma (AD), seven samples; carcinoma (CA), 16 samples) by using cDNA microarrays and developed ADMS (algorithm for diagnosing malignant state) method, selecting 335 clones characteristic of CA state. We, then, applied ADMS to 12 additional samples (five from primary lesions with metastasis and seven metastases); all 16 CAs and 12 metastatic tumors were diagnosed correctly as cancerous states. Although three of the seven ADs were diagnosed as "cancerous," the large size of two of these tumors suggested their potential malignancy. Our strategy for selecting clones characteristic of the malignant state is widely applicable to diagnosis and for predicting the stage of progression during multistep carcinogenesis. Of the 335 clones we selected, 135 were known genes. Included in the 135 genes were tumor suppressor and growth factor-related genes and were consistent with the literature. ADMS is a reliable means for identifying genes useful for the diagnosis of cancer.
Adenoma↗
SREBP-2 and NF-Y are involved in the transcriptional regulation of squalene epoxidase.
The expression of squalene epoxidase (SE) is highly regulated transcriptionally by cholesterol. To elucidate these molecular mechanisms, we isolated the human and rat genomic clones. The entire human SE gene was about 24 kb long and organized into 11 exons with 10 introns. Unidirectional deletion analysis of the human 5(')-flanking region indicated that the sequence between -264 and -230 bp conferred cholesterol sensitivity on a reporter gene. This region contained a potential copy of consensus sterol regulatory element (SRE) sequence (CCACGCAAC) previously identified in the promoter of cholesterogenic and its related genes. The transcriptional activation observed under overexpression of sterol regulatory element binding protein-2 (SREBP-2) supported the functional role of the SRE sequence. Another deletion analysis showed that the sequence -207 to -192 bp was also active and it contained nuclear factor Y (NF-Y) binding site. Both sites might play critical roles in sterol mediated regulation of SE gene.
5' Flanking Region↗
Combined Ala601-Thr-type dysplasminogenaemia and antiphospholipid antibody syndrome in a patient with recurrent thrombosis.
A 44-year-old man was admitted to our hospital because of recurrent thrombosis. Laboratory findings showed that he had antiphospholipid antibody syndrome (APS) associated with systemic lupus erythematosus. Plasminogen activity was reduced (21%), but its antigenic level was rather elevated (16.4 mg/dl). The discrepancy of plasminogen activity and antigen levels was also found in his three daughters. Gene analysis revealed a homozygous missense mutation (Ala601-->Thr) at exon 15 of the plasminogen gene in the patient and a heterozygous mutation in his three daughters, suggesting that the patient has dysplasminogenaemia, which was reported as "plasminogen Tochigi." Although it still remains controversial whether both dysplasminogenaemia and plasminogen deficiency are relevant independent thrombotic risk factors, the combination of this deficiency and APS should be considered as a strong predisposition to thrombosis in this patient.
Adult↗
Kidney-targeted naked DNA transfer by retrograde renal vein injection in rats.
Kidney-targeted gene transfer is expected to revolutionize the treatment of renal diseases. Previous gene transfer methods using nonviral vectors administered via renal arterial, pelvic, or ureteric routes into the glomerulus, tubules, or interstitial fibroblasts have resulted in low-level expression for <1 month. The peritubular capillaries (PTC) network is one of the main targets of kidney transplant rejection and of progressive tubulointerstitial fibrosis, which typifies all progressive renal diseases. To access the PTC, we retrogradely injected a lacZ expression plasmid in Ringer's solution into the renal vein of rats. We detected lacZ expression exclusively in the interstitial fibroblasts near the PTC of the injected kidney by immunoelectron microscopic analysis. Nephrotoxicity attributable to gene transfer was not apparent. We then used a rat erythropoietin (Epo) expression plasmid vector, pCAGGS-Epo, in a reporter assay. We obtained maximal Epo expression when the DNA solution was injected within 5 sec, and with a volume of 1.0 ml. We observed a dose-response relationship between serum Epo levels and the amount of injected DNA up to 100 microg. We detected the transgene-derived Epo mRNA by reverse transcription polymerase chain reaction only in the kidneys injected with pCAGGS-Epo. After an injection of 100 microg of pCAGGS-Epo, the serum Epo levels peaked at 208.3 +/- 71.8 mU/ml at week 5, and gradually decreased to 116.2 +/- 38.7 mU/ml at week 24. A similar pattern was obtained using smaller doses of plasmid, 2 microg or 30 microg of pCAGGS-Epo. Transgene-derived Epo secretion resulted in significant erythropoiesis. This novel technique is simple and safe, allowing high-level and long-term stable gene expression specific to the fibroblasts near the PTC, and should have therapeutic value for future applications in humans.
