Proteomics: in pursuit of effective traumatic brain injury therapeutics

Effective traumatic brain injury (TBI) therapeutics remain stubbornly elusive. Efforts in the field have been challenged by the heterogeneity of clinical TBI, with greater complexity among underlying molecular phenotypes than initially conceived. Future research must confront the multitude of factors comprising this heterogeneity, representing a big data challenge befitting the coming informatics age. Proteomics is poised to serve a central role in prescriptive therapeutic development, as it offers an efficient endpoint within which to assess post-TBI biochemistry. We examine rationale for multifactor TBI proteomic studies and the particular importance of temporal profiling in defining biochemical sequences and guiding therapeutic development. Lastly, we offer perspective on repurposing biofluid proteomics to develop theragnostic assays with which to prescribe, monitor and assess pharmaceutics for improved translation and outcome for TBI patients

Purinergic Receptor Stimulation Reduces Cytotoxic Edema and Brain Infarcts in Mouse Induced by Photothrombosis by Energizing Glial Mitochondria

Treatments to improve the neurological outcome of edema and cerebral ischemic stroke are severely limited. Here, we present the first in vivo single cell images of cortical mouse astrocytes documenting the impact of single vessel photothrombosis on cytotoxic edema and cerebral infarcts. The volume of astrocytes expressing green fluorescent protein (GFP) increased by over 600% within 3 hours of ischemia. The subsequent growth of cerebral infarcts was easily followed as the loss of GFP fluorescence as astrocytes lysed. Cytotoxic edema and the magnitude of ischemic lesions were significantly reduced by treatment with the purinergic ligand 2-methylthioladenosine 5′ diphosphate (2-MeSADP), an agonist with high specificity for the purinergic receptor type 1 isoform (P2Y1R). At 24 hours, cytotoxic edema in astrocytes was still apparent at the penumbra and preceded the cell lysis that defined the infarct. Delayed 2MeSADP treatment, 24 hours after the initial thrombosis, also significantly reduced cytotoxic edema and the continued growth of the brain infarction. Pharmacological and genetic evidence are presented indicating that 2MeSADP protection is mediated by enhanced astrocyte mitochondrial metabolism via increased inositol trisphosphate (IP3)-dependent Ca2+ release. We suggest that mitochondria play a critical role in astrocyte energy metabolism in the penumbra of ischemic lesions, where low ATP levels are widely accepted to be responsible for cytotoxic edema. Enhancement of this energy source could have similar protective benefits for a wide range of brain injuries

A pragmatic comparative study of palliative care clinician’s reports of the degree of shadowing visible on plain abdominal radiographs

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. The assessment of constipation symptoms is based on history and physical examination. However, the experience is highly subjective perhaps explaining why palliative medicine doctors continue to use plain abdominal radiographs as part of routine assessment of constipation. Previous studies have demonstrated poor agreement between clinicians with this work in palliative care, limited further by disparity of clinicians’ experience and training. The aim of this work was to explore whether there was less variation in the assessments of faecal shadowing made by more experienced clinicians compared to their less experienced colleagues. This pragmatic study was conducted across six palliative care services in Sydney (NSW, Australia). Doctors of varying clinical experience were asked to independently report their opinions of the amount of shadowing seen on 10 plain abdominal radiographs all taken from cancer patients who self-identified themselves as constipated. There were 46 doctors of varying clinical experience who participated including qualified specialists, doctors in specialist training and lastly, doctors in their second- and third post-graduate years. Poor agreement was seen between the faecal shadowing scores allocated by doctors of similar experience and training (Fleiss’s kappa (FK): RMO 0.05; registrar 0.06; specialist 0.11). Further, when the levels of agreement between groups were considered, no statistically significant differences were observed. Although the doctors did not agree on the appearance of the film, the majority felt they were able to extrapolate patients’ experiences from the radiograph’s appearance. As it remains challenging in palliative care to objectively assess and diagnose constipation by history and imaging, uniform and objective assessment and diagnostic criteria are required. It is likely that any agreed criteria will include a combination of imaging and history. The results suggest the use of radiographs alone to diagnose and assess constipation in palliative care represents low value care