Cardiac transplantation in a patient with emotionally triggered implantable cardioverter defibrillator storms

The implantable cardioverter defibrillator (ICD) may be responsible for psychological disorders especially among patients experiencing multiple shocks. An associated hyperadrenergic state (e.g., anger, anxiety) may trigger malignant ventricular arrhythmias repeatedly treated by ICD shocks, entertaining a "vicious circle” often difficult to interrupt. Despite aggressive cardiac and psychological therapeutic efforts, this condition may be refractory, finally leading to heart transplantation, as described in this case repor

Safety of low-dose spironolactone administration in chronic haemodialysis patients

Background. Prevention of cardiovascular diseases is essential in chronic haemodialysis patients. Recently, low-dose spironolactone has been shown to decrease cardiovascular mortality in patients with severe heart failure. However, since haemodialysis patients are prone to hyperkalaemia, a known side effect of spironolactone, this treatment is not used in this population. We performed a study to assess whether low-dose spironolactone (3 × 25 mg/week) could be administered without inducing hyperkalaemia in haemodialysis patients. Methods. The study design included a 2-week baseline period, followed by a 4-week treatment period in which doses of spironolactone were started at 12.5 mg three times/week for 2 weeks, then increased to 25 mg three times/week, and followed by a 2-week wash-out period. Fourteen patients receiving low-dose spironolactone after each dialysis were compared with 21 haemodialysis patients (control group). Results. Low-dose spironolactone did not change mean serum potassium (4.9 ± 0.7 vs 4.9 ± 0.3 mmol/l: control). The mean plasma canrenone level induced by administration of spironolactone 25 mg three times/week in the 14 treated patients was 13 ± 5.3 ng/ml. Serum aldosterone was not significantly modified by the administration of spironolactone in these patients [before, median 0.35; interquartile range (IQR) 0.11-2.83 nmol/l vs after, median 0.22; IQR 0.12-0.60 nmol/l, NS]. Dietary potassium intake and the use of ion-exchange resin, angiotensin-converting enzyme inhibitors and β-blockers were similar for the two groups throughout the study. Conclusion. This non-randomized and non-blinded study shows that administration of 25 mg spironolactone thrice weekly is not associated with an increased frequency of hyperkalaemia in haemodialysis patients when they are carefully monitored. More studies are required, however, before concluding that spironolactone administration is safe in the chronic haemodialysis populatio

Redox control of sulfur degassing in silicic magmas

International audienceExplosive eruptions involve mainly silicic magmas in which sulfur solubility and diffusivity are low. This inhibits sulfur exsolution during magma uprise as compared to more mafic magmas such as basalts. Silicic magmas can nevertheless liberate large quantities of sulfur as shown by the monitoring of SO2 in recent explosive silicic eruptions in arc settings, which invariably have displayed an excess of sulfur relative to that calculated from melt degassing. If this excess sulfur is stored in a fluid phase, it implies a strong preference of sulfur for the fluid over the melt under oxidized conditions, with fluid/melt partition coefficients varying between 50 and 2612, depending on melt composition. Experimentally determined sulfur partition coefficients for a dacite bulk composition confirm this trend and show that in volcanic eruptions displaying excess gaseous sulfur, the magmas were probably fluid-saturated at depth. The experiments show that in more reduced silicic magmas, those coexisting only with pyrrhotite, the partition coefficient decreases dramatically to values around 1, because pyrrhotite locks up nearly all the sulfur of the magma. Reevaluation of the sulfur yields of some major historical eruptions in the light of these results shows that for oxidized magmas, the presence of 1-5 wt % fluid may indeed account for the differences observed between the petrologic estimate of the sulfur yield and that constrained from ice core data. Explosive eruptions of very large magnitude but involving reduced and cool silicic magmas, such as the Toba or the Bishop events, release only minor amounts of sulfur and could have consequently negligible long-term (years to centuries) atmospherical effects. This redox control on sulfur release diminishes as the melt composition becomes less silicic and as temperature increases, because both factors favor more efficient melt sulfur degassing owing to the increased diffusivity of sulfur in silicate melts under such conditions

Critical role of TLR2 and MyD88 for functional response of macrophages to a group IIA-Secreted phospholipase A2 from snake venom

artículo (arbitrado) -- Universidad de Costa Rica, Instituto de Investigaciones Clodomiro Picado. 2014The snake venom MT-III is a group IIA secreted phospholipase A2 (sPLA2) enzyme with functional and structural similarities with mammalian pro-inflammatory sPLA2s of the same group. Previously, we demonstrated that MT-III directly activates the innate inflammatory response of macrophages, including release of inflammatory mediators and formation of lipid droplets (LDs). However, the mechanisms coordinating these processes remain unclear. In the present study, by using TLR22/2 or MyD882/2 or C57BL/6 (WT) male mice, we report that TLR2 and MyD88 signaling have a critical role in MT-III-induced inflammatory response in macrophages. MT-III caused a marked release of PGE2, PGD2, PGJ2, IL-1b and IL-10 and increased the number of LDs in WT macrophages. In MT-III-stimulated TLR22/2 macrophages, formation of LDs and release of eicosanoids and cytokines were abrogated. In MyD882/2 macrophages, MT-III-induced release of PGE2, IL-1b and IL-10 was abrogated, but release of PGD2 and PGJ2 was maintained. In addition, COX-2 protein expression seen in MT-III-stimulated WT macrophages was abolished in both TLR22/2 and MyD882/2 cells, while perilipin 2 expression was abolished only in MyD882/2 cells. We further demonstrated a reduction of saturated, monounsaturated and polyunsaturated fatty acids and a release of the TLR2 agonists palmitic and oleic acid from MT-III-stimulated WT macrophages compared with WT control cells, thus suggesting these fatty acids as major messengers for MT-III-induced engagement of TLR2/MyD88 signaling. Collectively, our findings identify for the first time a TLR2 and MyD88-dependent mechanism that underlies group IIA sPLA2- induced inflammatory response in macrophages.This investigation was supported by research grants from FAPESP, Sao Paulo, Brazil (www.fapesp.br), grants 11/21341-5 and 10/06345-1, INCTTOX, Sao Paulo, Brazil (www.incttox.com.br), grant 573790/2008-6, CNPq PQ, Brazil (www.cnpq.br), grant 306920/2011-5, Brazil, Spanish Ministery of Science and Innovation, Spain (http://web.micinn.es/), grant BFU2010-18826.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP

