The role of remote ischemic preconditioning in organ protection after cardiac surgery: a meta-analysis

Background

Remote ischemic preconditioning (RIPC) appears to protect distant organs from ischemia–reperfusion injury. We undertook meta-analysis of clinical studies to evaluate the effects of RIPC on organ protection and clinical outcomes in patients undergoing cardiac surgery.

Methods

A review of evidence for cardiac, renal, and pulmonary protection after RIPC was performed. We also did meta-regressions on RIPC variables, such as duration of ischemia, cuff pressure, and timing of application of preconditioning. Secondary outcomes included length of hospital and intensive care unit stay, duration of mechanical ventilation, and mortality at 30 days.

Results

Randomized control trials (n = 25) were included in the study for quantitative analysis of cardiac (n = 16), renal (n = 6), and pulmonary (n = 3) protection. RIPC provided statistically significant cardiac protection (standardized mean difference [SMD], −0.77; 95% confidence interval [CI], −1.15, −0.39; Z = 3.98; P < 0.0001) and on subgroup analysis, the protective effect remained consistent for all types of cardiac surgical procedures. However, there was no evidence of renal protection (SMD, 0.74; 95% CI, 0.53, 1.02; Z = 1.81; P = 0.07) or pulmonary protection (SMD, −0.03; 95% CI, −0.56, 0.50; Z = 0.12; P = 0.91). There was no statistical difference in the short-term clinical outcomes between the RIPC and control groups.

Conclusions

RIPC provides cardiac protection, but there is no evidence of renal or pulmonary protection in patients undergoing cardiac surgery using cardiopulmonary bypass. Larger multicenter trials are required to define the role of RIPC in surgical practice.     

Serum gamma glutamyl-transferase is a sensitive but unspecific marker of metastatic renal cell carcinoma

OBJECTIVE: To address the role of serum gamma-glutamyl transferase (GGT) as a marker of metastases in patients with renal cell carcinoma. METHODS: Serum alkaline phosphatase and GGT were determined in 156 patients with localized renal cell carcinoma and 60 patients with metastases as proven by echosonography, computerized tomography and bone scan. The control group consisted of 50 healthy subjects matched for sex and age. Sensitivity and specificity of both enzymes as markers of metastatic disease were compared. In metastatic patients, enzyme activities were analyzed according to the site of metastases. RESULTS: Both alkaline phosphatase and GGT activities were normal in majority of patients with localized renal cell carcinoma and increased in most of the patients with metastatic disease (80% and 70%, respectively). GGT did not significantly differ from alkaline phosphatase in terms of sensitivity (70% vs 80%) and specificity (89% vs 92%). Concerning the site of metastases, high frequencies of increased GGT and alkaline phosphatase were found in patients with liver-only metastases (80% and 90%, respectively). All of the patients with both liver and bone metastases exhibited increased activity of both enzymes. Despite the fact that bone cells do not express GGT, increased activity was found in patients with bone metastases-only (45%), suggesting that enzymes might be released from tumor cells. CONCLUSIONS: Our data provided evidence that GGT is a sensitive marker of metastatic renal cell carcinoma. However, findings of abnormal GGT activity cannot specify the site of involvement.     

Frequency of the C1236T, G2677T/A and C3435T MDR1 gene polymorphisms in the Serbian population

The multi-drug resistance 1 (MDR1) gene encodes for a P-glycoprotein (PGP), which acts as a gate-keeper against various kinds of xenobiotics. Several single nucleotide polymorphisms (SNPs) in the MDR1 gene that may influence PGP level and function have been identified. The aim of this study was to simultaneously analyze the three most important MDR1 SNPs, C3435T, G2677T/A and C1236T, in the Serbian population and to compare the results with those published for other ethnic groups. A group of 158 unrelated, healthy subjects was included in the present study. For determination of MDR1 SNPs, a multiplexed mutagenically separated PCR was performed. The genotype frequency of the analyzed MDR1 SNPs was as follows: 3435 nt - 0.19 (CC), 0.54 (CT) and 0.27 (TT); 2677 nt - 0.26 (GG), 0.52 (GT), 0.15 (TT), 0.03 (GA) and 0.064 (TA), and 1236 nt - 0.23 (CC), 0.61 (CT) and 0.16 (TT). Our results for the Serbian population could be relevant for further investigation of drugs that are substrates of PGPand for studies of interethnic diversity in MDR1 polymorphism frequency.     

Paraoxonase-1 (PON1) activity, but not PON1(Q192R) phenotype, is a predictor of coronary artery disease in a middle-aged Serbian population.

BACKGROUND: Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated serum enzyme that protects lipoproteins from oxidative modifications. Polymorphisms in the gene, including PON1Q192R, have been studied. However, inconsistencies regarding the above-mentioned polymorphism obscure its association with vascular disease. METHODS: Using a two-substrate (paraoxon/diazoxon) activity method, we investigated the frequencies of PON1Q192R phenotypes in 261 middle-aged subjects: 156 patients with angiographically assessed coronary heart disease (CHD) and 105 CHD-free subjects as the control group. The PON1(192) phenotype was predicted from examination of the two-dimensional plot of hydrolysis rates of diazoxon vs. paraoxon and by using the antimode of the histogram of the ratio of diazoxonase/paraoxonase activity. RESULTS: The PON1Q192R phenotype frequencies in 113 patients with occlusion >50% (coronary artery disease-positive, CAD+ group) vs. control population were as follows: QQ (0.552 vs. 0.510), QR (0.382 vs. 0.408) and RR (0.066 vs. 0.082); chi2=0.414, p=0.813. We found lower paraoxonase (POase) and diazoxonase (DZOase) activities in the CAD+ patients when compared to the control population. According to logistic regression analysis, POase activity was a better predictor of coronary disease onset compared with DZOase activity measurements and PON1Q192R phenotyping. CONCLUSIONS: We conclude that enzyme activity (within a particular phenotypic group) is more important than phenotype alone in predicting susceptibility to coronary artery disease.     

