Probabilistic Finite Element Analysis of Human Rib Biomechanics: A Framework for Improved Generalizability.

In dynamic impact events, thoracic injuries often involve rib fractures, which are closely related to injury severity. Previous studies have investigated the behavior of isolated ribs under impact loading conditions, but often neglected the variability in anatomical shape and tissue material properties. In this study, we used probabilistic finite element analysis and statistical shape modeling to investigate the effect of population-wide variability in rib cortical bone tissue mechanical properties and rib shape on the biomechanical response of the rib to impact loading. Using the probabilistic finite element analysis results, a response surface model was generated to rapidly investigate the biomechanical response of an isolated rib under dynamic anterior-posterior load given the variability in rib morphometry and tissue material properties. The response surface was used to generate pre-fracture force-displacement computational corridors for the overall population and a population sub-group of older mid-sized males. When compared to the experimental data, the computational mean response had a RMSE of 4.28N (peak force 94N) and 6.11N (peak force 116N) for the overall population and sub-group respectively, whereas the normalized area metric when comparing the experimental and computational corridors ranged from 3.32% to 22.65% for the population and 10.90% to 32.81% for the sub-group. Furthermore, probabilistic sensitivities were computed in which the contribution of uncertainty and variability of the parameters of interest was quantified. The study found that rib cortical bone elastic modulus, rib morphometry and cortical thickness are the random variables that produce the largest variability in the predicted force-displacement response. The proposed framework offers a novel approach for accounting biological variability in a representative population and has the potential to improve the generalizability of findings in biomechanical studies.

The I-PREDICT 50th Percentile Male Warfighter Finite Element Model: Development and Validation of the Thoracolumbar Spine.

Military personnel are commonly at risk of lower back pain and thoracolumbar spine injury. Human volunteers and postmortem human subjects have been used to understand the scenarios where injury can occur and the tolerance of the warfighter to these loading regimes. Finite element human body models (HBMs) can accurately simulate the mechanics of the human body and are a useful tool for understanding injury. In this study, a HBM thoracolumbar spine was developed and hierarchically ï»¿validated as part of the Incapacitation Prediction for Readiness in Expeditionary Domains: an Integrated Computational Tool (I-PREDICT) program. Constitutive material models were sourced from literature and the vertebrae and intervertebral discs were hexahedrally meshed from a 50th percentile male CAD dataset. Ligaments were modeled through attaching beam elements at the appropriate anatomical insertion sites. 94 simulations were replicated from experimental PMHS tests at the vertebral body, functional spinal unit (FSU), and regional lumbar spine levels. The BioRank (BRS) biofidelity ranking system was used to assess the response of the I-PREDICT model. At the vertebral body level, the I-PREDICT model showed good agreement with experimental results. The I-PREDICT FSUs showed good agreement in tension and compression and had comparable stiffness values in flexion, extension, and axial rotation. The regional lumbar spine exhibited "good" biofidelity when tested in tension, compression, extension, flexion, posterior shear, and anterior shear (BRS regional average = 1.05). The validated thoracolumbar spine of the I-PREDICT model can be used to better understand and mitigate injury risk to the warfighter.

Effect of body size and enhanced helmet systems on risk for motorsport drivers.

