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1.
Biomedicines ; 8(10)2020 Sep 29.
Article in English | MEDLINE | ID: mdl-33003373

ABSTRACT

Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.

2.
Neuroscience ; 442: 183-192, 2020 08 21.
Article in English | MEDLINE | ID: mdl-32652176

ABSTRACT

The bacterial exoenzyme C3 transferase (C3) irreversibly inhibits RhoA GTPase leading to stimulation of axonal outgrowth in injured neurons. C3 has been used successfully in models of neurotrauma and shows promise as an option to support cell survival and axonal growth of dopaminergic (DA) neurons in Parkinson's disease (PD) cell therapy. Whether the continuous expression of C3 in DA neurons is well-tolerated is unknown. To assess the potential neurotoxicity of sustained expression of C3 in DA neurons, we generated Cre recombinase-dependent adeno-associated viral vectors (AAV) for targeted C3 delivery to DA neurons of the mouse substantia nigra pars compacta (SNc). The effect of continuous expression of C3 on DA neurons was assessed by immunohistochemistry and compared to that of Enhanced Yellow Fluorescent Protein (EYFP) as negative controls. We did not find significant reduction of tyrosine hydroxylase (TH) expression levels nor the presence of cleaved activated caspase 3. Astrocytic activation as determined by GFAP expression was comparable to EYFP controls. To evaluate the impact of C3 expression on striatal terminals of the nigrostriatal pathway, we compared the rotational behavior of wildtype mice injected unilaterally with either C3 or 6-hydroxydopamine (6-OHDA). Mice injected with C3 exhibited similar ipsiversive rotations to the site of injection in comparison to control mice injected with EYFP and significantly fewer ipsiversive rotations compared to 6-OHDA lesioned mice. Non-significant difference between C3 and EYFP controls in behavioral and histological analyses demonstrate that transduced DA neurons express C3 continuously without apparent adverse effects, supporting the use of C3 in efficacy studies targeting DA neurons.


Subject(s)
Substantia Nigra , Transferases , Animals , Cell Death , Mice , Oxidopamine , Substantia Nigra/metabolism , Tyrosine 3-Monooxygenase/metabolism
3.
Paediatr Anaesth ; 26(6): 628-36, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27061749

ABSTRACT

BACKGROUND/AIMS: Guidelines for referral of children to general anesthesia (GA) to complete MRI studies are lacking. We devised a pediatric procedural sedation guide to determine whether a pediatric procedural sedation guide would decrease serious adverse events and decrease failed sedations requiring rescheduling with GA. METHODS: We constructed a consensus-based sedation guide by combining a retrospective review of reasons for referral of children to GA (n = 221) with published risk factors associated with the inability to complete the MRI study with sedation. An interrupted time series analysis of 11 530 local sedation records from the Pediatric Sedation Research Consortium between July 2008 and March 2013, adjusted for case-mix differences in the pre- and postsedation guide cohorts, evaluated whether a sedation guide resulted in decreased severe adverse events (SAE) and failed sedation rates. RESULTS: A significant increase in referrals to GA following implementation of a sedation guide occurred (P < 0.001), and fewer children with an ASA-PS class ≥III were sedated using procedural sedation (P < 0.001). There was no decrease in SAE (P = 0.874) or in SAE plus airway obstruction with concurrent hypoxia (P = 0.435). There was no change in the percentage of failed sedations (P = 0.169). CONCLUSIONS: More studies are needed to determine the impact of a sedation guide on pediatric procedural sedation services.


Subject(s)
Anesthesia, General/methods , Magnetic Resonance Imaging , Practice Guidelines as Topic , Referral and Consultation , Child , Child, Preschool , Female , Humans , Infant , Male , Retrospective Studies , Treatment Outcome
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