Effects of remote ischemic preconditioning in high-risk patients undergoing cardiac surgery (Remote IMPACT): a randomized controlled trial

Background:Remote ischemic preconditioning is a simple therapy that may reduce cardiac and kidney injury. We undertook a randomized controlled trial to evaluate the effect of this therapy on markers of heart and kidney injury after cardiac surgery.Methods:Patients at high risk of death within 30 days after cardiac surgery were randomly assigned to undergo remote ischemic preconditioning or a sham procedure after induction of anesthesia. The preconditioning therapy was three 5-minute cycles of thigh ischemia, with 5 minutes of reperfusion between cycles. The sham procedure was identical except that ischemia was not induced. The primary outcome was peak creatine kinase–myocardial band (CK-MB) within 24 hours after surgery (expressed as multiples of the upper limit of normal, with log transformation). The secondary outcome was change in creatinine level within 4 days after surgery (expressed as log-transformed micromoles per litre). Patient-important outcomes were assessed up to 6 months after randomization.Results:We randomly assigned 128 patients to remote ischemic preconditioning and 130 to the sham therapy. There were no significant differences in postoperative CK-MB (absolute mean difference 0.15, 95% confidence interval [CI] −0.07 to 0.36) or creatinine (absolute mean difference 0.06, 95% CI −0.10 to 0.23). Other outcomes did not differ significantly for remote ischemic preconditioning relative to the sham therapy: for myocardial infarction, relative risk (RR) 1.35 (95% CI 0.85 to 2.17); for acute kidney injury, RR 1.10 (95% CI 0.68 to 1.78); for stroke, RR 1.02 (95% CI 0.34 to 3.07); and for death, RR 1.47 (95% CI 0.65 to 3.31).Interpretation:Remote ischemic precnditioning did not reduce myocardial or kidney injury during cardiac surgery. This type of therapy is unlikely to substantially improve patient-important outcomes in cardiac surgery. Trial registration: ClinicalTrials.gov, no. {"type":"clinical-trial","attrs":{"text":"NCT01071265","term_id":"NCT01071265"}}NCT01071265.Each year, 2 million patients worldwide undergo cardiac surgery. For more than 25% of these patients, the surgery is complicated by myocardial infarction (MI) and/or acute kidney injury, both of which are strongly associated with morbidity and mortality.^1–3 Preventing MI and acute kidney injury after cardiac surgery would improve survival.An important cause of MI and acute kidney injury in patients undergoing cardiac surgery is ischemia–reperfusion injury.^4,5 This type of injury begins as ischemia, which is then exacerbated by a systemic inflammatory response upon restoration of organ perfusion.⁶ Remote ischemic preconditioning may mitigate ischemia–reperfusion damage. It is accomplished by inducing, before surgery, brief episodes of ischemia in a limb, which lead to widespread activation of endogenous cellular systems that may protect organs from subsequent severe ischemia and reperfusion.^7–9Small randomized controlled trials evaluating the efficacy of remote ischemic preconditioning have had mixed results.^10–17 Interpretation of their data is difficult because of small sample sizes and heterogeneity in the preconditioning procedures and patient populations (e.g., few trials have evaluated patients at high risk of organ injury and postoperative death). Whether remote ischemic preconditioning effectively mitigates ischemia–reperfusion injury therefore remains uncertain. We undertook the Remote Ischemic Preconditioning in Cardiac Surgery Trial (Remote IMPACT) to determine whether this procedure reduces myocardial and kidney injury. We proposed that a large trial to determine the effect on clinically important outcomes would be worthwhile only if a substantial effect on myocardial or kidney injury, or both, were observed in the current study.     

Characterization of Plasmodium phosphatidylserine decarboxylase expressed in yeast and application for inhibitor screening

Phospholipid biosynthesis is critical for the development, differentiation and pathogenesis of several eukaryotic pathogens. Genetic studies have validated the pathway for phosphatidylethanolamine synthesis from phosphatidylserine catalyzed by phosphatidylserine decarboxylase enzymes (PSD) as a suitable target for development of antimicrobials; however no inhibitors of this class of enzymes have been discovered. We show that the Plasmodium falciparum PSD can restore the essential function of the yeast gene in strains requiring PSD for growth. Genetic, biochemical and metabolic analyses demonstrate that amino acids between positions 40 and 70 of the parasite enzyme are critical for proenzyme processing and decarboxylase activity. We used the essential role of Plasmodium PSD in yeast as a tool for screening a library of anti‐malarials. One of these compounds is 7‐chloro‐N‐(4‐ethoxyphenyl)‐4‐quinolinamine, an inhibitor with potent activity against P. falciparum, and low toxicity toward mammalian cells. We synthesized an analog of this compound and showed that it inhibits PfPSD activity and eliminates Plasmodium yoelii infection in mice. These results highlight the importance of 4‐quinolinamines as a novel class of drugs targeting membrane biogenesis via inhibition of PSD activity     

