Kevin Ka- Wang

Accumulation of Calpain and Caspase-3 Proteolytic Fragments of Brain-Derived αII-Spectrin in Cerebral Spinal Fluid after Middle Cerebral Artery Occlusion in Rats

Preclinical studies have identified numerous neuroprotective drugs that attenuate brain damage and improve functional outcome after cerebral ischemia. Despite this success in animal models, neuroprotective therapies in the clinical setting have been unsuccessful. Identification of biochemical markers common to preclinical and clinical cerebral ischemia will provide a more sensitive and objective measure of injury severity and outcome to facilitate clinical management and treatment. However, there are currently no effective biomarkers available for assessment of stroke. Nonerythroid αII-spectrin is a cytoskeletal protein that is cleaved by calpain and caspase-3 proteases to signature αII-spectrin breakdown products (αII-SBDPs) after cerebral ischemia in rodents. This investigation examined accumulation of calpain- and caspase-3-cleaved αII-SBDPs in cerebrospinal fluid (CSF) of rodents subjected to 2 hours of transient focal cerebral ischemia produced by middle cerebral artery occlusion (MCAO) followed by reperfusion. After MCAO injury, full-length αII-spectrin protein was decreased in brain tissue and increased in CSF from 24 to 72 hours after injury. Whereas αII-SBDPs were undetectable in sham-injured control animals, calpain but not caspase-3 specific αII-SBDPs were significantly increased in CSF after injury. However, caspase-3 αII-SBDPS were observed in CSF of some injured animals. These results indicate that αII-SBDPs detected in CSF after injury, particularly those mediated by calpain, may be useful diagnostic indicators of cerebral infarction that can provide important information about specific neurochemical events that have occurred in the brain after acute stroke.

Quantitative pupillometry and neuron-specific enolase independently predict return of spontaneous circulation following cardiogenic out-of-hospital cardiac arrest: a prospective pilot study

This study aimed to identify neurological and pathophysiological factors that predicted return of spontaneous circulation (ROSC) among patients with out-of-hospital cardiac arrest (OHCA). This prospective 1-year observational study evaluated patients with cardiogenic OHCA who were admitted to a tertiary medical center, Nippon Medical School Hospital. Physiological and neurological examinations were performed at admission for quantitative infrared pupillometry (measured with NPi-200, NeurOptics, CA, USA), arterial blood gas, and blood chemistry. Simultaneous blood samples were also collected to determine levels of neuron-specific enolase (NSE), S-100b, phosphorylated neurofilament heavy subunit, and interleukin-6. In-hospital standard advanced cardiac life support was performed for 30 minutes.The ROSC (n = 26) and non-ROSC (n = 26) groups were compared, which a revealed significantly higher pupillary light reflex ratio, which was defined as the percent change between maximum pupil diameter before light stimuli and minimum pupil diameter after light stimuli, in the ROSC group (median: 1.3% [interquartile range (IQR): 0.0–2.0%] vs. non-ROSC: (median: 0%), (Cut-off: 0.63%). Furthermore, NSE provided the great sensitivity and specificity for predicting ROSC, with an area under the receiver operating characteristic curve of 0.86, which was created by plotting sensitivity and 1-specificity. Multivariable logistic regression analyses revealed that the independent predictors of ROSC were maximum pupillary diameter (odds ratio: 0.25, 95% confidence interval: 0.07–0.94, P = 0.04) and NSE at admission (odds ratio: 0.96, 95% confidence interval: 0.93–0.99, P = 0.04). Pupillary diameter was also significantly correlated with NSE concentrations (r = 0.31, P = 0.027). Conclusively, the strongest predictors of ROSC among patients with OHCA were accurate pupillary diameter and a neuronal biomarker, NSE. Quantitative pupillometry may help guide the decision to terminate resuscitation in emergency departments using a neuropathological rationale. Further large-scale studies are needed.

Multi-Center Pre-clinical Consortia to Enhance Translation of Therapies and Biomarkers for Traumatic Brain Injury: Operation Brain Trauma Therapy and Beyond

Current approaches have failed to yield success in the translation of neuroprotective therapies from the pre-clinical to the clinical arena for traumatic brain injury (TBI). Numerous explanations have been put forth in both the pre-clinical and clinical arenas. Operation Brain Trauma Therapy (OBTT), a pre-clinical therapy and biomarker screening consortium has, to date, evaluated 10 therapies and assessed three serum biomarkers in nearly 1,500 animals across three rat models and a micro pig model of TBI. OBTT provides a unique platform to exploit heterogeneity of TBI and execute the research needed to identify effective injury specific therapies toward precision medicine. It also represents one of the first multi-center pre-clinical consortia for TBI, and through its work has yielded insight into the challenges and opportunities of this approach. In this review, important concepts related to consortium infrastructure, modeling, therapy selection, dosing and target engagement, outcomes, analytical approaches, reproducibility, and standardization will be discussed, with a focus on strategies to embellish and improve the chances for future success. We also address issues spanning the continuum of care. Linking the findings of optimized pre-clinical consortia to novel clinical trial designs has great potential to help address the barriers in translation and produce successes in both therapy and biomarker development across the field of TBI and beyond.