Abstract only
The amiloride‐sensitive epithelial sodium channels (ENaC) are essential for maintaining sodium homeostasis, transducting mechanical stimuli, and sensing acidosis. The expression of ENaC ...in bone and the correlation of Na content with bone disease have been reported. We thus studied the distribution and regulation of ENaC by cGMP/PKG signal in normal and cGK knockout mouse bone and primary cultured osteoblasts. Our immunostaining and RT‐PCR results showed that three ENaC subunits, namely ,
α
,
β
and
γ
were expressed in osteoblasts of normal mice. Amiloride‐sensitive Na currents were detected in primary osteoblasts clamped in whole‐cell mode. Furthermore, we found that 8‐pCPT‐cGMP (0.2mM, 24hr) stimulated ENaC channel activity in oocytes (P<0.05, n=9). On the other hand, regulation of ENaC expression by cGMP was examined by comparing the protein expression levels of ENaC in normal and cGKII knockout mice. The protein expression levels for ENaC, as measured by densitometry of Western blot strikingly reduced in cGKII knockout mice which are dwarfs (P<0.05, n=3). Similar observations were seen in immunohistochemical images. Our results suggest that regulation of ENaC channel expression and function by cGMP/cGKII signal pathway may be a potential target for developing pharmaceutical intervention for metabolic bone diseases. Supported by HL87017 and National Natural Science Foundation of China 30740085.
Abstract
We compared the prognostic value of nutritional or volumetric parameters measured by body composition in hospitalized patients on maintenance hemodialysis. We conducted a cohort study to ...assess the association of different parameters of body composition with all-cause mortality in inpatients admitted to our nephrology department from January 2014 to December 2016. Of the 704 study patients, 160 (22.7%) died during a median follow-up of 33 months. In multivariate adjusted Cox models, higher ratio of extracellular water to body cell mass (ECW/BCM) (adjusted HR per 1-SD, 1.49; 95% CI, 1.19 to 1.85), lower lean tissue index (LTI) (adjusted HR per 1-SD, 0.70; 95% CI, 0.57 to 0.86) and lower body cell mass index (BCMI) (adjusted HR per 1-SD, 0.70; 95% CI, 0.58 to 0.85) were associated with a significantly greater risk of death. When these parameters were added to the fully adjusted model, BCMI performed best in improving the predictability for all-cause mortality (integrated discrimination improvement = 0.02, P = 0.04; net reclassification index = 0.11, P = 0.04). Among body composition indexes, ECW/BCM was the most relevant fluid volume indices to mortality and BCMI and LTI were the most relevant nutritional status indices to mortality in maintenance hemodialysis patients.
Purpose
Ensartinib is a novel, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK) that has promising clinical activity and low toxicity in patients with ALK-positive non-small ...cell lung cancer. This study was conducted to investigate the pharmacokinetics, metabolism and excretion of ensartinib following a single 200 mg/100 μCi oral dose of radiolabeled ensartinib to healthy subjects.
Methods
Six healthy male subjects were enrolled and administrated an oral suspension in a fasted state. Blood, urine and feces were collected. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of ensartinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and characterization.
Results
The mean total recovery was 101.21% of the radiolabeled dose with 91.00% and 10.21% excreted in feces and urine, respectively. Unchanged ensartinib was the predominant drug-related component in urine and feces, representing 4.39% and 38.12% of the administered dose, respectively. Unchanged ensartinib and its metabolite M465 were the major circulating components, accounting for the same 27.45% of the plasma total radioactivity (AUC
0–24h
pool), while other circulating metabolites were minor, accounting for less than 10%. Mean
C
max
, AUC
0–∞,
T
1/2
and
T
max
values for ensartinib in plasma were 185 ng/mL, 3827 h ng/mL, 18.3 h and 3.25 h, respectively. The total radioactivity in plasma was cleared with terminal half-life of 27.2 h. Treatment with ensartinib was well tolerated, and no serious adverse events were reported.
Conclusion
It was well tolerated in the six healthy male subjects following a single oral administration of 200 mg/100 μCi dose of ensartinib. Besides unchanged ensartinib, metabolite of M465 was the predominant circulating drug-related component. The drug was primarily eliminated in feces.
Clinical trial registration
ClinicalTrials.gov NCT03804541.
The aim of this study is to analyze the association between the ratio of overhydration and extracellular water (OH/ECW) and the ratio of extracellular water and body cell mass (ECW/BCM) measured by ...bioelectrical impedance and outcomes of patients with acute kidney injury (AKI) requiring kidney replacement therapy (KRT).
Patients with severe AKI treated with KRT in our hospital between September 2016 and August 2018 were enrolled. These patients were assessed using a body composition monitor before KRT, and on the 3rd day and the 7th day after initiation of KRT. The predictors mainly included OH/ECW and ECW/BCM. The association between all-cause mortality and predictors were analyzed using Cox regression.
A total of 152 patients were included in this study with a median follow-up of 39 (interquartile range 8-742) days. The 28-day mortality, 90-day mortality, and 1-year mortality were 46.7%, 54.6%, and 60.5%, respectively. A high ratio of OH/ECW (adjusted hazard ratio per standard deviation, 1.45; 95% confidence interval = 1.15-1.82, P = .002) and a high ratio of ECW/BCM (adjusted hazard ratio per standard deviation, 1.33, 95% confidence interval = 1.07-1.64, P = .009) before KRT were associated with all-cause mortality during follow-up. Higher ECW/BCM rather than OH/ECW at 7th day was associated with poorer outcomes. Furthermore, a reduction of OH/ECW with an increase of ECW/BCM had higher 1-year mortality as compared to others (85.7% vs. 51.2%, P = .004) in patients who survived 7 days after KRT initiation.
ECW/BCM performed better than OH/ECW in assessment of fluid status in AKI patients requiring KRT. This study suggested that a simple reduction of OH/ECW without decreasing ECW/BCM may not improve outcomes.
The aim of this study is to investigate the association between body composition, measured by bioelectrical impedance analysis, and outcomes in patients with acute kidney injury (AKI) receiving ...kidney replacement therapy (KRT).
Patients with severe AKI treated with KRT in our hospital between September 2016 and August 2018 were enrolled. These patients were assessed by body composition analysis before KRT, and on the 3rd day and the 7th day after initiation of KRT. The predictors included lean tissue index (LTI), fat tissue index, and body cell mass index (BCMI). The association between all-cause mortality and predictors was analyzed using Cox regression.
A total of 152 patients were included in this study, with a 28-day mortality of 46.7% and 1-year mortality of 60.5%. LTI (adjusted hazard ratio per standard deviation: 0.37; 95% confidence interval = 0.21-0.66, P < .001) and BCMI (adjusted hazard ratio per standard deviation: 0.37; 95% confidence interval = 0.21-0.67, P < .001) on day 7 after initiation of KRT, rather than before KRT, were associated with mortality during follow-up. LTI and BCMI before KRT were associated with 28-day mortality rather than 1-year mortality.
LTI and BCMI before KRT were associated with short-term prognosis, and those on day 7 after KRT initiation were associated with intermediate mortality in patients with AKI requiring KRT.
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