Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function

Voltage-gated sodium (NaV) channels are critical regulators of neuronal excitability and are targeted by many toxins that directly interact with the pore-forming α subunit, typically via extracellular loops of the voltage-sensing domains, or residues forming part of the pore domain. Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived NaV channel modulating peptide toxin. Here we show that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for pharmacological activity of ExTxA at NaV channels, and that co-expression of TMEM233 modulates the gating properties of NaV1.7. These findings identify TMEM233 as a previously unknown NaV1.7-interacting protein, position TMEM233 and the dispanins as accessory proteins that are indispensable for toxin-mediated effects on NaV channel gating, and provide important insights into the function of NaV channels in sensory neurons

Global Metabolomic Profiling of Acute Myocarditis Caused by Trypanosoma cruzi Infection

© 2014 Gironès et al. Chagas disease is caused by Trypanosoma cruzi infection, being cardiomyopathy the more frequent manifestation. New chemotherapeutic drugs are needed but there are no good biomarkers for monitoring treatment efficacy. There is growing evidence linking immune response and metabolism in inflammatory processes and specifically in Chagas disease. Thus, some metabolites are able to enhance and/or inhibit the immune response. Metabolite levels found in the host during an ongoing infection could provide valuable information on the pathogenesis and/or identify deregulated metabolic pathway that can be potential candidates for treatment and being potential specific biomarkers of the disease. To gain more insight into those aspects in Chagas disease, we performed an unprecedented metabolomic analysis in heart and plasma of mice infected with T. cruzi. Many metabolic pathways were profoundly affected by T. cruzi infection, such as glucose uptake, sorbitol pathway, fatty acid and phospholipid synthesis that were increased in heart tissue but decreased in plasma. Tricarboxylic acid cycle was decreased in heart tissue and plasma whereas reactive oxygen species production and uric acid formation were also deeply increased in infected hearts suggesting a stressful condition in the heart. While specific metabolites allantoin, kynurenine and p-cresol sulfate, resulting from nucleotide, tryptophan and phenylalanine/tyrosine metabolism, respectively, were increased in heart tissue and also in plasma. These results provide new valuable information on the pathogenesis of acute Chagas disease, unravel several new metabolic pathways susceptible of clinical management and identify metabolites useful as potential specific biomarkers for monitoring treatment and clinical severity in patients.This work was supported by ‘‘Ministerio de Ciencia e Innovación’’ (SAF2010-17833); ‘‘Fondo de Investigaciones Sanitarias’’ (PS09/00538 and PI12/00289); ‘‘Red de Investigación de Centros de Enfermedades Tropicales’’ (RICET RD12/0018/0004); European Union (HEALTH-FE-2008-22303, ChagasEpiNet);‘‘Universidad Autónoma de Madrid’’ and ‘‘Comunidad de Madrid’’ (CC08-UAM/SAL-4440/08); AECID Cooperation with Argentine (A/025417/09 and A/031735/10), Comunidad de Madrid (S-2010/BMD-2332) and ‘‘Fundación Ramón Areces’Peer Reviewe

Should the dilated ascending aorta be repaired at the time of bicuspid aortic valve replacement?

OBJECTIVES Bicuspid aortic valve (BAV) is the most common congenital valvular abnormality and frequently presents with accelerated calcific aortic valve disease, requiring aortic valve replacement (AVR) and thoracic aortic aneurysm and dissection. Supporting evidence for Association Guidelines of aortic dimensions for aortic resection is sparse. We sought to determine whether concurrent repair of dilated or aneurysmal aortic disease during AVR in patients with BAV substantially improves morbidity and mortality outcomes. METHODS Mortality and reoperation outcomes of 1301 adults with BAV and dilated aorta undergoing AVR-only surgery were compared to patients undergoing AVR with aortic resection (AVR-AR) using Cox proportional hazards modelling and patient matching. RESULTS Clinically important differences in patient characteristics, aortic valve function and aortic dimensions were identified between cohorts. Event rates were low, with rates of reoperation and death within 1 year of only 1.8% and 5.4%, respectively, and no aortic dissection observed during follow-up. There were no significant differences in reoperation or mortality outcomes between the AVR-only and AVR-AR cohorts. Age, aortic dimension or a combination thereof was not associated with better or worse outcomes after each AVR-AR compared with AVR. CONCLUSIONS We conclude AVR-only and AVR-AR surgery have low morbidity and mortality and have utility over a wide range of age and aortic sizes. Our results do not provide support for the 45-mm aortic dimension recommended in the current guidelines for aortic resection while performing AVR or any other specific dimension