Prise en charge de l’insuffisance cardiaque terminale

Non-medical approaches to end-stage heart failure (ESHF) include heart transplantation, but also implantable cardioverter-defibrillators, cardiac resynchronization therapy and ventricular assist devices. These techniques might be used as a bridge to transplant, as a bridge to recovery or as destination therapy. Optimal medical therapy of ESHF should include an angiotensin-converting enzyme inhibitor, a beta-blocker and spironolactone. Risk stratification in ESHF allows to determine the individual prognosis of each patient with parameters such as echocardiographic criteria, peak exercise oxygen consumption, or plasma BNP levels. Heart transplantation is to be considered if the individual prognosis obtained after stratification is worse than the expected survival of transplant recipients

The ratio of mouse insulin I:insulin II does not reflect that of the corresponding preproinsulin mRNAs

Rats and mice both express two, non-allelic, insulin genes. In the rat the ratio of the two preproinsulin mRNAs closely matches that of the mature insulin peptides. The experiments reported here demonstrate that this is not the case in the mouse. The relative amounts of the two murine proinsulin RNAs were measured by an S1 nuclease assay. The ratio of preproinsulin I mRNA to preproinsulin II mRNA was 4:1 in RNA extracted from the pancreas of mice fed ad libitum or fasted for 72 h. A similar value was found in mouse islets of Langerhans after maintenance in tissue culture for 48 h at either 2.8 or 16.7 mM glucose. The ratio of insulin I:insulin II peptides, assessed by separating the two insulins using reversed phase high-performance liquid chromatography, was approximately 1:3 in both pancreas and islets. Thus in the mouse, unlike the rat, the ratio of the two insulin peptides does not reflect that of the two preproinsulin mRNAs

Preclinical Characterization of a Next-Generation Brain Permeable, Paradox Breaker BRAF Inhibitor

PURPOSE Disease progression in BRAF V600E/K positive melanomas to approved BRAF/MEK inhibitor therapies is associated with the development of resistance mediated by RAF dimer inducing mechanisms. Moreover, progressing disease after BRAFi/MEKi frequently involves brain metastasis. Here we present the development of a novel BRAF inhibitor (Compound Ia) designed to address the limitations of available BRAFi/MEKi. EXPERIMENTAL DESIGN The novel, brain penetrant, paradox breaker BRAFi is comprehensively characterized in vitro, ex vivo, and in several preclinical in vivo models of melanoma mimicking peripheral disease, brain metastatic disease, and acquired resistance to first-generation BRAFi. RESULTS Compound Ia manifested elevated potency and selectivity, which triggered cytotoxic activity restricted to BRAF-mutated models and did not induce RAF paradoxical activation. In comparison to approved BRAFi at clinical relevant doses, this novel agent showed a substantially improved activity in a number of diverse BRAF V600E models. In addition, as a single agent, it outperformed a currently approved BRAFi/MEKi combination in a model of acquired resistance to clinically available BRAFi. Compound Ia presents high central nervous system (CNS) penetration and triggered evident superiority over approved BRAFi in a macro-metastatic and in a disseminated micro-metastatic brain model. Potent inhibition of MAPK by Compound Ia was also demonstrated in patient-derived tumor samples. CONCLUSIONS The novel BRAFi demonstrates preclinically the potential to outperform available targeted therapies for the treatment of BRAF-mutant tumors, thus supporting its clinical investigation

Interleukin-33-Activated Islet-Resident Innate Lymphoid Cells Promote Insulin Secretion through Myeloid Cell Retinoic Acid Production

Pancreatic-islet inflammation contributes to the failure of β cell insulin secretion during obesity and type 2 diabetes. However, little is known about the nature and function of resident immune cells in this context or in homeostasis. Here we show that interleukin (IL)-33 was produced by islet mesenchymal cells and enhanced by a diabetes milieu (glucose, IL-1β, and palmitate). IL-33 promoted β cell function through islet-resident group 2 innate lymphoid cells (ILC2s) that elicited retinoic acid (RA)-producing capacities in macrophages and dendritic cells via the secretion of IL-13 and colony-stimulating factor 2. In turn, local RA signaled to the β cells to increase insulin secretion. This IL-33-ILC2 axis was activated after acute β cell stress but was defective during chronic obesity. Accordingly, IL-33 injections rescued islet function in obese mice. Our findings provide evidence that an immunometabolic crosstalk between islet-derived IL-33, ILC2s, and myeloid cells fosters insulin secretion