Biomedical subjects
Hiroki Shimura
Publications and source records attributed to Hiroki Shimura.
Focal segmental glomerulosclerosis associated with essential thrombocythemia.
Focal segmental glomerulosclerosis (FSGS) is a primary glomerular disease that is characterized by progressive proteinuria and declining renal function. Secondary FSGS is known to be associated with various diseases. However, an association of FSGS with essential thrombocythemia (ET) has been reported in few cases. We report a 76-year-old man who presented with nephrotic syndrome and hepatosplenomegaly. He had thrombocythemia after a splenectomy, which had been carried out at a nearby hospital. A renal biopsy showed that he had focal segmental glomerulosclerosis (FSGS), while assessment of the bone-marrow specimen revealed that he had ET. A possible relationship between FSGS, which occurred in association with a dramatic increase of thrombocytes after a splenectomy in a patient with ET, and increased serum levels of transforming growth factor (TGF)-beta, basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF)-BB was suggested.
Immunopathological and genetic features in slowly progressive insulin-dependent diabetes mellitus and latent autoimmune diabetes in adults.
In 1982 we proposed the presence of a subtype of type 1 diabetes [slowly progressive insulin-dependent diabetes mellitus (SPIDDM)], which was characterized by persistently positive islet cell antibody, late age of onset, noninsulin-dependent diabetes, and slowly progressive beta cell failure. Since then many studies demonstrated that this subtype of type 1 diabetes is prevalent in many ethnic groups and was later called the latent autoimmune diabetes in adults (LADA). Recent epidemiological studies reported that about 10% of patients with apparent type 2 diabetes have at least one autoantibodies against islet-specific antigen with high potential to progress to insulin-dependent state. Between SPIDDM and LADA some differences are reported in terms of some genetic predispositions including HLA class II and class I genes, vitamin D receptor gene, and CTLA4 genes. Common features in SPIDDM and LADA including preserved beta cells at the onset of diabetes and weak T cell response to residual beta cells suggest that these subtypes of type 1 diabetes are suitable candidates for prevention treatment for further progression of beta cell failure.
Serum level of macrophage colony-stimulating factor and atherosclerosis in hemodialysis patients.
BACKGROUND/AIMS: Atherosclerosis and its related complications are the leading causes of death in the hemodialysis (HD) population. Aortic calcification index (ACI), intima-media thickness (IMT) in common carotid arteries, and electrocardiogram (ECG) are atherosclerotic parameters that are available in usual clinical outpatient settings. Macrophage colony-stimulating factor (MCSF) and monocyte chemoattractant protein-1 (MCP-1) play important roles in atherosclerosis. METHODS: We performed a cross-sectional study of 133 outpatients on maintenance HD in a single HD outpatient center. We measured serum levels of MCSF and MCP-1, determined the ACI using computed tomography scan and the IMT using high-sensitivity ultrasound B-mode imaging, and performed ECGs. RESULTS: Stepwise multivariate regression analysis revealed that the MCSF level correlated with age-adjusted mean and maximum IMT (F = 10.811, p = 0.001, and F = 6.784, p = 0.010, respectively) as well as with the diastolic blood pressure. Age and MCSF level (F = 4.866, p = 0.029) were independently related to an increased ACI. High-sensitivity C-reactive protein (hsCRP) was not related to IMT and ACI. The hsCRP level (chi2 = 5.002, p = 0.025) correlated with ECG changes followed by MCSF (chi2 = 3.940, p = 0.047). MCP-1 was not related to the above atherosclerotic parameters. CONCLUSION: A head-to-head comparison between MCSF and hsCRP revealed that MCSF was more closely associated with IMT and ACI in HD patients.
Extensive pancreatic necrosis in microscopic polyangiitis.
We encountered an 84-year-old woman with microscopic polyangiitis who was found to have pancreatitis on autopsy. The patient was admitted to Yamanashi University Hospital because of fever and progressive renal failure. She was diagnosed with anti-myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-related microscopic polyangiitis (MPA) and was treated successfully with prednisolone pulse therapy. Two months later, she was found unconscious at home and was transferred to hospital, where she died of cardiac arrest after 6 days. Autopsy revealed systemic vasculitis with fibrinoid necrosis (with the most severe form found in the pancreas), interstitial pneumonia, and crescentic glomerulonephritis. A review of the literature revealed that pancreatic involvement in vasculitis, although rare, is one of the complications of MPA; however, the present study is the first report to focus on the pancreatic involvement of MPA. We recommend that nephrologists consider the possibility of pancreatic involvement in this disease.
