Project description:Pharmacotherapy for traumatic brain injury (TBI) is focused on resuscitation, prevention of secondary injury, rehabilitation and recovery. Pharmacogenomics may play a role in TBI for predicting therapies for sedation, analgesia, seizure prevention, intracranial pressure-directed therapy and neurobehavioral/psychiatric symptoms. Research into genetic predictors of outcomes and susceptibility to complications may also help clinicians to tailor therapeutics for high-risk individuals. Additionally, the expanding use of genomics in the drug development pipeline has provided insight to novel investigational and repurposed medications that may be useful in the treatment of TBI and its complications. Genomics in the context of treatment and prognostication for patients with TBI is a promising area for clinical progress of pharmacogenomics.
Project description:History of traumatic brain injury (TBI) represents a significant risk factor for development of dementia and neurodegenerative disorders in later life. While histopathological sequelae and neurological diagnostics of TBI are well defined, the molecular events linking the post-TBI signaling and neurodegenerative cascades remain unknown. It is not only due to the brain's inaccessibility to direct molecular analysis but also due to the lack of well-defined and highly informative peripheral biomarkers. MicroRNAs (miRNAs) in blood are promising candidates to address this gap. Using integrative bioinformatics pipeline including miRNA:target identification, pathway enrichment, and protein-protein interactions analysis we identified set of genes, interacting proteins, and pathways that are connected to previously reported peripheral miRNAs, deregulated following severe traumatic brain injury (sTBI) in humans. This meta-analysis revealed a spectrum of genes closely related to critical biological processes, such as neuroregeneration including axon guidance and neurite outgrowth, neurotransmission, inflammation, proliferation, apoptosis, cell adhesion, and response to DNA damage. More importantly, we have identified molecular pathways associated with neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, based on purely peripheral markers. The pathway signature after acute sTBI is similar to the one observed in chronic neurodegenerative conditions, which implicates a link between the post-sTBI signaling and neurodegeneration. Identified key hub interacting proteins represent a group of novel candidates for potential therapeutic targets or biomarkers.
Project description:Severe traumatic brain injury (sTBI) is a major contributor to long-term disability and a leading cause of death worldwide. Medical management of the sTBI patient, beginning with prehospital triage, is aimed at preventing secondary brain injury. This review discusses prehospital and emergency department management of sTBI, as well as aspects of TBI management in the intensive care unit where advances have been made in the past decade. Areas of emphasis include intracranial pressure management, neuromonitoring, management of paroxysmal sympathetic hyperactivity, neuroprotective strategies, prognostication, and communication with families about goals of care. Where appropriate, differences between the third and fourth editions of the Brain Trauma Foundation guidelines for the management of severe traumatic brain injury are highlighted.
Project description:Improved understanding of the molecular mechanisms of secondary brain injury has informed the optimum depth and duration of cooling and led to increased clinical interest in the therapeutic moderate hypothermia for severe traumatic brain injury over the past two decades. Although several large multi-center clinical trials have not found a treatment effect, multiple single-center trials have, and a recent meta-analysis by Crossley and colleagues now finds that the cumulative findings of those single-center trials dilute the multi-center trial results and show an overall reduction in mortality and poor outcomes associated with cooling. The need for consistent support of key physiologic parameters during cooling is emphasized by this finding.
Project description:A 23-year-old man with recurrent acute myeloid leukemia (AML) underwent successful reinduction and was judged posttherapy to be in complete remission. Soon thereafter, he complained of pain in his left buttock radiating into his left posterior thigh. Neurologic examination was unremarkable. Radiographic evaluation demonstrated a left S2 lesion suggestive of a nerve sheath tumor (figure 1). An open biopsy was performed that revealed a chloroma pathologically (figure 2), sometimes referred to as a myeloid sarcoma.(1,2) Most chloromas are found in patients with recurrent AML and are overwhelmingly intracranial.(1) Infrequently, chloromas are paraspinal, and in this location present with epidural spinal cord compression.(2) Intraspinal invasion by a chloroma is rare. Systemic evaluation confirmed recurrent AML, for which he was successfully treated with reinduction and whole-body irradiation followed by an allogeneic transplant. He is currently disease-free and neurologically asymptomatic 1 year posttransplant.