Genetic control of postoperative systemic inflammatory reaction and pulmonary and renal complications after coronary artery surgery

BACKGROUND: Although some data suggest that the individual genetic predisposition for developing major or minor degrees of postoperative systemic inflammatory reaction may influence postoperative morbidity, this hypothesis has not been clinically tested to date.Methods and results The -174 G/C polymorphism of the promoter of the interleukin 6 gene was determined preoperatively in 111 consecutive patients submitted to primary isolated coronary artery bypass. The results of the genetic analysis were then correlated with the postoperative interleukin 6 levels and the development of postoperative renal and pulmonary complications. G homozygotes had significantly higher interleukin 6 levels postoperatively (P <.0001 for the difference between areas under the curve). These patients also had worse postoperative pulmonary and renal function. The mean perioperative difference in serum creatinine, potassium, and nitrogen was 0.82 +/- 0.34, 0.99 +/- 0.44, and 10.1 +/- 7.8 mg/dL versus 0.18 +/- 0.14, 0.15 +/- 0.48, and 2.6 +/- 4.1 mg/dL for GG versus non-GG carriers (P <.0001), respectively. The mean respiratory index at 6 and 12 hours was 2.9 +/- 0.8 and 2.8 +/- 0.3 versus 2.1 +/- 0.5 and 1.3 +/- 0.1, respectively (P <.0001). The mean duration of mechanical ventilation was 22.5 +/- 2.1 versus 12.7 +/- 6.7 hours (P <.01). A correlation was found between postoperative interleukin 6 levels and renal and pulmonary complications. CONCLUSION: The interleukin 6 -174 G/C polymorphism modulates postoperative interleukin 6 levels and is associated with the degree of postoperative renal and pulmonary dysfunction and in-hospital stay after coronary surgery.     

Hepatocyte transplantation in the treatment of acute liver failure: microencapsulated hepatocytes versus hepatocytes attached to an autologous biomatrix

A liver transplant is considered today to be the only effective therapeutic solution for many otherwise intractable hepatic disorders. However, liver transplantation is beset by shortage of donors. Over the years, many liver support systems have been developed to supply the liver functions, mostly as a bridge to transplantation. Transplantation of isolated hepatocytes (HcTx) instead of whole liver has constituted one of the most appealing possibilities to treat several diseases. We compared two different models of HcTx in a surgical model of acute liver failure in pigs, using microencapsulated hepatocytes (MHcTx) and hepatocytes attached to a porcine biomatrix (PBMHcTx), both transplanted into peritoneum. The collected data were survival, laboratory findings, hemodynamic parameters, light microscopy, histology, MTT, and glycogen content. The group with PBMHcTx has a better outcome than the group with MHcTx (p < 0.05). Histology showed normal morphology of the hepatocytes, high glycogen content, 75% viability, positive MTT, and 95% adhesion of the hepatocytes to the biomatrix. Our biomatrix (PBM) provides cell-to-cell contact and interaction with extracellular matrix, which have been shown to play major roles in hepatocyte survival and physiologic regulation of gene expression, and guarantee a prompt engraftment and an adequate neovascularization. PBMHcTx is a useful method to treat acute liver failure and it indicates a possible liver-direct gene therapy in the treatment of inherited and acquired disorders.     

Sustained-release diltiazem reduces myocardial ischemic episodes in end-stage renal disease: a double-blind,randomized, crossover,placebo-controlled trial

End-stage renal disease (ESRD) patients receiving maintenance hemodialysis and suffering from coronary artery disease (CAD) often receive doses of calcium channel antagonists that are too low. This may be the result of physician's desire to avoid adverse side effects during hemodialysis. The aim of this study was the assessment of the safety and efficacy of incremental doses of diltiazem for the treatment of myocardial ischemia in ERSD patients with CAD to identify the optimal dose of the drug. A total of 196 chronic hemodialysis patients were enrolled with CAD showing more than 5 min of transient myocardial ischemia during a 48-h Holter ECG monitoring. A double-blind, randomized, crossover, placebo-controlled trial design was used. Incremental doses of diltiazem (120 to 240 mg/d) were administered in 4 mo. With a dose of 120 and 180 mg/d, a significant reduction in the number and duration of total and symptomatic ischemic episodes was observed (P < 0.001), but the number and the duration of silent ischemic episodes were not reduced. Conversely, the efficacy on silent myocardial ischemia was obtained with a dosage of diltiazem of 240 mg/d (P < 0.001). In addition, with a sustained-release formulation (120 mg twice daily), the efficacy was similar to that obtained with four 60-mg tablets, but the safety was improved, especially during hemodialytic session. The circadian variations analysis of transient ischemic episodes showed a significant reduction in both ischemic peaks observed at baseline only with 240 mg/d of diltiazem. The findings emphasize that sustained-release diltiazem (120 mg twice daily) can be largely useful in uremic patients with CAD on maintenance dialysis. Diltiazem reduces the number and the duration of silent ischemic episodes, has a good tolerability, and positively modifies the circadian pattern of ischemic episodes.     

IX Antonio Arrigo Award. Clinical neurophysiology in neuromuscular disorders: usefulness and limitations

This lecture focuses on the impact of classic and modern electrophysiological techniques on the diagnostic approach to patients with neuromuscular disorders, placing emphasis on the limitations of currently used techniques and on the future prospects of clinical neurophysiology. The refinement of old techniques together with the development of new ones will hopefully improve the diagnostic capability of neurophysiology, improve understanding of the complex pathogenic mechanisms underlying neuromuscular disorders and help further the research of new therapeutic strategies.     

