Salinomycin induces calpain and cytochrome c-mediated neuronal cell death

Salinomycin is a polyether antibiotic with properties of an ionophore, which is commonly used as cocciodiostatic drug and has been shown to be highly effective in the elimination of cancer stem cells (CSCs) both in vitro and in vivo. One important caveat for the potential clinical application of salinomycin is its marked neural and muscular toxicity. In the present study we show that salinomycin in concentrations effective against CSCs exerts profound toxicity towards both dorsal root ganglia as well as Schwann cells. This toxic effect is mediated by elevated cytosolic Na+ concentrations, which in turn cause an increase of cytosolic Ca2+ by means of Na+/Ca2+ exchangers (NCXs) in the plasma membrane as well as the mitochondria. Elevated Ca2+ then leads to calpain activation, which triggers caspase-dependent apoptosis involving caspases 12, 9 and 3. In addition, cytochrome c released from depolarized mitochondria directly activates caspase 9. Combined inhibition of calpain and the mitochondrial NCXs resulted in significantly decreased cytotoxicity and was comparable to caspase 3 inhibition. These findings improve our understanding of mechanisms involved in the pathogenesis of peripheral neuropathy and are important to devise strategies for the prevention of neurotoxic side effects induced by salinomycin

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

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Generalized AA-amyloidosis in Siamese and Oriental cats

During a 7 year period (1987-1994), 194 Siamese cats including a colour variant designated Oriental cat, were presented for post-mortem examination. Twelve of these animals (6.2%) were diagnosed with amyloidosis. Major gross pathological findings included enlarged pale livers with haemorrhages, pale and swollen spleens, and dilated intestines. Deposits of amyloid were found in these tissues. The amyloid was found to cross-react with anti dog AA- antiserum when examined with peroxidase antiperoxidase (PAP) staining (four cases). Amyloid fibrils were purified by the water extraction method and its major constituting protein (AA) was isolated by gel filtration. Amino acid sequence analysis of this protein from a Siamese cat and an Abyssinian cat revealed a significant difference between these breeds. In the Siamese protein AA two amino acid substitutions (46 R for Q and 52 V for A) were encountered. This finding indicates the existence of a new feline amyloid A protein occurring in the Siamese breed which differs from presently known (apoS)AA-proteins. Additionally, the pedigree analysis of affected cats suggests a familial trait