Preinjury Health Status of Adults With Traumatic Brain Injury: A Preliminary Matched Case-Control Study.

OBJECTIVE: To discern whether there is evidence that individuals who sustained a traumatic brain injury (TBI) had the greater odds of preexisting health conditions and/or poorer health behaviors than matched controls without TBI. SETTING: Brain Injury Inpatient Rehabilitation Unit at Mount Sinai Hospital. Midlife in the United States (MIDUS) control data were collected via random-digit-dialing phone survey. PARTICIPANTS: TBI cases were enrolled in the TBI Health Study and met at least 1 of the following 4 injury severity criteria: abnormal computed tomography scan; Glasgow Coma Scale score between 3 and 12; loss of consciousness greater than 30 minutes; or post-TBI amnesia longer than 24 hours. Sixty-two TBI cases and 171 matched MIDUS controls were included in the analyses; controls were excluded if they reported having a history of head injury. DESIGN: Matched case-control study. MAIN MEASURES: Self-reported measures of depression symptoms, chronic pain, health status, alcohol use, smoking status, abuse of controlled substances, physical activity, physical health composite score, and behavioral health composite score. RESULTS: Pre-index injury depression was nearly 4 times higher in TBI cases than in matched controls (OR= 3.98, 95% CI, 1.71-9.27; P = .001). We found no significant differences in the odds of self-reporting 3 or more medical health conditions in year prior to index injury (OR = 1.52; 95% CI, 0.82-2.81; P = .183) or reporting more risky health behaviors (OR = 1.48; 95% CI; 0.75-2.91; P = .254]) in individuals with TBI than in controls. CONCLUSION: These preliminary findings suggest that the odds of depression in the year prior to index injury far exceed those reported in matched controls. Further study in larger samples is required to better understand the relative odds of prior health problems in those who sustain a TBI, with a goal of elucidating the implications of preinjury health on post-TBI disease burden.

Targeting a Potassium Channel/Syntaxin Interaction Ameliorates Cell Death in Ischemic Stroke.

The voltage-gated K+ channel Kv2.1 has been intimately linked with neuronal apoptosis. After ischemic, oxidative, or inflammatory insults, Kv2.1 mediates a pronounced, delayed enhancement of K+ efflux, generating an optimal intracellular environment for caspase and nuclease activity, key components of programmed cell death. This apoptosis-enabling mechanism is initiated via Zn2+-dependent dual phosphorylation of Kv2.1, increasing the interaction between the channel's intracellular C-terminus domain and the SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor) protein syntaxin 1A. Subsequently, an upregulation of de novo channel insertion into the plasma membrane leads to the critical enhancement of K+ efflux in damaged neurons. Here, we investigated whether a strategy designed to interfere with the cell death-facilitating properties of Kv2.1, specifically its interaction with syntaxin 1A, could lead to neuroprotection following ischemic injury in vivo The minimal syntaxin 1A-binding sequence of Kv2.1 C terminus (C1aB) was first identified via a far-Western peptide screen and used to create a protherapeutic product by conjugating C1aB to a cell-penetrating domain. The resulting peptide (TAT-C1aB) suppressed enhanced whole-cell K+ currents produced by a mutated form of Kv2.1 mimicking apoptosis in a mammalian expression system, and protected cortical neurons from slow excitotoxic injury in vitro, without influencing NMDA-induced intracellular calcium responses. Importantly, intraperitoneal administration of TAT-C1aB in mice following transient middle cerebral artery occlusion significantly reduced ischemic stroke damage and improved neurological outcome. These results provide strong evidence that targeting the proapoptotic function of Kv2.1 is an effective and highly promising neuroprotective strategy.SIGNIFICANCE STATEMENT Kv2.1 is a critical regulator of apoptosis in central neurons. It has not been determined, however, whether the cell death-enabling function of this K+ channel can be selectively targeted to improve neuronal survival following injury in vivo The experiments presented here demonstrate that the cell death-specific role of Kv2.1 can be uniquely modulated to provide neuroprotection in an animal model of acute ischemic stroke. We thus reveal a novel therapeutic strategy for neurological disorders that are accompanied by Kv2.1-facilitated forms of cell death.