Persistent white matter vulnerability in a mouse model of mild traumatic brain injury.

BACKGROUND: Following one mild traumatic brain injury (mTBI), there is a window of vulnerability during which subsequent mTBIs can cause substantially exacerbated impairments. Currently, there are no known methods to monitor, shorten or mitigate this window. METHODS: To characterize a preclinical model of this window of vulnerability, we first gave male and female mice one or two high-depth or low-depth mTBIs separated by 1, 7, or 14 days. We assessed brain white matter integrity using silver staining within the corpus callosum and optic tracts, as well as behavioural performance on the Y-maze test and visual cliff test. RESULTS: The injuries resulted in windows of white matter vulnerability longer than 2 weeks but produced no behavioural impairments. Notably, this window duration is substantially longer than those reported in any previous preclinical vulnerability study, despite our injury model likely being milder than the ones used in those studies. We also found that sex and impact depth differentially influenced white matter integrity in different white matter regions. CONCLUSIONS: These results suggest that the experimental window of vulnerability following mTBI may be longer than previously reported. Additionally, this work highlights the value of including white matter damage, sex, and replicable injury models for the study of post-mTBI vulnerability and establishes important groundwork for the investigation of potential vulnerability mechanisms, biomarkers, and therapies.

Electrophysiological Measurement of Rat Atrial Epicardium Using a Novel Stereotaxic Apparatus.

Flexible, in vivo maneuverable electrophysiology mapping techniques are not available in rat models. A novel cardiac stereotactic electrophysiology epicardial mapping system (CREAMS) allows for various measurements, including: (1) recording unipolar electrograms at multiple sites; (2) positioning of mapped sites and precision testing (Distance between the two "centers" = 297 ± 54 µm, n = 15); (3) evaluation of electrophysiology in an in vivo Sprague-Dawley rat model with high-frequency stimulation (HFS)-induced Atrial fibrillation (AF) at high right atrium (HRA) sites. We found that of the right atrium dispersion of effective refractory period (P < 0.05) and the window of vulnerability (P < 0.01) were significantly increased (P < 0.05) after HRA HFS. CREAMS has the potential for convenient electrophysiology assessment in a rat AF model through stereo-positioning, and flexible operating manipulation.

As temperature increases, predator attack rate is more important to survival than a smaller window of prey vulnerability.

Climate change can have strong effects on species interactions and community structure. Temperature-dependent effects on predator-prey interactions are a major mechanism through which these effects occur. To understand the net effects of predator attack rates and dynamic windows of prey vulnerability, we examined the impacts of temperature on the interaction of a caterpillar (Arctia virginalis) and its ant predator (Formica lasioides). We conducted field experiments to examine attack rates on caterpillars relative to temperature, ant abundance, and body size, and laboratory experiments to determine the effects of temperature on caterpillar growth. We modeled temperature-dependent survival based on the integrated effects of temperature-dependent growth and temperature- and size-dependent predation. Attack rates on caterpillars increased with warming and ant recruitment, but decreased with caterpillar size. Caterpillar growth rates increased with temperature, narrowing the window of vulnerability. The model predicted that net caterpillar survival would decrease with temperature, suggesting that A. virginalis populations could be depressed with future climate warming. Theoretical work suggests that the net outcome of predator-prey interactions with increasing temperature depends on the respective responses of interacting species in terms of velocity across space, whereas the present study suggests the importance of effects of temperature on prey window of vulnerability, or "velocity" across time.

Trimester-specific hemodynamics of per- and polyfluoroalkyl substances and its relation to lipid profile in pregnant women.

Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants widely detected in blood from pregnant women, yet limited study evaluated the trimester-specific variance of serum PFAS, and even less is known for the window of vulnerability to lipids metabolism interrupting effects of PFAS during pregnancy. We quantified 16 legacy, 3 emerging PFAS, and lipid biomarkers in 286 serum samples from 118 pregnant women. All target PFAS, except perfluorotridecanoic acid (PFTrDA), in maternal serum showed moderate to low temporal irregular variability across gestation (average intraclass correlation coefficients ≥ 0.57), while the generalized estimating equations showed a significant declining trend in the serum levels during pregnancy (p for trend < 0.05). The decline of 6:2 chlorinated polyfluorinated ether sulfonate in maternal serum was the greatest with a change of - 21.63% from 1st to 2nd trimester, which indicated a possible higher accumulation of this emerging PFAS in fetal compartment. Multiple linear regression, multiple informant model and Bayesian kernel machine regression showed a higher vulnerability in the 1st trimester to effects of PFAS exposure on serum lipids of pregnant women. The results highlighted the importance of the study timing of PFAS exposure during pregnancy.

Elimination of Purkinje Fibers by Electroporation Reduces Ventricular Fibrillation Vulnerability.

