Parathyroid Diseases and Animal Models

Circulating calcium and phosphate are tightly regulated by three hormones: the active form of vitamin D (1,25-dihydroxyvitamin D), fibroblast growth factor (FGF)-23, and parathyroid hormone (PTH). PTH acts to stimulate a rapid increment in serum calcium and has a crucial role in calcium homeostasis. Major target organs of PTH are kidney and bone. The oversecretion of the hormone results in hypercalcemia, caused by increased intestinal calcium absorption, reduced renal calcium clearance, and mobilization of calcium from bone in primary hyperparathyroidism. In chronic kidney disease, secondary hyperparathyroidism of uremia is observed in its early stages, and this finally develops into the autonomous secretion of PTH during maintenance hemodialysis. Receptors in parathyroid cells, such as the calcium-sensing receptor, vitamin D receptor, and FGF receptor (FGFR)-Klotho complex have crucial roles in the regulation of PTH secretion. Genes such as Cyclin D1, RET, MEN1, HRPT2, and CDKN1B have been identified in parathyroid diseases. Genetically engineered animals with these receptors and the associated genes have provided us with valuable information on the patho-physiology of parathyroid diseases. The application of these animal models is significant for the development of new therapies

Geriatric Nutritional Risk Index (GNRI) and Creatinine Index Equally Predict the Risk of Mortality in Hemodialysis Patients: J-DOPPS

The geriatric nutritional risk index (GNRI) and creatinine (Cr) index are indexes often used as nutritional surrogates in patients receiving hemodialysis. However, few studies have directly compared the clinical characteristics of these two indexes. We investigated 3, 536 hemodialysis patients enrolled in the Japan DOPPS phases 4 and 5. The primary outcome was all-cause mortality and the main exposures were the GNRI and Cr index. We confirmed and compared the association between these indexes and mortality risk as estimated by a multivariable-adjusted Cox proportional hazards model. During the median 2.2-year follow-up period, 414 patients died of any cause. In the multivariable-adjusted model, lower GNRI and Cr index were both associated with increased risk of all-cause mortality, and these associations were further confirmed by restricted cubic spline curves. The predictability of all-cause mortality, as represented by the c-statistic, was comparable between the two indexes. Furthermore, baseline nutritional surrogates that corresponded with lower GNRI or Cr index values were comparable between the two indexes. Given that calculating the GNRI is simpler than calculating the Cr index, our data suggest that the GNRI may be preferable to the Cr index for predicting clinical outcomes in patients undergoing maintenance hemodialysis

Phosphorus intake regulates intestinal function and polyamine metabolism in uremia

Phosphorus intake regulates intestinal function and polyamine metabolism in uremia. This study found that 5/6-nephrectomized uremic rats showed secondary hyperparathyroidism as reflected by an increase in their serum parathyroid hormone (PTH) level in association with a decrease in serum 1,25-dihydroxyvitamin D [1,25-(OH)2D]. These changes recovered partially upon phosphorus restriction. Calcium absorption and gene expression of calbindin-D9k were decreased in uremia and were also improved by phosphorus restriction. In uremia, intestinal spermidine/spermine N1-acetyl-transferase activity was decreased, while ornithine decarboxylase (ODC) activity and its gene expression were potentiated. Enhancement of c-fos and c-jun gene expressions was also observed in uremia. These phenomena suggest that the intestinal villus may proliferate in uremia. Phosphorus restriction prevented increases in the expression of ODC, c-fos and c-jun observed in uremia. Since phosphorus restriction caused a rise in the serum 1,25-(OH)2D level, the role of 1,25-(OH)2D in uremia-induced intestinal dysfunction was examined. A single injection of 1,25-(OH)2D3 to uremic rats caused an increase in the steady-state calbindin-D9k mRNA level, and decreases in steady state c-fos and ODC mRNA levels, suggesting that the deficiency of 1,25-(OH)2D3 is responsible for intestinal dysfunction in uremia. In conclusion, altered polyamine metabolism caused by 1,25-(OH)2D deficiency is intimately involved in intestinal dysfunction and the development of the proliferative state of the intestinal villus in uremia

Targeted Proteomics of Isolated Glomeruli from the Kidneys of Diabetic Rats: Sorbin and SH3 Domain Containing 2 Is a Novel Protein Associated with Diabetic Nephropathy

