Cardiovascular remodeling during long-term nocturnal home hemodialysis.

BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality in patients with kidney failure. Nocturnal home hemodialysis (NHD) is a form of kidney replacement therapy whereby hemodialysis is performed for at least 6-h overnight, at least 4 days per week. Little is known about the effects of NHD on cardiovascular remodeling as assessed by transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR). OBJECTIVES: The primary objective of the study was to determine the long-term effects of NHD on cardiovascular remodeling using different imaging modalities over a one-year follow-up. METHODS AND RESULTS: A total of 11 patients were included in the study (6 males, mean age 48 ± 16 years) between 2009 and 2011 inclusive at a single tertiary care center. All patients underwent TTE and CMR at baseline and after 1 year of NHD. Left ventricular mass index decreased significantly at 1 year by both TTE (152 ± 7-129 ± 8 g/m(2), p < 0.05) and CMR (162 ± 4-124 ± 4 g/m(2), p < 0.05). There was also a significant decrease in both left and right atrial volume as well as in right ventricular mass index over 1 year of follow-up. Diastolic dysfunction, graded from 0 to 4, improved from a baseline grade of 3.4 to 1.2 at 1-year follow-up. CONCLUSIONS: Long-term nocturnal hemodialysis leads to favorable cardiovascular remodeling with a reduction in cavity dimensions, regression of left ventricular hypertrophy, and an improvement in diastolic function, as assessed by both TTE and CMR.

The over-expression of TRPC6 channels in HEK-293 cells favours the intracellular accumulation of zinc.

TRPC6 are plasma membrane cation channels. By means of live-cell imaging and spectroscopic methods, we found that HEK cells expressing TRPC6 channels (HEK-TRPC6) are enriched in zinc and sulphur and have a reduced copper content when compared to HEK cells and HEK cells expressing TRPC3 channels (HEK-TRPC3). Hence, HEK-TRPC6 cells have larger pools of mobilizable Zn2+ and are more sensitive to an oxidative stress. Synchrotron X-ray fluorescence experiments showed a higher zinc content in the nuclear region indicating that the intracellular distribution of this metal was influenced by the over-expression of TRPC6 channels. Their properties were investigated with the diacylglycerol analogue SAG and the plant extract hyperforin. Electrophysiological recordings and imaging experiments with the fluorescent Zn2+ probe FluoZin-3 demonstrated that TRPC6 channels form Zn2+-conducting channels. In cortical neurons, hyperforin-sensitive channels co-exist with voltage-gated channels, AMPA and NMDA receptors, which are known to transport Zn2+. The ability of these channels to regulate the size of the mobilizable pools of Zn2+ was compared. The data collected indicate that the entry of Zn2+ through TRPC6 channels can up-regulate the size of the DTDP-sensitive pool of Zn2+. By showing that TRPC6 channels constitute a Zn2+ entry pathway, our study suggests that they could play a role in zinc homeostasis.

Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression.

BACKGROUND: The anaplastic lymphoma kinase (ALK) gene is frequently involved in translocations that lead to gene fusions in a variety of human malignancies, including lymphoma and lung cancer. Fusion partners of ALK include NPM, EML4, TPM3, ATIC, TFG, CARS, and CLTC. Characterization of ALK fusion patterns and their resulting clinicopathological profiles could be of great benefit in better understanding the biology of lung cancer. RESULTS: RACE-coupled PCR sequencing was used to assess ALK fusions in a cohort of 103 non-small cell lung carcinoma (NSCLC) patients. Within this cohort, the EML4-ALK fusion gene was identified in 12 tumors (11.6%). Further analysis revealed that EML4-ALK was present at a frequency of 16.13% (10/62) in patients with adenocarcinomas, 19.23% (10/52) in never-smokers, and 42.80% (9/21) in patients with adenocarcinomas lacking EGFR and KRAS mutations. The EML4-ALK fusion was associated with non-smokers (P = 0.03), younger age of onset (P = 0.03), and adenocarcinomas without EGFR/KRAS mutations (P = 0.04). A trend towards improved survival was observed for patients with the EML4-ALK fusion, although it was not statistically significant (P = 0.20). Concurrent deletion in EGFR exon 19 and fusion of EML4-ALK was identified for the first time in a Chinese female patient with an adenocarcinoma. Analysis of ALK expression revealed that ALK mRNA levels were higher in tumors positive for the EML-ALK fusion than in negative tumors (normalized intensity of 21.99 vs. 0.45, respectively; P = 0.0018). However, expression of EML4 did not differ between the groups. CONCLUSIONS: The EML4-ALK fusion gene was present at a high frequency in Chinese NSCLC patients, particularly in those with adenocarcinomas lacking EGFR/KRAS mutations. The EML4-ALK fusion appears to be tightly associated with ALK mRNA expression levels. RACE-coupled PCR sequencing is a highly sensitive method that could be used clinically for the identification of EML4-ALK-positive patients.