Expression of familial Alzheimer disease presenilin 1 gene attenuates vesicle traffic and reduces peptide secretion in cultured astrocytes devoid of pathologic tissue environment

In the brain, astrocytes provide metabolic and trophic support to neurones. Failure in executing astroglial homeostatic functions may contribute to the initiation and propagation of diseases, including Alzheimer disease (AD), characterized by a progressive loss of neurones over years. Here, we examined whether astrocytes from a mice model of AD isolated in the presymptomatic phase of the disease exhibit alterations in vesicle traffic, vesicular peptide release and purinergic calcium signaling. In cultured astrocytes isolated from a newborn wild‐type (wt) and 3xTg‐AD mouse, secretory vesicles and acidic endosomes/lysosomes were labeled by transfection with plasmid encoding atrial natriuretic peptide tagged with mutant green fluorescent protein (ANP.emd) and by LysoTracker, respectively. The intracellular Ca²⁺ concentration ([Ca²⁺]_i) was monitored with Fluo‐2 and visualized by confocal microscopy. In comparison with controls, spontaneous mobility of ANP‐ and LysoTracker‐labeled vesicles was diminished in 3xTg‐AD astrocytes; the track length (TL), maximal displacement (MD) and directionality index (DI) were all reduced in peptidergic vesicles and in endosomes/lysosomes (P < 0.001), as was the ATP‐evoked attenuation of vesicle mobility. Similar impairment of peptidergic vesicle trafficking was observed in wt rat astrocytes transfected to express mutated presenilin 1 (PS1_M146V). The ATP‐evoked ANP discharge from single vesicles was less efficient in 3xTg‐AD and PS1_M146V‐expressing astrocytes than in respective wt controls (P < 0.05). Purinergic stimulation evoked biphasic and oscillatory [Ca²⁺]_i responses; the latter were less frequent (P < 0.001) in 3xTg‐AD astrocytes. Expression of PS1_M146V in astrocytes impairs vesicle dynamics and reduces evoked secretion of the signaling molecule ANP; both may contribute to the development of AD. GLIA 2016;64:317–329     

The influence of obesity on the oxidative stress status and the concentration of leptin in type 2 diabetes mellitus patients

The aim of this study was to determinate both the oxidative stress/anti-oxidative defense status and the concentration of leptin in obese, overweight and normal weight type 2 diabetes mellitus patients to seek possible association between oxidative stress and hyperleptinemia. Oxidative stress status parameters [thiobarbituric acid-reacting substances (TBARS), superoxide anion (O(2)(-)), superoxide dismutase (SOD) activity and total sulphydryl groups] and the concentration of leptin were measured in 312 subjects (178 patients and in 134 control subjects). Obese patients had a significantly higher concentration of leptin compared to obese subjects in the control population (P<0.001). They also had significantly higher plasma concentrations of TBARS, O(2)(-) and SOD activity in combination with a lower sulphydryl group concentration when compared to control subjects. Obese patients had significantly higher concentrations of both TBARS and O(2)(-) and increased SOD activity compared to normal weight patients. The odds ratio for the degree of association between oxidative stress status parameters and hyperleptinemia was strongest for TBARS [odds ratio 2.66, 95% CI (1.02-6.94), P=0.045]. The observed positive correlation between TBARS and leptin (rho=0.29, P<0.01) in obese patients suggests that increased oxidative stress and hyperleptinemia, both consequences of obesity, may play a role in type 2 diabetes mellitus development.     

Molecular dissection of water and glycerol permeability of the aquaglyceroporin from Plasmodium falciparum by mutational analysis

The selectivity of aquaporins for water and solutes is determined by pore diameter. Paradoxically, the wider pores of glycerol facilitators restrict water passage by an unknown mechanism. Earlier we characterized an aquaglyceroporin from Plasmodium falciparum with high permeability for both glycerol and water. We use point mutations to demonstrate that amino acids directly lining the pore are not responsible for the excellent water permeability of the Plasmodium aquaglyceroporin but affect permeability of pentitols. Within a conserved WET triad in the extracellular C-loop we identified a Plasmodium aquaglyceroporin-specific glutamate (E125) located in proximity to a conserved arginine (R196) at the pore mouth. Mutation of E125 to serine largely abolished water permeability. Concomitantly, the activation energy for water permeation was increased by 4 kcal/mol. Mutation of the adjacent tryptophan to cysteine led to irreversible inhibition of water passage by Hg(2+). This unequivocally proves the proximity of the couple W124/E125 close to the pore mouth. We conclude that in the Plasmodium aquaglyceroporin the electrostatic environment at the extracellular pore entry regulates water permeability.