Animals↗
Association between single-nucleotide polymorphisms in selectin genes and immunoglobulin A nephropathy.
Although intensive efforts have been undertaken to elucidate the genetic background of immunoglobulin A nephropathy (IgAN), genetic factors associated with the pathogenesis of this disease are still not well understood. We designed a case-control association study that was based on linkage disequilibrium among single-nucleotide polymorphisms (SNPs) in the selectin gene cluster on chromosome 1q24-25, and we found two SNPs in the E-selectin gene (SELE8 and SELE13) and six SNPs in the L-selectin gene (SELL1, SELL4, SELL5, SELL6, SELL10, and SELL11) that were significantly associated with IgAN in Japanese patients. All eight SNPs were in almost complete linkage disequilibrium. SELE8 and SELL10 caused amino acid substitutions from His to Tyr and from Pro to Ser (chi2=9.02, P=.0026, odds ratio = 2.73 [95% confidence interval [CI] 1.38--5.38] for His-to-Tyr substitutions; chi2=17.4, P=.000031, odds ratio = 3.61 [95% CI 1.91--6.83] for Pro-to-Ser substitutions), and SELL1 could affect promoter activity of the L-selectin gene (chi2=19.5, P=.000010, odds ratio = 3.77 [95% CI 2.02--7.05]). The TGT haplotype at these three loci was associated significantly with IgAN (chi2=18.67, P=.000016, odds ratio = 1.88 [95% CI 1.41--2.51]). Our results suggest that these eight SNPs in selectin genes may be useful for screening populations susceptible to the IgAN phenotype that involves interstitial infiltration.
Case-Control Studies↗
Single-nucleotide polymorphisms in the class II region of the major histocompatibility complex in Japanese patients with immunoglobulin A nephropathy.
Immunoglobulin A nephropathy (IgAN) is a form of chronic glomerulonephritis of unknown etiology and pathogenesis. Immunogenetic studies have not conclusively indicated that human leukocyte antigen (HLA) is involved. As a first step in investigating a possible relationship between HLA class II genes and IgAN, we analyzed the extent of linkage disequilibrium (LD) in this region of chromosome 6p21.3 in a Japanese test population and found extended LD blocks within the class II locus. We designed a case-control association study of single-nucleotide polymorphisms (SNPs) in each of those LD blocks, and determined that SNPs located in the HLA- DRA gene were significantly associated with an increased risk of IgAN ( P = 0.000001, odds ratio = 1.91 [95% confidence interval 1.46-2.49]); SNPs in other LD blocks were not. Our data imply that some haplotype of the HLA- DRA locus has an important role in the development of IgAN in Japanese patients.
Adult↗
Liver injury due to sequential activation of natural killer cells and natural killer T cells by carrageenan.
BACKGROUND/AIMS: Carrageenan is a high molecular weight polysaccharide and is widely used as a food additive for the solidification of plant oils and the thickening of many beverages. It is known that acute toxicity of carrageenan is possibly induced by the activation of phagocytic cells. We investigated other effects of carrageenan on lymphocytes in this study. METHODS: Carrageenan was intraperitoneally injected once into mice and phenotypic and functional characterizations were conducted in various immune organs. RESULTS: Natural killer (NK) cells were prominently activated in the liver, lungs, and spleen. A time-kinetic study showed sequential activation of NK and natural killer T (NKT) cells in the liver on days 3-10 after the injection. In parallel with the activation of NK and NKT cells in number, NK and NKT cytotoxicities were augmented. At this time, liver injury was induced, accompanied by massive hepatic necrosis and the elevation of transaminases. The in vivo elimination of NK cells reduced the liver injury induced by carrageenan. Direct binding of carrageenan onto NK cells was also demonstrated. Such a binding then induced a subsequent production of IFN gamma. Perforin molecules of NK cells were responsible for this liver injury. CONCLUSIONS: These results suggest that not only phagocytic cells but also primitive lymphocyte (mainly NK cells) subsets might be important targets for the acute toxicity of carrageenan.