OBJECTIVE: Computational modeling has been shown to be a useful tool for simulating representative motorsport impacts and analyzing data for relative injury risk assessment. Previous studies have used computational modeling to analyze the probability of injury in specific regions of a 50th percentile male driver. However, NASCAR drivers can represent a large range in terms of size and female drivers are becoming increasingly more common in the sport. Additionally, motorsport helmets can be outfitted with external attachments, or enhanced helmet systems (EHS), whose effect is unknown relative to head and neck kinematics. The current study expands on this previous work by incorporating the F05-OS and M95-OS into the motorsport environment in order to determine correlations between metrics and factors such as PDOF, resultant ΔV occupant size, and EHS. METHODS: A multi-step computational process was used to integrate the Global Human Body Models Consortium family of simplified occupant models into a motorsport environment. This family included the 5th percentile female (F05-OS), 50th percentile male (M50-OS), and 95th percentile male (M95-OS), which provide a representative range for the size and sex of drivers seen in NASCAR's racing series'. A series of 45 representative impacts, developed from real-world crash data, and set of observed on-track severe impacts were conducted with these models. These impacts were run in triplicate for three helmet configurations: bare helmet, helmet with visor, helmet with visor and camera. This resulted in 450 total simulations. A paired t-test was initially performed as an exploratory analysis to study the effect of helmet configuration on 10 head and neck injury metrics. A mixed-effects model with unstructured covariance matrix was then utilized to correlate the effect between five independent variables (resultant ΔV, body size, helmet configuration, impact quadrant, and steering wheel position) and a selection of 25 metrics. All simulations were conducted in LS-Dyna R. 9.1. RESULTS: Risk estimates from the M50-OS with bare helmet were used as reference values to determine the effect of body size and helmet configuration. The paired t-test found significance for helmet configuration in select head-neck metrics, but the relative increase in these metrics was low and not likely to increase injury risk. The mixed-effects model analyzed statistical relationships across multiple types of variables. Within the mixed-effects model, no significance was found between helmet configuration and metrics. The greatest effect was found from resultant ΔV, body size, and impact quadrant. CONCLUSIONS: Overall, smaller drivers showed statistically significant reductions in injury metrics, while larger drivers showed statistically significant increases. Lateral impacts showed the greatest effect on neck metrics and, on average, showed decreases for head metrics related to linear acceleration and increases for head metrics related to angular velocity. HBM parametric studies such as this may provide an avenue to assist injury detection for motorsport incidents, improve triage effectiveness, and assist in the development of safety standards.

Rank normalization empowers a t-test for microbiome differential abundance analysis while controlling for false discoveries.

A major task in the analysis of microbiome data is to identify microbes associated with differing biological conditions. Before conducting analysis, raw data must first be adjusted so that counts from different samples are comparable. A typical approach is to estimate normalization factors by which all counts in a sample are multiplied or divided. However, the inherent variation associated with estimation of normalization factors are often not accounted for in subsequent analysis, leading to a loss of precision. Rank normalization is a nonparametric alternative to the estimation of normalization factors in which each count for a microbial feature is replaced by its intrasample rank. Although rank normalization has been successfully applied to microarray analysis in the past, it has yet to be explored for microbiome data, which is characterized by high frequencies of 0s, strongly correlated features and compositionality. We propose to use rank normalization as an alternative to the estimation of normalization factors and examine its performance when paired with a two-sample t-test. On a rigorous 3rd-party benchmarking simulation, it is shown to offer strong control over the false discovery rate, and at sample sizes greater than 50 per treatment group, to offer an improvement in performance over commonly used normalization factors paired with t-tests, Wilcoxon rank-sum tests and methodologies implemented by R packages. On two real datasets, it yielded valid and reproducible results that were strongly in agreement with the original findings and the existing literature, further demonstrating its robustness and future potential. Availability: The data underlying this article are available online along with R code and supplementary materials at https://github.com/matthewlouisdavisBioStat/Rank-Normalization-Empowers-a-T-Test.

Simulation-based assessment of injury risk for an average male motorsport driver.

OBJECTIVE: While well-protected through a variety of safety countermeasures, motorsports drivers can be exposed to a large variety of crash modes and severities. Computational human body models (HBMs) are currently used to assess occupant safety for the general driving public in production vehicles. The purpose of this study was to incorporate a HBM into a motorsport environment using a simulation-based approach and provide quantitative data on relative risk for on-track motorsport crashes. METHODS: Unlike a traditional automotive seat, the NASCAR driver environment is driver-customized and form-fitting. A multi-step process was developed to integrate the Global Human Body Models Consortium (GHBMC) 50th percentile male simplified occupant into a representative motorsport environment which includes a donned helmet, a 7-point safety belt system, head and neck restraint (HNR), poured-foam seat, steering wheel, and leg enclosure. A series of 45 representative impacts, developed from real-world crash data, of varying severity (10 kph ≤ ΔV ≤ 100 kph) and impact direction (∼290° ≤ PDOF ≤ 20°) were conducted with the GHBMC 50th percentile male simplified occupant (M50-OS v2.2). Kinematic and kinetic data, and a variety of injury criteria, were output from each of the simulations and used to calculate AIS 1+, 2+, and 3+ injury risk. All simulations were conducted in LS-Dyna R. 9.1. RESULTS: Injury risk of the occupant using the previously mentioned injury criteria was calculated for the head, neck, thorax, and lower extremity, and the probability of injury for each region was plotted. Of the simulated impacts, five had a maximum AIS 1+ injury risk >20%, six had a maximum AIS 2+ injury risk >10%, and no cases had a maximum AIS 3+ injury >1%. Overall, injury risk estimates were reasonable compared to on-track data reported from Patalak et al. (2020). CONCLUSIONS: Beyond injury risk, the study is the first of its kind to provide mechanical loading values likely experienced during motorsports crash incidents with crash pulses developed from real-world data. Given the severity of the crash pulses, the simulated environments reinforce the need for the robust safety environment implemented by NASCAR.