Thermus parvatiensis RLT sp. nov., Isolated from a Hot Water Spring,Located Atop the Himalayan Ranges at Manikaran,India

A Gram negative, yellow pigmented, rod shaped bacterium designated as RL^T was isolated from a hot water spring (90–98 °C) located at Manikaran in Northern India. The isolate grows at 60–80 °C (optimum, 70 °C) and at pH 7.0–9.0 (optimum pH 7.2). Phylogenetic analysis of 16S rRNA gene sequences and levels of DNA–DNA relatedness together indicate that the new isolate represents a novel species of the genus Thermus with closest affinity to Thermus thermophilus HB8^T (99.5 %) followed by Thermus arciformis (96.4 %). A comparative analysis of partial sequences of housekeeping genes (HKG) further revealed that strain RL^T is a novel species belonging to the genus Thermus. The melting G+C content of strain RL^T was calculated as 68.7 mol%. The DNA–DNA relatedness value of strain RL^T with its nearest neighbours (>97 %) was found to be less than 70 % indicating that strain RL^T represents a novel species of the genus Thermus. MK-8 was the predominant respiratory quinone. The presence of characteristic phospholipid and glycolipid further confirmed that strain RL^T belongs to the genus Thermus. The predominant fatty acids of strain RL^T were iso-C_17:0 (23.67 %) and iso-C_15:0 (24.50 %). The results obtained after DNA–DNA hybridization, biochemical and physiological tests clearly distinguished strain RL^T from its closely related species. Thus, strain RL^T represents a novel species of the genus Thermus for which the name Thermus parvatiensis is proposed (=DSM 21745^T= MTCC 8932^T).

Electronic supplementary material

The online version of this article (doi:10.1007/s12088-015-0538-4) contains supplementary material, which is available to authorized users.     

Evaluation of Source-Zone Attenuation at LUFT Sites with Mobile LNAPL

The objective of this study is to better understand the effect of mobile LNAPL on source-zone attenuation at sites using a statistical evaluation of 3,523 leaking underground fuel tank (LUFT) sites from GeoTracker, an extensive database of chemical release sites in California. Our analysis indicates that sites with mobile LNAPL (i.e., sites with measurable LNAPL thicknesses in one or more groundwater monitoring wells (LNAPL sites)) have higher maximum dissolved groundwater constituent concentrations and significantly slower source-zone attenuation rates (i.e., changes in maximum concentrations over time) compared to sites with a history of no measurable LNAPL thickness (non-LNAPL sites). However, the evaluation indicates that, for mobile LNAPL sites, physical recovery (skimming and bailing) does not increase source attenuation rates. The results suggest a need for more careful evaluation of the potential benefits of physical LNAPL technologies.     

Preferential elimination of chromosome 1D from homoeologous group-1 alien addition lines in hexaploid wheat

Alien chromosome addition lines are useful genetic material for studying the effect of an individual chromosome in the same genetic background. However, addition lines are sometimes unstable and tend to lose the alien chromosome in subsequent generations. In this study, we report preferential removal of chromosome 1D rather than the alien chromosome from homoeologous group-1 addition lines. The Agropyron intermedium chromosome 1Agi (1E) addition line, created in the background of 'Vilmorin 27', showed loss of a part of chromosome 1D, thereby losing its HMW glutenin locus. Even in the case of Aegilops longissima and Ae. peregrina, the genomes of which are closer to the B genome than D genome, chromosome 1D was lost from chromosome 1Sl and 1Sv addition lines in cv. 'Chinese Spring' rather than chromosome 1B during transfer from one generation to another. A similar observation was also observed in the case of a chromosome 1E disomic addition line of Ag. elongatum and alloplasmic common wheat line with Ag. intermedium ssp. trichophorum cytoplasm. The reason for this strange observation is thought to lie in the history of wheat evolution, the size of chromosome 1D compared to 1A and 1B, or differing pollen competition abilities.     

