Serum magnesium and sudden death in European hemodialysis patients

Despite suggestions that higher serum magnesium (Mg) levels are associated with improved outcome, the association with mortality in European hemodialysis (HD) patients has only scarcely been investigated. Furthermore, data on the association between serum Mg and sudden death in this patient group is limited. Therefore, we evaluated Mg in a posthoc analysis using pooled data from the CONvective TRAnsport STudy (CONTRAST, NCT00205556), a randomized controlled trial (RCT) evaluating the survival risk in dialysis patients on hemodiafiltration (HDF) compared to HD with a mean follow-up of 3.1 years. Serum Mg was measured at baseline and 6, 12, 24 and 36 months thereafter. Cox proportional hazards models, adjusted for confounders using inverse probability weighting, were used to estimate hazard ratios (HRs) of baseline serum Mg on all-cause mortality, cardiovascular mortality, non-cardiovascular mortality and sudden death. A generalized linear mixed model was used to investigate Mg levels over time. Out of 714 randomized patients, a representative subset of 365 (51%) were analyzed in the present study. For every increase in baseline serum Mg of 0.1 mmol/L, the HR for all-cause mortality was 0.85 (95% CI 0.77-94), the HR for cardiovascular mortality 0.73 (95% CI 0.62-0.85) and for sudden death 0.76 (95% CI 0.62-0.93). These findings did not alter after extensive correction for potential confounders, including treatment modality. Importantly, no interaction was found between serum phosphate and serum Mg. Baseline serum Mg was not related to non-cardiovascular mortality. Mg decreased slightly but statistically significant over time (Ä -0.011 mmol/L/year, 95% CI -0.017 to -0.009, p = 0.03). In short, serum Mg has a strong, independent association with all-cause mortality, cardiovascular mortality and sudden death in European HD patients. Serum Mg levels decrease slightly over time

Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases

Artificial endonucleases consisting of a Fokl cleavage domain tethered to engineered zinc-finger DNA-binding proteins have proven useful for stimulating homologous recombination in a variety of cell types. Because the catalytic domain of zinc-finger nucleases (ZFNs) must dimerize to become active, two subunits are typically assembled as heterodimers at the cleavage site. The use of ZFNs is often associated with significant cytotoxicity, presumably due to cleavage at off- target sites. Here we describe a structure- based approach to reducing off- target cleavage. Using in silico protein modeling and energy calculations, we increased the specificity of target site cleavage by preventing homodimerization and lowering the dimerization energy. Cell-based recombination assays confirmed that the modified ZFNs were as active as the original ZFNs but elicit significantly less genotoxicity. The improved safety profile may facilitate therapeutic application of the ZFN technology

Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases

Artificial endonucleases consisting of a Fokl cleavage domain tethered to engineered zinc-finger DNA-binding proteins have proven useful for stimulating homologous recombination in a variety of cell types. Because the catalytic domain of zinc-finger nucleases (ZFNs) must dimerize to become active, two subunits are typically assembled as heterodimers at the cleavage site. The use of ZFNs is often associated with significant cytotoxicity, presumably due to cleavage at off- target sites. Here we describe a structure- based approach to reducing off- target cleavage. Using in silico protein modeling and energy calculations, we increased the specificity of target site cleavage by preventing homodimerization and lowering the dimerization energy. Cell-based recombination assays confirmed that the modified ZFNs were as active as the original ZFNs but elicit significantly less genotoxicity. The improved safety profile may facilitate therapeutic application of the ZFN technology

Urinary phosphorus levels in 5/6^th nephrectomized rats on a normal (NP) or high phosphorus (HP) diet treated with either vehicle (veh), 185 or 375 mg/kg/day CaMg.

<p>*: p<0.05 vs NP, same dose; #: p<0.05 vs vehicle, same diet; °: p<0.05 vs week −4, same diet and dose.</p

Static and dynamic bone parameters of 5/6^th nephrectomized rats on a normal (NP) or high phosphorus (HP) diet treated with either vehicle (veh), 185 or 375 mg/kg/day CaMg.

<p>*: p<0.05 vs. NP, same dose.</p

Calcium and magnesium content in the tibia of 5/6^th nephrectomized rats on a normal (NP) or high phosphorus (HP) diet treated with either vehicle (veh), 185 or 375 mg/kg/day CaMg.

<p>Calcium and magnesium content in the tibia of 5/6^th nephrectomized rats on a normal (NP) or high phosphorus (HP) diet treated with either vehicle (veh), 185 or 375 mg/kg/day CaMg.</p

Setup of the study addressing the effect of calcium acetate/magnesium carbonate (CaMg) on bone.

<p>The three groups presented in the clear bars received a normal phosphorus diet; those presented in the hatched bars received a high phoshorus diet. Nx: 5/6^th nephrectomy.</p

Aortic calcification in vehicle versus 185 mg/kg CaMg treated chronic renal failure (CRF) rats.

<p>*: p<0.05 vs. CRF + vehicle.</p

Serum biochemistry of vehicle versus 185 mg/kg CaMg treated adenine-induced CRF rats.

<p>*: p<0.05 vs. vehicle treated CRF rats, same time point.</p><p>°: p<0.05 vs. week 0, same treatment group.</p><p>Serum biochemistry of vehicle versus 185 mg/kg CaMg treated adenine-induced CRF rats.</p

Urine biochemistry over time of 5/6^th nephrectomized rats receiving normal phosphorus (NP) or high phosphorus (HP) diet, in combination with vehicle (Veh), 185 or 375 mg/kg CaMg.

<p>*: p<0.05 vs NP, same dose.</p><p>°: p<0.05 vs week −4, same diet and dose.</p><p>Urine biochemistry over time of 5/6^th nephrectomized rats receiving normal phosphorus (NP) or high phosphorus (HP) diet, in combination with vehicle (Veh), 185 or 375 mg/kg CaMg.</p