Avoiding the effect of linked genes is crucial to elucidate the role of Apcs in autoimmunity.
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Distinct diagnostic criteria for ultrasonographic examination of papillary thyroid carcinoma: a multicenter study.
Recent advances permitting high-resolution ultrasonography have made ultrasonographic examination of nodular thyroid diseases an accessible examination for routine practice. However, diagnostic criteria for ultrasonographic examination of thyroid nodules are not surely established. To identify the optimal strategy for well standardized differential diagnosis of papillary thyroid carcinoma and benign nodules, we evaluated the significance of individual ultrasonographic characteristics of thyroid nodules in a multicenter study. Ten characteristics in ultrasonograms from 53 patients scored by 17 investigators from 15 centers were analyzed by t tests and logistic regression analyses. Between benign and papillary thyroid cancer groups, all characteristics but not size or multiplicity of strong echoes, which suggest calcifications, were significant parameters. Logistic regression analyses showed that border character, shape, and internal echo level are highly significant parameters (p < 0.0005). A multiple logistic regression showed to be the most important predictors of pathologic diagnosis. The diagnostic criterion with border character and internal echo level yielded 93% sensitivity and 92% specificity. In conclusion, univariate and multivariate analyses identified border character, shape, internal echo level, but not strong echoes (calcifications), as important characteristics in differentiating papillary thyroid carcinoma from benign nodules. These results will contribute to standardization of accurate ultrasonographic diagnosis of papillary thyroid carcinoma.
Adenovirus-mediated transfer of thyroid transcription factor-1 induces radioiodide organification and retention in thyroid cancer cells.
Loss of thyroid-specific gene expression and functions accompanied by loss of thyroid transcription factors render them unresponsive to radioiodide therapy in poorly differentiated and anaplastic thyroid cancer. In anticipation of reactivation of thyroid functions, we investigated the effect of thyroid transcription factor-1 (TTF-1) gene transfer on thyroid cancer cells. Reexpression of thyroperoxidase (TPO) and thyroglobulin (Tg) mRNA and protein was detected in poorly differentiated human thyroid cancer cells that were infected with an adenovirus vector containing TTF-1 (AdTTF-1). Although TTF-1 gene transfer faintly induced iodide uptake, the induction of sodium/iodide symporter (NIS) mRNA was not observed in AdTTF-1-infected cells. To analyze the effect of TTF-1 on iodide metabolism, we transfected an NIS expression vector into BHP18-21v cells and cloned a cell line (N-BHP18-21v) that stably expressed NIS. The treatment of N-BHP18-21v cells with AdTTF-1 significantly increased the amount of protein-bound radioiodide and prolonged the iodide efflux. AdTTF-1 injections significantly induced iodide retention and organification in tumors formed from N-BHP18-21v cells in nude mice. These results indicate that AdTTF-1 specifically induces iodide organification and retards iodide efflux in thyroid cancer cells in vitro and in vivo.
Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin.
Iodide uptake by the thyroid is mediated by the sodium/iodide symporter. Upon iodide uptake, thyroperoxidase catalyzes iodination of tyrosine residues in thyroglobulin, retaining iodide within thyroid follicles. Dedifferentiation-induced loss of these functions in cancers, rendering them unresponsive to radioiodide, occurs with most poorly differentiated and anaplastic tumors. We focused on the histone deacetylase (HDAC) inhibitors (HDACI) as a way to induce differentiation of thyroid cancer cells. We assessed re-expression of thyroid-specific genes mRNA induced by HDACI using quantitative RT-PCR and immunostaining in poorly differentiated papillary and anaplastic thyroid cancer cells. HDACI induced expression of thyroid-specific gene mRNAs and proteins, and accumulation of radioiodide through iodination of generic cellular proteins were detected. HDACI-treated tumors could specifically accumulate (125)I as revealed by imaging experiments and radioiodide concentration in vivo. In an attempt to determine the mechanism by which these gene expressions occurred, we detected the inhibition of protein synthesis by cycloheximide, which up-regulated the expression of thyroperoxidase and thyroglobulin mRNA in HDACI-treated cells and down-regulated that of sodium/iodide symporter mRNA. Together, our results suggest that HDACI-induced expression of thyroid-specific genes, some of which is mediated by some protein synthesis, may contribute to development of novel strategy against thyroid cancer.
Distinct diagnostic criteria of fulminant type 1 diabetes based on serum C-peptide response and HbA1c levels at onset.
