ABSTRACT
In June 2003, sevelamer hydrochloride became widely available in Japan and was expected to control hyperphosphatemia in hemodialysis patients without inducing hypercalcemia. To evaluate the impact of sevelamer therapy on mineral metabolism, we recruited 954 hemodialysis patients from 21 renal units just before the general release of sevelamer in Japan. The serum calcium, phosphate, and parathyroid hormone levels determined on enrollment were compared with those later measured in June 2004. Sevelamer was prescribed for 169 of the 859 patients for whom data were available in 2004. The mean calcium level, phosphate level, and calcium x phosphate product were all significantly reduced during the 12-month study period, but the intact parathyroid hormone (iPTH) level did not change. As a result, the percentage of patients who achieved a calcium x phosphate product of <55 mg(2)/dL(2) was significantly increased, but there were no changes in that of patients who achieved the target ranges for phosphate (3.5-5.5 mg/dL) or iPTH (150-300 pg/mL). Among sevelamer-treated patients, iPTH significantly increased, and this change was more marked in the patients with an initial iPTH level <150 pg/mL. Sevelamer was useful for reducing the serum calcium level and calcium x phosphate product, but hyperphosphatemia and hyperparathyroidism were not improved in our study population at 12 months after the release of sevelamer. A decrease in the calcium load might result in the exacerbation of hyperparathyroidism. However, among patients with relative hypoparathyroidism, sevelamer therapy may be beneficial for the prevention of adynamic bone disease.
Subject(s)
Chelating Agents/therapeutic use , Hyperparathyroidism, Secondary/drug therapy , Hyperparathyroidism, Secondary/prevention & control , Polyamines/therapeutic use , Renal Dialysis , Adolescent , Adult , Aged , Aged, 80 and over , Calcium/blood , Female , Humans , Japan , Male , Middle Aged , Parathyroid Hormone/blood , Phosphorus/blood , Prospective Studies , SevelamerABSTRACT
AIM: To investigate c-met expression during early pancreatic carcinogenesis. METHODS: We used 46 bulk tissues and 36 micro-dissected samples, including normal pancreas, chronic pancreatitis, and pancreatic cancer, for quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: In bulk tissue analyses, pancreatic cancer tissues expressed significantly higher levels of c-met than did chronic pancreatitis and normal pancreas tissues. c-met levels did not differ between chronic pancreatitis and normal pancreas tissues. In microdissection-based analyses, c-met was expressed at higher levels in microdissected pancreatic cancer cells and pancreatitis-affected epithelial cells than in normal ductal epithelial cells (both, P < 0.01). Interestingly, pancreatitis-affected epithelial cells expressed levels of c-met similar to those of pancreatic cancer cells. CONCLUSION: Overexpression of c-met occurs during the early stage of pancreatic carcinogenesis, and a single alteration of c-met expression is not sufficient for progression of chronic pancreatitis-affected epithelial cells to pancreatic cancer cells.
Subject(s)
Pancreatic Neoplasms/genetics , Pancreatitis, Chronic/genetics , Precancerous Conditions/genetics , Proto-Oncogene Proteins c-met/metabolism , Biomarkers, Tumor/analysis , Cell Line, Tumor , Cell Transformation, Neoplastic , Cells, Cultured , DNA, Neoplasm/analysis , DNA, Neoplasm/genetics , Disease Progression , Epithelial Cells/chemistry , Epithelial Cells/cytology , Epithelial Cells/pathology , Fibroblasts/chemistry , Fibroblasts/cytology , Fibroblasts/pathology , Gene Expression Regulation, Neoplastic , Humans , Pancreatic Neoplasms/chemistry , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/physiopathology , Pancreatitis, Chronic/pathology , Pancreatitis, Chronic/physiopathology , Precancerous Conditions/chemistry , Precancerous Conditions/pathology , Precancerous Conditions/physiopathology , RNA, Messenger/analysis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Advanced glycation end products (AGEs) appear to contribute to the diabetic complications. This study reports the inhibitory effect of OPB-9195 (OPB), an inhibitor of AGEs formation, and the role of a collagen-specific molecular chaperone, a 47-kDa heat shock protein (HSP47) in diabetic nephropathy. Transgenic mice carrying nitric-oxide synthase cDNA fused with insulin promoter (iNOSTg) leads to diabetes mellitus. The iNOSTg mice at 6 months of age represented diffuse glomerulosclerosis, and the expression of HSP47 was markedly increased in the mesangial area in parallel with increased expression of types I and IV collagens. OPB treatment ameliorated glomerulosclerosis in the iNOSTg mice associated with the decreased expression of HSP47 and types I and IV collagens. The expression of transforming growth factor-beta (TGF-beta) was increased in glomeruli of iNOSTg mice and decreased after treatment with OPB. To confirm these mechanisms, cultured mesangial cells were stimulated with AGEs. AGEs significantly increased the expression of HSP47, type IV collagen, and TGF-beta mRNA. Neutralizing antibody for TGF-beta inhibited the overexpression of both HSP47 and type IV collagen in vitro. In conclusion, AGEs increase the expression of HSP47 in association with collagens, both in vivo and in vitro. The processes may be mediated by TGF-beta.