Animals↗
Pulmonary diffusion capacity in patients with systemic lupus erythematosus.
OBJECTIVE: The aim of this study was to clarify the characteristics of pulmonary function tests (PFT), especially carbon monoxide diffusion capacity (DLCO), and their correlation with clinical features and immunological findings in patients with systemic lupus erythematosus (SLE). METHODOLOGY: Vital capacity (VC) and DLCO were analysed retrospectively in 110 sequential Japanese SLE patients with active disease between 1985 and 1999. In 38 patients, serial measurements of PFT were also assessed during high-dose corticosteroid therapy. RESULTS: DLCO was reduced in 52 patients (47%) and a restrictive impairment of PFT was observed in nine patients (8%). The prevalence of pulmonary fibrosis was 13%. Reduced DLCO was frequently observed, even in patients with neither pulmonary fibrosis nor a restrictive pattern. No correlation between immunological data and reduced DLCO was found, except for the presence of anti-RNP. Patients with Raynaud's phenomenon showed a higher prevalence of DLCO impairment than those without this phenomenon. Although immunological parameters improved significantly after the corticosteroid therapy, no significant change in the level of DLCO was observed. CONCLUSIONS: Impairment of DLCO was frequently observed in patients with SLE who had no clinical respiratory abnormalities. DLCO impairments were correlated with Raynaud's phenomenon clinically, and the presence of anti-RNP immunologically. No significant correlation was found between impairment of DLCO and disease activity of SLE.
Adolescent↗
Impairment of vascular regeneration precedes progressive glomerulosclerosis in anti-Thy 1 glomerulonephritis.
BACKGROUND: It has been proposed that glomerular hemodynamic changes or glomerular growth response may promote the development of glomerulosclerosis, irrespective of its etiology. Further experimental models are needed to clarify the cellular and molecular mechanisms that lead to progressive glomerulosclerosis with an irreversible course. We designed a model of irreversible glomerulosclerosis, using anti-Thy-1.1 injection followed by uninephrectomy, and examined the role of glomerular endothelial cell responses in the process of progressive sclerotic changes. METHOD: Rats were injected with anti-Thy-1.1 monoclonal antibody, 1-22-3, and 30 minutes later, unilateral nephrectomy (one-kidney group) or sham operation (two-kidney group) was performed. Rats were sacrificed for histological examination on days 3, 14, 56, and 84 after injection. The density of the glomerular capillary tuft was assessed by immunofluorescent staining for endothelial specific antigens. The mRNA expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule-1 (PECAM-1), and vascular endothelial growth factor (VEGF) also was followed up by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Semiquantitative analysis revealed that the capillary density and mRNA expression of PECAM-1, VCAM-1 and VEGF were significantly lower in the one-kidney group compared to the two-kidney group on day 14. On day 84, progressive glomerulosclerotic lesions were found, followed by a decrease of the capillary density in the one-kidney group, while the glomerular architecture recovered to an almost normal state in the two-kidney group. CONCLUSIONS: Progressive glomerulosclerosis can be induced in the rat by a one shot injection of anti-Thy 1.1 monoclonal antibody followed by unilateral nephrectomy. This model shows that there is a positive association between impairment of vascular regeneration and the development of glomerulosclerosis.
Animals↗
Role of uteroglobin G38A polymorphism in the progression of IgA nephropathy in Japanese patients.