Background The Purkinje network appears to play a pivotal role in the triggering as well as maintenance of ventricular fibrillation. Irreversible electroporation ( IRE ) using direct current has shown promise as a nonthermal ablation modality in the heart, but its ability to target and ablate the Purkinje tissue is undefined. Our aim was to investigate the potential for selective ablation of Purkinje/fascicular fibers using IRE . Methods and Results In an ex vivo Langendorff model of canine heart (n=8), direct current was delivered in a unipolar manner at various dosages from 750 to 2500 V, in 10 pulses with a 90-µs duration at a frequency of 1 Hz. The window of ventricular fibrillation vulnerability was assessed before and after delivery of electroporation energy using a shock on T-wave method. IRE consistently eradicated all Purkinje potentials at voltages between 750 and 2500 V (minimum field strength of 250-833 V/cm). The ventricular electrogram amplitude was only minimally reduced by ablation: 0.6±2.3 mV ( P=0.03). In 4 hearts after IRE delivery, ventricular fibrillation could not be reinduced. At baseline, the lower limit of vulnerability to ventricular fibrillation was 1.8±0.4 J, and the upper limit of vulnerability was 19.5±3.0 J. The window of vulnerability was 17.8±2.9 J. Delivery of electroporation energy significantly reduced the window of vulnerability to 5.7±2.9 J ( P=0.0003), with a postablation lower limit of vulnerability=7.3±2.63 J, and the upper limit of vulnerability=18.8±5.2 J. Conclusions Our study highlights that Purkinje tissue can be ablated with IRE without any evidence of underlying myocardial damage.

Arrhythmia Vulnerability in Diabetic Cardiac Tissue is Species-Dependent: Effects of I KATP, Uncoupling, and Connexin Lateralization.

Amongst the complications of diabetes is arrhythmia, the risk of which depends on multiple factors. This study was designed to investigate several factors, including the effects of ATP-sensitive potassium current, lateralized connexins, and gap junction uncoupling. ATP-sensitive potassium channel (I KATP) opening is caused by ischemia, which can occur in diabetic or non-diabetic hearts. I KATP opening was simulated in this work to determine if the risk of ischemia-induced arrhythmias is affected by diabetes. Simulations were performed using healthy and diabetic models of rat and rabbit ventricle. Results showed that the diabetic rat model is less vulnerable to reentrant arrhythmia than the healthy rat model. The diabetic rabbit model was more vulnerable to reentrant arrhythmia than the healthy rabbit model. In both rabbit models, the vulnerability increased as the gap junctional coupling decreased. Opening of I KATP resulted in larger window of vulnerability. Conduction reserve was simulated based on 1D simulations for both rat and rabbit models. There was no difference between rat and rabbit conduction reserve. Our results showed that the simulation results are model-dependent, i.e., results from the rabbit model are similar to human clinical data, while the results from the rat model contradict human clinical observations, suggesting a significant species-dependence in arrhythmia vulnerability in the diabetic heart.

"Playing Through It": Delayed Reporting and Removal From Athletic Activity After Concussion Predicts Prolonged Recovery.

CONTEXT: Preclinical research has demonstrated a window of vulnerability in the immediate aftermath of concussion wherein continued activity and stimulation can impair or prolong neurobehavioral recovery. However, this concept has not been quantified in a human population. OBJECTIVE: To examine the effect of delayed reporting and removal from athletic activity after concussion on recovery time. DESIGN: Cross-sectional study. SETTING: A National Collegiate Athletic Association Division I university. PATIENTS OR OTHER PARTICIPANTS: Ninety-seven athletes who sustained a sport-related concussion between 2008 and 2015 were analyzed (age = 20.4 ± 1.3 years). Athletes were grouped as immediate removal from activity (I-RFA) or delayed removal from activity (D-RFA). MAIN OUTCOME MEASURE(S): Days missed was defined as the number of days between the concussion-causing event and clearance for return to contact. Associations between RFA group and prolonged (8 or more days') versus normal (7 or fewer days') recovery were also analyzed. RESULTS: Fifty (51.5%) of the 97 athletes did not immediately report concussion symptoms. The D-RFA athletes averaged 4.9 more days missed than the I-RFA athletes. Membership in the specific RFA group predicted days missed even after controlling for sex, concussion history, learning disability or attention-deficit/hyperactivity disorder diagnosis, diagnosed psychological disorder, and acute symptom severity (R( 2) change = 0.097, ß = .319, P = .002). The D-RFA athletes were approximately 2.2 times more likely to have a prolonged recovery (8 or more days) compared with the I-RFA athletes (χ(2) = 10.268, P = .001, ϕ = 0.325). CONCLUSIONS: Athletes who do not immediately report symptoms of a concussion and continue to participate in athletic activity are at risk for longer recoveries than athletes who immediately report symptoms and are immediately removed from activity. Continuing to participate in athletic activity during the immediate aftermath of a concussion potentially exposes the already injured brain to compounded neuropathophysiologic processes.