Photomodulation of PS-modified oligonucleotides containing azobenzene substituent at pre-selected positions in phosphate backbone

A new protocol has been developed for incorporation of a photoisomerizable azobenzene moiety into synthetic stereo-enriched [R_p] and [S_p] PS-oligonucleotides. The azobenzene pendant is attached at pre-selected positions in internucleotidic phosphorothioate oligonucleotides of both [R_p] and [S_p] diastereomers using a novel reagent, N-iodoacetyl-p-aminoazobenzene, 1. The modified oligomers are purified on HPLC, characterized by LC–MS, and examined for their thermal and photoisomerization properties. The azobenzene moiety imparts greater stability to oligomer duplexes in (E) NN configuration as compared to (Z) configuration. The placement of the azobenzene pendant close to 5′-terminus (n − 1) and 3′-terminus of the modified PS-oligos contributes maximum stability to the duplex while a gradual decline in stability occurs with azobenzene moving toward middle of the duplex. Circular Dichroism studies reveal that the chiral environment at the phosphorus center of the PS-oligos does not alter the global conformation of the DNA duplex as such, suggesting conservation of conformation of the modified DNA strands.     

Transgenerational inheritance of the insulin-resistant phenotype in embryo-transferred intrauterine growth-restricted adult female rat offspring

To determine mechanisms underlying the transgenerational presence of metabolic perturbations in the intrauterine growth-restricted second-generation adult females (F2 IUGR) despite normalizing the in utero metabolic environment, we examined in vivo glucose kinetics and in vitro skeletal muscle postinsulin receptor signaling after embryo transfer of first generation (F1 IUGR) to control maternal environment. Female F2 rats, procreated by F1 pre- and postnatally nutrient- and growth-restricted (IUGR) mothers but embryo transferred to gestate in control mothers, were compared with similarly gestating age- and sex-matched control (CON) F2 progeny. Although there were no differences in birth weight or postnatal growth patterns, the F2 IUGR had increased hepatic weight, fasting hyperglycemia, hyperinsulinemia, and unsuppressed hepatic glucose production, with no change in glucose futile cycling or clearance, compared with F2 CON. These hormonal and metabolic aberrations were associated with increased skeletal muscle total GLUT4 and pAkt concentrations but decreased plasma membrane-associated GLUT4, total pPKCzeta, and PKCzeta enzyme activity, with no change in total SHP2 and PTP1B concentrations in IUGR F2 compared with F2 CON. We conclude that transgenerational presence of aberrant glucose/insulin metabolism and skeletal muscle insulin signaling of the adult F2 IUGR female offspring is independent of the immediate intrauterine environment, supporting nutritionally induced heritable mechanisms contributing to the epidemic of type 2 diabetes mellitus.     

Availability of Essential Elements in Nutrient Supplements Used as Antidiabetic Herbal Formulations

Five brands of antidiabetic herbal formulations as tablets, Diabetex, Divya Madhu Nashini, Jambrushila, Diabeticin, and Madhumeh Nashini, from different pharmacies were analyzed for six minor (Na, K, Ca, Cl, Mg, and P) and 20 trace (As, Ba, Br, Ce, Co, Cr, Cs, Cu, Fe, Hg, La, Mn, Rb, Sb, Sc, Se, Sm, Th, V, and Zn) elements by thermal neutron irradiation followed by high-resolution gamma ray spectrometry. Further Ni, Cd, and Pb were determined by atomic absorption spectrophotometry. Most elements vary in a narrow range by a factor of 2–4 while a few others vary in a wide range, e.g., Na (0.05–0.67 mg/g), Mn (26.7–250 μg/g), and V (0.26–2.50 μg/g). All the five brands contain K, Cl, Mg, P, and Ca as minor constituents along with mean trace amounts of Cr (2.11 ± 0.67 μg/g), Cu (15.7 ± 7.11 μg/g), Fe (459 ± 171 μg/g), Mn (143 ± 23 μg/g), Se (238 ± 112 ng/g), and V (0.99 ± 0.93 μg/g). Jambrushila is enriched in Na, Ca, Mg, Cl, Fe, Cu, Se, and Zn, essential nutrients responsible for curing diabetes. Dietary intake of Mn, Fe, and Cu are greater than 10% of the recommended dietary allowance, whereas that for Zn and Se is less than 2%. Mean contents of toxic elements (As, Cd, Hg, and Pb) were found below permissible limits except in Jambrushila. Cr and Zn were inversely correlated with r = −0.81, whereas Rb and Cs exhibit linear correlation (r = 0.93) in five brands. C, H, N analysis showed C ∼ 55%, H ∼ 12%, and N ∼ 2% with a total of ∼70% organic matter. However, thermal decomposition studies at 700°C suggest less than 5% nonvolatile metal oxides. Herbal formulations contain minor and trace elements in bioavailable forms that favorably influence glucose tolerance and possibly increase the body’s ability to ameliorate development of diabetes.