BACKGROUND: Uteroglobin is a multifunctional protein and both its gene knockout and antisense transgenic mouse models develop the pathological and clinical features of IgA nephropathy. A genetic polymorphism in uteroglobin has been reported to be associated with progression of IgA nephropathy in a Caucasian population, but the findings remain controversial. METHODS: Genomic DNA was isolated from 595 individuals including 239 patients with IgAN, 160 patients with glomerulonephritis distinct from IgAN, and 196 healthy controls. The uteroglobin G38A genotype was determined by PCR-RFLP with Sau96I. To examine the possible association of uteroglobin gene polymorphism in the patients with and without IgAN, the uteroglobin genotype and allele frequency were compared between the two groups. In addition, associations between the polymorphism and blood pressure, proteinuria and prognosis of renal function were analyzed in the patients with IgAN to investigate the role of this gene polymorphism in the risk of progressive renal dysfunction in IgAN patients. RESULTS: The Cox proportional hazard regression model revealed that hypertension and proteinuria at the time of renal biopsy were independent risk factors for poor renal survival. Uteroglobin genotype was not significantly associated with the renal survival rate. However, in the patients with heavy proteinuria (more than 2 g/day) or in those with hypertension at the time of renal biopsy, the renal survival of patients with the GG genotype was significantly worse than the other genotypes. CONCLUSION: Uteroglobin GG genotype may be a genetic marker for rapid disease progression to end-stage renal failure, especially in the IgAN patients with heavy proteinuria or high blood pressure.
Adult↗
Fractalkine expression and the recruitment of CX3CR1+ cells in the prolonged mesangial proliferative glomerulonephritis.
BACKGROUND: We established the reversible and the prolonged models of mesangial proliferative glomerulonephritis (GN) with anti-Thy 1 antibody 1-22-3. However, the essential factors leading to the prolonged glomerular alterations have not been identified. METHODS: The expressions of several chemokines and cytokines were compared in the reversible and the prolonged models. Expression of fractalkine and the number of the fractalkine receptor CX3CR1-positive cells in the glomeruli in the prolonged model were significantly higher than those in the reversible model. Then, the localization of fractalkine and the characteristics of CX3CR1+ cells were analyzed in glomeruli. To elucidate the significance of the fractalkine expression, we analyzed the expression in the model treated with angiotensin II receptor antagonist, candesartan. RESULTS: Immunostaining of fractalkine was detected on endothelial cells on the fifth day, and fractalkine staining also was detected in the mesangial area on day 14. Major parts of the CX3CR1+ cells in the glomeruli were macrophages, especially ED3+ cells. Candesartan treatment ameliorated the glomerular morphological findings at six weeks after disease induction. Although the treatment did not ameliorate the morphological finding at two weeks, decreased expression of fractalkine and CX3CR1+ were already detected at two weeks in rats treated with candesartan. CONCLUSIONS: Fractalkine expression and the recruitment of CX3CR1+ cells in glomeruli might play an important role in the development of the prolonged disease. These expressions could be predictors of the prolonged disease of the mesangial proliferative glomerulonephritis.
Animals↗
A(-20)C polymorphism of the angiotensinogen gene and progression of IgA nephropathy.
BACKGROUND: The M235T polymorphism of the angiotensinogen gene (AGT) is associated with an increased risk of primary hypertension, which may then lead to progressive renal disease. Recent studies showed that nucleotide substitution in the 5' upstream core promoter region of AGT affects the basal transcription rate of the gene. METHODS: To evaluate the role of AGT polymorphisms in the progression of IgA nephropathy (IgAN), we analyzed the association of A(-20)C and M235T polymorphisms with renal prognosis in histologically-proven IgAN patients using the Kaplan-Meier method and Cox proportional hazards regression model. RESULTS: The incidence of hypertension during the course was associated with T235, but not with C(-20). The renal survival rate for 137 patients with creatinine clearance (C(Cr)) of 70 mL/min or greater at the time of renal biopsy, and follow-up time of two years or more was significantly lower in the patients with C(-20) (P = 0.008). The Cox proportional hazards regression model showed an increased hazard ratio (HR) for urinary protein (more than 2 g/day) of 28.3 (95% CI, 7.3 to 109.8; P < 0.001), hypertension at the time of renal biopsy of 4.6 (95% CI, 1.8 to 11.9; P = 0.002), and C(-20) of 3.6 (95% CI, 1.5 to 8.7; P = 0.004). CONCLUSION: This work provides evidence that the C(-20) polymorphism of AGT, a subset of T235 alleles, is associated with progression of renal dysfunction in IgAN.
Adult↗
Increased circulating levels of osteoclastogenesis inhibitory factor (osteoprotegerin) in patients with chronic renal failure.