Injury risk curves in far-side lateral motor vehicle crashes by AIS level, body region and injury code.

OBJECTIVE: The objective of this study was to develop injury risk curves as a function of change in vehicle velocity for occupants in far-side lateral motor vehicle crashes (MVCs) by AIS level, body region, and specific AIS codes that commonly occur in this crash mode. METHODS: The National Automotive Sampling System-Crashworthiness Data System (NASS-CDS) years 2000-2015 database was queried, resulting in 4,495 non-weighted far-side crashes. For each case, occupant age, sex, and the following metadata were collected: vehicle model year, vehicle body type, lateral delta-v, normalized PDOF, multiple impacts, belt use, seat position, object contacted, striking vehicle body type, maximum crush extent and side airbag deployment. Multivariable logistic regression was used to develop risk curves for AIS 2+ through 5+ injuries, AIS 2+ injuries by body region (head, thorax, lower extremity), and for each of the 10 most frequent far-side AIS 2+ injuries. Significant covariates were determined by backwards elimination (p < 0.05). The full dataset and a subsampled dataset of only cases with side airbag deployment were used to develop risk curves. RESULTS: For AIS 2+ through 5+ injury, greater delta-V was associated with greater injury risk (OR's: 2.48-3.66 per 11.9 kph increase) and belt use was associated with lower risk (OR's: 0.04-0.36 compared to unbelted). Multiple impacts were significant predictors of increased AIS 3+, 4+ and 5+ injury risk (OR's: 2.56, 2.27 and 2.83 compared to single impact). For AIS 2+ body region injuries, lateral delta-V and maximum CDC extent were positively associated with increased head, thorax and lower extremity injury risk while belt use was associated with lower risk. Increased lateral delta-v, unbelted status, and greater maximum CDC extent frequently increased injury risk for the most common far-side injuries. Side airbag deployment was not a significant covariate for the injury risk models. CONCLUSIONS: The resulting risk models expand upon previous literature gaps to provide a more comprehensive view of contributors to injury risk for occupants in far-side MVCs. This study yields risk curves based on the latest available NASS-CDS data.

The Tri-phasic Role of Hydrogen Peroxide in Blood-Brain Barrier Endothelial cells.

Hydrogen peroxide (H2O2) plays an important role physiologically as the second messenger and pathologically as an inducer of oxidative stress in injury, ischemia and other conditions. However, it is unclear how H2O2 influences various cellular functions in health and disease differentially, particularly in the blood-brain barrier (BBB). We hypothesized that the change in cellular concentrations of H2O2 is a major contributor in regulation of angiogenesis, barrier integrity/permeability and cell death/apoptosis in BBB endothelial cells. Rat brain microvascular endothelial cells were exposed to various concentrations of H2O2 (1 nM to 25 mM). BBB tight junction protein (zonula ocludens-1; ZO-1) localization and expression, cytoskeletal organization, monolayer permeability, angiogenesis, cell viability and apoptosis were evaluated. H2O2 at low concentrations (0.001 µM to 1 µM) increased endothelial cell tube formation indicating enhanced angiogenesis. H2O2 at 100 µM and above induced monolayer hyperpermeability significantly (p < 0.05). H2O2 at 10 mM and above decreased cell viability and induced apoptosis (p < 0.05). There was a decrease of ZO-1 tight junction localization with 100 µm H2O2, but had no effect on protein expression. Cytoskeletal disorganizations were observed starting at 1 µm. In conclusion H2O2 influences angiogenesis, permeability, and cell death/apoptosis in a tri-phasic and concentration-dependent manner in microvascular endothelial cells of the blood-brain barrier.

Cirrhosis, Operative Trauma, Transfusion, and Mortality: A Multicenter Retrospective Observational Study.