OBJECTIVE: Diagnostic criteria in fulminant type 1 diabetes, a novel subtype of type 1 diabetes, remain unclear. RESEARCH DESIGN AND METHODS: We analyzed basal and longitudinal changes of serum C-peptide levels during a 75-g oral glucose tolerance test (OGTT) in 125 consecutively recruited patients with type 1 diabetes including fulminant type 1 diabetes (n = 25) and acute-onset type 1 diabetes (n = 100). Discriminating criteria of fulminant type 1 diabetes were examined using receiver-operating characteristic curve analysis and multiple logistic regression analysis. RESULTS: The integrated values of serum C-peptide response during OGTT (SigmaC-peptide) in fulminant type 1 diabetes at onset, 1 year, and 2 years after onset were markedly lower than those in acute-onset type 1 diabetes. None of the patients with fulminant type 1 diabetes had improvement of C-peptide response to OGTT. Fasting C-peptide values at onset in fulminant type 1 diabetes were significantly lower than those in acute-onset type 1 diabetes. We established diagnostic criteria of serum C-peptide and HbA(1c) levels at onset that discriminate fulminant type 1 diabetes from acute-onset type 1 diabetes with high sensitivity and specificity: a criterion in which the levels of both the fasting C-peptide is <or=0.033 nmol/l and HbA(1c) is <or=8.0% or a criterion in which the levels of both the SigmaC-peptide is <or=0.540 nmol/l and HbA(1c) is <or=8.0%. CONCLUSIONS: Fulminant type 1 diabetes has extremely low beta-cell function at onset that rarely recovers after onset. Sensitive and specific diagnostic criteria were established for detection of fulminant type 1 diabetes based on serum C-peptide and HbA(1c) levels at onset.
Suppression of experimental crescentic glomerulonephritis by peroxisome proliferator-activated receptor (PPAR)gamma activators.
BACKGROUND: It has been recently reported that peroxisome proliferator-activated receptors (PPARs)gamma exist in various tissues and that they exibit anti-inflammatory effects. METHODS: We investigated the effects of PPARgamma activators on the development of crescentic glomerulonephritis. Crescentic glomerulonephritis was induced by the injection of rabbit anti-rat glomerular basement membrane antibody in WKY rats. RESULTS: Administration of troglitazone suppressed urinary protein excretion and crescent formation as indicated by crescent scores. Pioglitazone, a PPARgamma activator, mimicked the effect of troglitazone, but bezafibrate, a PPARalpha-activator, did not. Immunohistology revealed that troglitazone and pioglitazone inhibited the infiltration of ED-1-positive monocyte/macrophages and CD8-positive cells into glomeruli. CONCLUSIONS: In the present study, we demonstrated that PPARgamma activators exert antinephritic effects by suppressing the recruitment of inflammatory cells via a PPARgamma-dependent mechanism.
Activation of peroxisome proliferator-activated receptor-gamma inhibits apoptosis induced by serum deprivation in LLC-PK1 cells.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) belongs to a superfamily of nuclear receptors, which plays important roles in lipid and glucose metabolism. However, expression of PPARgamma in extra-adipose tissues and stimulation of apoptosis by PPARgamma activators has been previously reported. We investigated the functions of PPARgamma using a clonal kidney cell line (LLC-PK1). RT-PCR revealed the expression of PPARgamma in LLC-PK1 cells. The cells accumulated fat droplets and increased beta-oxidation of free fatty acids in response to troglitazone, a ligand for PPARgamma. At physiological concentrations, ligands for PPARgamma including troglitazone, BRL49653, and 15-deoxy-delta-12,14-prostaglandin J(2) inhibited serum-deprivation-induced apoptosis of the cells. On the other hand, PPARalpha activators did not inhibit the apoptosis. Apoptosis of LLC-PK1 cells was determined by a cell viability assay, condensation of the nucleus on fluorescent and electron microscopy, and DNA fragmentation as indicated by the appearance of nucleosomal ladders on an agarose gel. Troglitazone also suppressed serum-deprivation-induced activation of Caspase 3. However, troglitazone did not suppress apoptosis induced by ATP deprivation. Anti-apoptotic effects of troglitazone were partially blocked by a phosphatidylinositol-3-kinase (PI3K) inhibitor, wortmannin, but not by other kinase inhibitors such as PD98059 and AG490. These results suggest that PPARgamma is functionally expressed in LLC-PK1 cells, and its activation inhibits apoptosis induced by serum deprivation, at least in part, through the PI3K pathway.