Skeletal resistance to parathyroid hormone (PTH) is one of the major abnormalities underlying bone diseases in uremia, the mechanism of which has not yet been fully elucidated. Osteoclastogenesis inhibitory factor (OCIF), or osteoprotegerin, is a natural decoy receptor for osteoclast differentiation factor (ODF), produced by osteoblasts in response to PTH. To elucidate the kinetics and roles of OCIF in chronic renal failure, serum OCIF levels were measured in 46 predialysis patients and 21 dialysis patients by means of enzyme-linked immunosorbent assay (ELISA). Serum OCIF levels in predialysis patients increased as renal function declined (OCIF = 1.178 + 0.233 x creatinine; r2 = 0.413; P < 0.0001). Twenty-four-hour creatinine clearance and 1/OCIF in predialysis patients showed a clear positive correlation and a straight line regression (1/OCIF = 0.443 + 0.004 x creatinine clearance; r2 = 0.425; P < 0.0001). In dialysis patients, serum OCIF levels were significantly elevated (5.18 +/- 1.48 ng/mL) to a level that would inhibit 50% osteoclast formation in vitro. These findings suggest that OCIF accumulates in serum of patients with renal dysfunction. Because serum levels of OCIF with the ability to bind ODF in vitro (active OCIF) correlated well with those of OCIF detected by standard ELISA (active OCIF = 0.251 + 0.877 x OCIF; r2 = 0.829; P < 0.0001), OCIF accumulated in serum may be a candidate uremic toxin responsible for the skeletal resistance to PTH seen in chronic renal failure. Further studies with serum parameters and bone histological evaluation are needed to assess this possibility.
Aged↗
Circulating osteoprotegerin is not removed through haemodialysis membrane.
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Glycoproteins↗
Pulmonary artery involvement in Takayasu's arteritis with lung infarction and pulmonary aspergillosis.
We describe a patient with a chronic case of pulmonary involvement of Takayasu's arteritis in the resected lung. A 49-year-old woman was first diagnosed with Takayasu's arteritis at age 30 years. On her first admission, she presented with Takayasu's arteritis and pneumonia with cavitation in the left lung. After recovering from pneumonia, she was treated initially with prednisolone, 30 mg/day, and remained well until she developed hemoptysis at age 34 years. Findings suggesting aspergilloma were found in the same lobe on chest x-ray film when she was 46 years of age. By age 49 years, the hemoptysis became massive, and she was admitted for surgery. Left upper lobectomy and partial resection of S6 and S8 pulmonary segments were performed. Histologic analysis of the resected lung revealed typical pathologic findings of pulmonary artery involvement in Takayasu's arteritis, such as stenosis recanalization and a vessel-in-vessel feature, but not active vasculitis. Infection probably occurred in the cavity of the infarcted tissue. Pulmonary artery involvement is common in Takayasu's arteritis, but the aspergilloma in this corticosteroid-treated patient is an uncommon complication.
Journal Article↗
[Protective effect of azithromycin against verotoxin].
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Animals↗
Effects of azithromycin on shiga toxin production by Escherichia coli and subsequent host inflammatory response.
Shiga toxin (Stx)-producing Escherichia coli (STEC) colonizes the human intestinal mucosa, produces Stx from phage, and causes the development of hemolytic-uremic syndrome via Stx-induced inflammatory cytokine production. Azithromycin exhibited strong in vitro activity against STEC without inducing Stx-converting phage, in marked contrast to norfloxacin. Azithromycin decreased the tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 production from Stx-treated human peripheral mononuclear cells or monocytes to a greater extent than did clarithromycin. In Stx-injected mice, azithromycin significantly suppressed Stx-induced TNF-alpha, IL-1beta, and IL-6 levels in serum and improved the outcome as assessed by survival rate. In the STEC oral infection experiment using immature mice immediately after weaning (weaned immature-mouse model), all mice died within 7 days postinfection. Azithromycin administration gave the mice 100% protection from killing, while ciprofloxacin administration gave them 67% protection. The data suggest that azithromycin (at least at higher concentrations) has a strong effect on Stx production by STEC and on the Stx-induced inflammatory host response and prevents death in mice. Azithromycin may have a beneficial effect on STEC-associated disease.
Animals↗