DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity

A review of enhanced paramedic roles during and after hospital handover of stroke, myocardial infarction and trauma patients

BackgroundAmbulance paramedics play a critical role expediting patient access to emergency treatments. Standardised handover communication frameworks have led to improvements in accuracy and speed of information transfer but their impact upon time-critical scenarios is unclear. Patient outcomes might be improved by paramedics staying for a limited time after handover to assist with shared patient care. We aimed to categorize and synthesise data from studies describing development/extension of the ambulance-based paramedic role during and after handover for time-critical conditions (trauma, stroke and myocardial infarction).MethodsWe conducted an electronic search of published literature (Jan 1990 to Sep 2016) by applying a structured strategy to eight bibliographic databases. Two reviewers independently assessed eligible studies of paramedics, emergency medical (or ambulance) technicians that reported on the development, evaluation or implementation of (i) generic or specific structured handovers applied to trauma, stroke or myocardial infarction (MI) patients; or (ii) paramedic-initiated care processes at handover or post-handover clinical activity directly related to patient care in secondary care for trauma, stroke and MI. Eligible studies had to report changes in health outcomes.ResultsWe did not identify any studies that evaluated the health impact of an emergency ambulance paramedic intervention following arrival at hospital. A narrative review was undertaken of 36 studies shortlisted at the full text stage which reported data relevant to time-critical clinical scenarios on structured handover tools/protocols; protocols/enhanced paramedic skills to improve handover; or protocols/enhanced paramedic skills leading to a change in in-hospital transfer location. These studies reported that (i) enhanced paramedic skills (diagnosis, clinical decision making and administration of treatment) might supplement handover information; (ii) structured handover tools and feedback on handover performance can impact positively on paramedic behaviour during clinical communication; and (iii) additional roles of paramedics after arrival at hospital was limited to ‘direct transportation’ of patients to imaging/specialist care facilities.ConclusionsThere is insufficient published evidence to make a recommendation regarding condition-specific handovers or extending the ambulance paramedic role across the secondary/tertiary care threshold to improve health outcomes. However, previous studies have reported non-clinical outcomes which suggest that structured handovers and enhanced paramedic actions after hospital arrival might be beneficial for time-critical conditions and further investigation is required

Apoptosis-linked changes in the phosphorylation status and subcellular localization of the spliceosomal autoantigen U1-70K.

Contains fulltext : 69873.pdf (publisher's version ) (Closed access)Apoptosis consists of highly regulated pathways involving post-translational modifications and cleavage of proteins leading to sequential inactivation of the main cellular processes. Here, we focused on the apoptotic processing of one of the essential components of the mRNA splicing machinery, the U1-70K snRNP protein. We found that at an early stage of apoptosis, before the cleavage of the C-terminal part of the protein by caspase-3, the basal phosphorylation of the Ser140 residue located within the RNA recognition motif, increases very significantly. A caspase-dependent, PP1-mediated dephosphorylation of other serine residues takes place in a subset of U1-70K proteins. The U1-70K protein phosphorylated at Ser140 is clustered in heterogeneous ectopic RNP-derived structures, which are finally extruded in apoptotic bodies. The elaborate processing of the spliceosomal U1-70K protein we identified might play an important role in the regulated breakdown of the mRNA splicing machinery during early apoptosis. In addition, these specific changes in the phosphorylation/dephosphorylation balance and the subcellular localization of the U1-70K protein might explain why the region encompassing the Ser140 residue becomes a central autoantigen during the autoimmune disease systemic lupus erythematosus