Background: Although attention has recently focused on electrolyte-free water clearance (E-CH2O) as a replacement for solute-free water clearance (CH2O), especially from the viewpoint of plasma sodium regulation, a thorough comparison of the two has yet to be conducted. Methods: CH2O and E-CH2O were systematically compared in normal subjects in different diuretic stages, including furosemide-induced solute diuresis, and in patients with renal disease. Results: The normal renal ability to conserve free water based on E-CH2O was only 41% of that based on CH2O. E-CH2O remained positive until the urinary osmolality exceeded 500 mosm/kg H2O, markedly different from the 300 mosm/kg H2O for CH2O. The difference between E-CH2O and CH2O could ultimately be attributed to urea osmolar clearance, i.e., urea excretion rate/plasma osmolality, which accounted for about 40% of the osmolar clearance. CH2O underestimated the free water clearance by about 1 ml/min on average at all diuretic stages. Conclusions: E-CH2O is a more correct parameter than CH2O with regard to the regulation of both plasma sodium and plasma osmolality. However, there is the opinion that the concept of E-CH2O is difficult to understand and that E-CH2O is still not a generally accepted parameter. It is expected that the results of the present study will lead to more general acceptance.
Myostatin, a member of the transforming growth factor-β superfamily, is an attractive target for muscle disease therapy because of its role as a negative regulator of muscle growth and strength. Here, we describe a novel antibody therapeutic approach that maximizes the potential of myostatin-targeted therapy. We generated an antibody, GYM329, that specifically binds the latent form of myostatin and inhibits its activation. Additionally, via “sweeping antibody technology”, GYM329 reduces or “sweeps” myostatin in the muscle and plasma. Compared with conventional anti-myostatin agents, GYM329 and its surrogate antibody exhibit superior muscle strength-improvement effects in three different mouse disease models. We also demonstrate that the superior efficacy of GYM329 is due to its myostatin specificity and sweeping capability. Furthermore, we show that a GYM329 surrogate increases muscle mass in normal cynomolgus monkeys without any obvious toxicity. Our findings indicate the potential of GYM329 to improve muscle strength in patients with muscular disorders.
Ion channels in the apical membrane of rat inner medullary collecting duct (IMCD) were investigated by the patch clamp technique. Owing to the histological heterogeneity of IMCD, cells were cultured from the lower half of the inner medulla of Wistar rat kidney. Channel activity was rarely seen in cell attached patch, but membrane excision activated multiple units of 28.2 +/- 0.7 pS cation selective channel. A Na or K selective channel was not found. The 28 pS channel showed membrane voltage dependency, no rectification, almost equal permeability to monovalent cations (Na/K/Li/Cs/Rb/NH4 = 1:1.00:0.82:0.97:1.10:1.71) and no significant permeation to anions or divalent cations. Calcium of the cytoplasmic side from 10(-7) M to 10(-4) M affected the mean number of open channels (nPo) dose-dependently in excised patch (IC50 = 5 x 10(-6) M). 1 mM of ATP, ADP, AMP and gadolinium reversibly suppressed nPo to near zero whereas amiloride, cAMP or cGMP had no effect. Multiple conductance substates were frequently observed. These results suggested that this channel belongs to the nonselective cation channels which has been identified in other epithelia and is not responsible for amiloride sensitive Na transport through IMCD cells.
Shigella flexneri, but not a non-invasive mutant derivative, rapidly induced cell death in human monoblastic U937 cells as well as in differentiated cells pretreated with interferon-Q (IFNQ) or retinoic acid (RA). We investigated the morphological and biochemical characteristics of bacterial invasion-induced cell death in these differentiated U937 cells. IFNQ-differentiated cells showed morphological changes typical of apoptosis and their DNA was cleaved giving a ladder-like electrophoretic pattern after infection by Shigellae. In contrast, swelling of the cytoplasm and blebbing of the plasma membrane were observed in RAdifferentiated and undifferentiated cells invaded by the bacteria. No condensation of nuclei was observed in these cells by light microscopy, and no internucleosomal fragmentation of DNA was detected on agarose gels, which resembled the features of oncosis. Furthermore, cleavage of poly(ADP-ribose) polymerase, a substrate for apoptotic caspases, was seen only in IFNQpretreated cells but not in RA-pretreated or undifferentiated cells. These findings suggested that virulent Shigella flexneri induces distinct types of cell death in U937 cells depending on their differentiation state. z
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