To evaluate proteins associated with the development of diabetic nephropathy, a major cause of the end-stage renal disease, we analyzed protein expression in isolated glomeruli from spontaneous type 2 diabetic (OLETF) rats and their age-matched control littermates (LETO) in the early and proteinuric stages of diabetic nephropathy using QSTAR Elite LC-MS/MS. Among the 191 and 218 proteins that were altered significantly in the OLETF rats, twenty-four were actin cytoskeleton-associated proteins implicated in the formation of stress fibers, and the impairment of actin polymerization, intermediate filaments and microtubules. Importantly, sorbin and SH3 domain containing 2 (SORBS2), which is involved in the formation of stress fibers, was significantly upregulated in both stages of diabetic nephropathy (1.49- and 1.97-fold, resp.). Immunohistochemical and quantitative-PCR analyses revealed upregulation of SORBS2 in podocytes of glomeruli of OLETF rats. Our findings suggested that SORBS2 may be associated with the development of diabetic nephropathy possibility by reorganization of actin filaments

Factors associated with quality of bystander CPR: The presence of multiple rescuers and bystander-initiated CPR without instruction

Aims: To identify the factors associated with good-quality bystander cardiopulmonary resuscitation (BCPR). Methods: Data were prospectively collected from 553 out-of-hospital cardiac arrests (OHCAs) managed with BCPR in the absence of emergency medical technicians (EMT) during 2012. The quality of BCPR was evaluated by EMTs at the scene and was assessed according to the standard recommendations for chest compressions, including proper hand positions, rates and depths. Results: Good-quality BCPR was more frequently confirmed in OHCAs that occurred in the central/urban region (56.3% [251/446] vs. 39.3% [42/107], p= 0.0015), had multiple rescuers (31.8% [142/446] vs. 11.2% [12/107], p< 0.0001) and received bystander-initiated BCPR (22.0% [98/446] vs. 5.6% [6/107], p< 0.0001). Good-quality BCPR was less frequently performed by family members (46.9% [209/446] vs. 67.3% [72/107], p= 0.0001), elderly bystanders (13.5% [60/446] vs. 28.0% [30/107], p= 0.0005) and in at-home OHCAs (51.1% [228/446] vs. 72.9% [78/107], p< 0.0001). BCPR duration was significantly longer in the good-quality group (median, 8 vs. 6. min, p= 0.0015). Multiple logistic regression analysis indicated that multiple rescuers (odds ratio. = 2.8, 95% CI 1.5-5.6), bystander-initiated BCPR (2.7, 1.1-7.3), non-elderly bystanders (1.9, 1.1-3.2), occurrence in the central region (2.1, 1.3-3.3) and duration of BCPR (1.1, 1.0-1.1) were associated with good-quality BCPR. Moreover, good-quality BCPR was initiated earlier after recognition/witness of cardiac arrest compared with poor-quality BCPR (3 vs. 4. min, p= 0.0052). The rate of neurologically favourable survival at one year was 2.7 and 0% in the good-quality and poor-quality groups, respectively (p= 0.1357). Conclusions: The presence of multiple rescuers and bystander-initiated CPR are predominantly associated with good-quality BCPR. © 2013 Elsevier Ireland Ltd

Enhanced Urinary Bladder, Liver and Colon Carcinogenesis in Zucker Diabetic Fatty Rats in a Multiorgan Carcinogenesis Bioassay: Evidence for Mechanisms Involving Activation of PI3K Signaling and Impairment of p53 on Urinary Bladder Carcinogenesis

In the present study, modifying effects of diabetes on carcinogenesis induced in type 2 diabetes mellitus model Zucker diabetic fatty (ZDF) rats were investigated using a multiorgan carcinogenesis bioassay. Our re sults demonstrated enhancement of urinary bladder, colon and liver carcinogenesis in ZDF rats treated with five types of carcinogens (DMBDD). Elevated insulin and leptin and decreased adiponectin levels in the serum may be responsible for the high susceptibility of type 2 diabetes mellitus model rats to carcinogenesis in these organs. Possible mechanisms of increased susceptibility of diabetic rats to bladder carcinogenesis could be activation of the PI3K pathway and suppression of p53 in the urothelium in consequence of the above serum protein alterations