Sudden ventricular fibrillation and death during ibrutinib therapy—A case report

Ibrutinib is an oral inhibitor of Bruton tyrosine kinase approved for the treatment of chronic lymphocytic leukaemia, mantle cell lymphoma and refractory Waldenstrom's disease. It increases progression‐free survival, overall survival, response rate. The most frequent adverse reactions, are increased risk in of bleeding and atrial fibrillation, but several reports of more dangerous rhythm disturbances have been recently reported in literature. A case of a patient with refractory Waldenstrom's disease, who developed ventricular fibrillation while taking ibrutinib, is reported, along with a concise literature review.     

Rimonabant Precipitates Anxiety in Rats Withdrawn from Palatable Food: Role of the Central Amygdala

The anti-obesity medication rimonabant, an antagonist of cannabinoid type-1 (CB₁) receptor, was withdrawn from the market because of adverse psychiatric side effects, including a negative affective state. We investigated whether rimonabant precipitates a negative emotional state in rats withdrawn from palatable food cycling. The effects of systemic administration of rimonabant on anxiety-like behavior, food intake, body weight, and adrenocortical activation were assessed in female rats during withdrawal from chronic palatable diet cycling. The levels of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and the CB₁ receptor mRNA and the protein in the central nucleus of the amygdala (CeA) were also investigated. Finally, the effects of microinfusion of rimonabant in the CeA on anxiety-like behavior, and food intake were assessed. Systemic administration of rimonabant precipitated anxiety-like behavior and anorexia of the regular chow diet in rats withdrawn from palatable diet cycling, independently from the degree of adrenocortical activation. These behavioral observations were accompanied by increased 2-AG, CB₁ receptor mRNA, and protein levels selectively in the CeA. Finally, rimonabant, microinfused directly into the CeA, precipitated anxiety-like behavior and anorexia. Our data show that (i) the 2-AG-CB₁ receptor system within the CeA is recruited during abstinence from palatable diet cycling as a compensatory mechanism to dampen anxiety, and (ii) rimonabant precipitates a negative emotional state by blocking the beneficial heightened 2-AG-CB₁ receptor signaling in this brain area. These findings help elucidate the link between compulsive eating and anxiety, and it will be valuable to develop better pharmacological treatments for eating disorders and obesity.     

Azaindole derivatives are inhibitors of microtubule dynamics,with anti-cancer and anti-angiogenic activities

Background and Purpose

Drugs targeting microtubules are commonly used for cancer treatment. However, the potency of microtubule inhibitors used clinically is limited by the emergence of resistance. We thus designed a strategy to find new cell-permeable microtubule-targeting agents.

Experimental Approach

Using a cell-based assay designed to probe for microtubule polymerization status, we screened a chemical library and identified two azaindole derivatives, CM01 and CM02, as cell-permeable microtubule-depolymerizing agents. The mechanism of the anti-tumour effects of these two compounds was further investigated both in vivo and in vitro.

Key Results

CM01 and CM02 induced G2/M cell cycle arrest and exerted potent cytostatic effects on several cancer cell lines including multidrug-resistant (MDR) cell lines. In vitro experiments revealed that the azaindole derivatives inhibited tubulin polymerization and competed with colchicines for this effect, strongly indicating that tubulin is the cellular target of these azaindole derivatives. In vivo experiments, using a chicken chorioallantoic xenograft tumour assay, established that these compounds exert a potent anti-tumour effect. Furthermore, an assay probing the growth of vessels out of endothelial cell spheroids showed that CM01 and CM02 exert anti-angiogenic activities.

Conclusions and Implications

CM01 and CM02 are reversible microtubule-depolymerizing agents that exert potent cytostatic effects on human cancer cells of diverse origins, including MDR cells. They were also shown to inhibit angiogenesis and tumour growth in chorioallantoic breast cancer xenografts. Hence, these azaindole derivatives are attractive candidates for further preclinical investigations.     

Alpha-tocopherol metabolism is abnormal in scavenger receptor class B type I (SR-BI)-deficient mice

Despite the physiologic importance of vitamin E, in particular its alpha-tocopherol (alpha-T) isoform, the molecular mechanisms involved in the cellular uptake of this antioxidant from plasma lipoproteins have not been well-defined. Recent studies have suggested that selective lipid uptake, rather than endocytosis, is important for alpha-T delivery to cells. Here we show that the scavenger receptor class B type I (SR-BI), which mediates cellular selective cholesteryl ester uptake from lipoproteins, facilitates efficient transfer of alpha-T from HDL to cultured cells. In SR-BI-deficient mutant mice, relative to wild-type control animals, there was a significant increase in plasma alpha-T levels (1.1- to 1.4-fold higher) that was mostly due to the elevated alpha-T content of their abnormally large plasma HDL-like particles. This increase in plasma alpha-T in SR-BI knockout mice was accompanied by a significant decrease (65-80%) in the alpha-T concentrations in bile and several tissues including ovary, testis, lung and brain. SR-BI deficiency did not alter the alpha-T concentrations of the liver, spleen, kidney or white fat. These data show that SR-BI plays an important role in transferring alpha-T from plasma lipoproteins to specific tissues. Also, in the case of the liver as was previously shown for SR-BI-dependent hepatic cholesterol transport, SR-BI-mediated uptake of alpha-T was primarily coupled to biliary excretion rather than to tissue accumulation. Defective tissue uptake of lipoprotein alpha-T in SR-BI-deficient mice may contribute to the reproductive and cardiovascular pathologies exhibited by these animals.