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Rimonabant Precipitates Anxiety in Rats Withdrawn from Palatable Food: Role of the Central Amygdala

The anti-obesity medication rimonabant, an antagonist of cannabinoid type-1 (CB₁) receptor, was withdrawn from the market because of adverse psychiatric side effects, including a negative affective state. We investigated whether rimonabant precipitates a negative emotional state in rats withdrawn from palatable food cycling.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Systemic administration of rimonabant precipitated anxiety-like behavior and anorexia of the regular chow diet in rats withdrawn from palatable diet cycling, independently from the degree of adrenocortical activation.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.     

Cognitive evaluation of patients with glaucoma and its comparison with individuals with Alzheimer’s disease

Purpose

To evaluate the cognitive performance of patients with glaucoma and compare it to individuals with Alzheimer’s disease (AD).

Methods

This is a prospective, cross-sectional and case–control study. All subjects were assessed using the Mini-Mental State Examination (MMSE) and its subtests verbal fluency, word list memory, delayed recall of the word list, word list recognition test, Boston naming and constructive praxis from Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). The results were compared among the groups.

Results

A total of 50 healthy elderly with a mean age of 71.2 ± 5.2 years; 41 patients with glaucoma (72.2 ± 4.4 years); and 21 patients with AD (79.0 ± 7.6 years) were included. There was a reduction in all cognitive assessment tests evaluated, both for patients with glaucoma, and for those with AD compared with controls (p < 0.001 for all). Comparing the patients with glaucoma and AD, it was noted that the last had lower cognitive function (p < 0.001), except for the CERAD tests Boston (p = 0.1) and praxis (p = 0.6). Glaucoma patients, however, presented results of cognitive tests similar to those described for patients with mild AD, including lower values for MMSE (21.9 ± 3.7), Boston (10.6 ± 2.6) and praxis (5.9 ± 2.3).

Conclusion

Glaucoma patients had reduction in cognition when compared to normal individuals. They were similar to the values reported in the literature for patients with mild AD, mostly, and also in some subjects with the presence of advanced AD.

     

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.     

The role of enemas in the small intestine in the study of ileal subocclusion

In mechanical subocclusions, when there isn't immediate urgency, is it possible and necessary to probe radiologic examination, for a better surgical evaluation. The authors describe their own experience, achieved in about 3 years, on small bowel double contrast enema. They examined 143 patients; 16 of them were suboccluded. The security and the diagnostic reliability of used method are stressed by the authors to define lesions' morphology and localization.     

Morphologic and immunohistochemical evaluation of splenic hematopoietic proliferations in neoplastic and benign disorders.

Spleen is a common site of extramedullary hematopoiesis. Extramedullary hematopoiesis seen in non-neoplastic conditions can occasionally be extensive and raise concerns for a myeloid neoplasm. We compared the morphologic and immunohistochemical features of splenic hematopoietic proliferations seen in neoplastic myeloid disorders (eg chronic myeloproliferative disorders, myelodysplastic/myeloproliferative disorders and acute myeloid leukemias) to extramedullary hematopoiesis seen in a variety of reactive conditions. In all, 80 spleen specimens were reviewed. The presence of each marrow-derived lineage, dysplasia and immunohistochemical results were evaluated (CD34, CD117, myeloperoxidase, CD68, p53, TdT, CD42b and hemoglobin). Neoplastic hematopoietic proliferations in chronic myeloproliferative disorders are characterized by trilineage hematopoiesis with significant dysplasia in all cell lineages. Acute myeloid leukemia showed an increase in immature forms, which were highlighted by immunohistochemistry. Reactive extramedullary hematopoiesis showed variability in histologic features. Post-bone marrow transplant and thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome spleens showed extramedullary hematopoiesis with some morphologic features of immaturity, which could simulate chronic myeloproliferative disorder. However, they lacked characteristic immunohistochemical features of neoplastic myeloid disorders such as positivity for CD34 or CD117.     

Use of Sugar Cane Vinasse to Mitigate Aluminum Toxicity to <Emphasis Type="Italic">Saccharomyces cerevisiae</Emphasis>

Owing to its toxicity, aluminum (Al), which is one of the most abundant metals, inhibits the productivity of many cultures and affects the microbial metabolism. The aim of this work was to investigate the capacity of sugar cane vinasse to mitigate the adverse effects of Al on cell growth, viability, and budding, as the likely result of possible chelating action. For this purpose, Fleischmann’s yeast (Saccharomyces cerevisiae) was used in growth tests performed in 125-mL Erlenmeyer flasks containing 30 mL of YED medium (5.0 g/L yeast extract plus 20 g/L glucose) supplemented with the selected amounts of either vinasse or Al in the form of AlCl₃ · H₂O. Without vinasse, the addition of increasing levels of Al up to 54 mg/L reduced the specific growth rate by 18%, whereas no significant reduction was observed in its presence. The toxic effect of Al on S. cerevisiae growth and the mitigating effect of sugar cane vinasse were quantified by the exponential model of Ciftci et al. (Biotechnol Bioeng 25:2007–2023, 1983). The cell viability decreased from 97.7% at the start to 84.0% at the end of runs without vinasse and to 92.3% with vinasse. On the other hand, the cell budding increased from 7.62% at the start to 8.84% at the end of runs without vinasse and to 17.8% with vinasse. These results demonstrate the ability of this raw material to stimulate cell growth and mitigate the toxic effect of Al.