BACKGROUND: In trauma patients with cirrhosis who require laparotomy, little data exists to establish clinical predictors of the outcome. We sought to determine the prognosticators of mortality in this population. METHODS: We performed a 10-year review at four, busy Level I trauma centers of patients with cirrhosis identified during trauma laparotomy. We compared vital signs, laboratory values, and transfusion requirements for those who survived versus those who died. A linear regression was then conducted to determine the variables associated with death in this population. RESULTS: A total of 66 patients were included and 47% (31/66) died. The model for end-stage liver disease (MELD) score was low (7.8 in Lived, 10.2 in Died). Packed red blood cell (PRBC) transfusion at six hours was greater in those who died; those receiving > 6 units of PRBCs at 6 hours had an increased likelihood of death (odds ratio OR 5.8 (95% CI 1.9, 17.4)). All patients receiving ≥ 17 units of PRBCs died. We found an association between lower preoperative platelets (PLTs), higher preoperative international normalized ratio (INR) and partial thromboplastin time (PTT), lower preoperative pH (presence of profound acidemia), increased intraoperative crystalloid use, and increased intraoperative blood product administration to be associated with death (p < 0.05). CONCLUSIONS: Cirrhotic trauma patients requiring laparotomy should be considered to have a high chance of mortality if they receive six or more PRBCs, are acidotic (pH ≤ 7.25) at the time of hospital arrival, or have coagulopathy at the time of admission (INR > 1.2, PTT > 40).

Finite Element-Based Pelvic Injury Metric Creation and Validation in Lateral Impact for a Human Body Model.

Pelvic fractures are serious injuries resulting in high mortality and morbidity. The objective of this study is to develop and validate local pelvic anatomical, cross section-based injury risk metrics for a finite element (FE) model of the human body. Cross-sectional instrumentation was implemented in the pelvic region of the Global Human Body Models Consortium (GHBMC M50-O) 50th percentile detailed male FE model (v4.3). In total, 25 lateral impact FE simulations were performed using input data from cadaveric lateral impact tests performed by Bouquet et al. The experimental force-time data were scaled using five normalization techniques, which were evaluated using log rank, Wilcoxon rank sum, and correlation and analysis (CORA) testing. Survival analyses with Weibull distribution were performed on the experimental peak force (scaled and unscaled) and the simulation test data to generate injury risk curves (IRCs) for total pelvic injury. Additionally, IRCs were developed for regional injury using cross-sectional forces from the simulation results and injuries documented in the experimental autopsies. These regional IRCs were also evaluated using the receiver operator characteristic (ROC) curve analysis. Based on the results of all the evaluation methods, the equal stress equal velocity (ESEV) and ESEV using effective mass (ESEV-EM) scaling techniques performed best. The simulation IRC shows slight under prediction of injury in comparison to these scaled experimental data curves. However, this difference was determined not to be statistically significant. Additionally, the ROC curve analysis showed moderate predictive power for all regional IRCs.

A Mouse Controlled Cortical Impact Model of Traumatic Brain Injury for Studying Blood-Brain Barrier Dysfunctions.

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. It is a silently growing epidemic with multifaceted pathogenesis, and current standards of treatments aim to target only the symptoms of the primary injury, while there is a tremendous need to explore interventions that can halt the progression of the secondary injuries. The use of a reliable animal model to study and understand the various aspects the pathobiology of TBI is extremely important in therapeutic drug development against TBI-associated complications. The controlled cortical impact (CCI) model of TBI described here, uses a mechanical impactor to inflict a mechanical injury into the mouse brain. This method is a reliable and reproducible approach to inflict mild, moderate or severe injuries to the animal for studying TBI-associated blood-brain barrier (BBB) dysfunctions, neuronal injuries, brain edema, neurobehavioral changes, etc. The present method describes how the CCI model could be utilized for determining the BBB dysfunction and hyperpermeability associated with TBI. Blood-brain barrier disruption is a hallmark feature of the secondary injury that occur following TBI, frequently associated with leakage of fluid and proteins into the extravascular space leading to vasogenic edema and elevation of intracranial pressure. The method described here focuses on the development of a CCI-based mouse model of TBI followed by the evaluation of BBB integrity and permeability by intravital microscopy as well as Evans Blue extravasation assay.

Implementation of a standardized handoff protocol for post-operative admissions to the surgical intensive care unit.

BACKGROUND: The transfer of critically ill patients from the operating room (OR) to the surgical intensive care unit (SICU) involves handoffs between multiple providers. Incomplete handoffs lead to poor communication, a major contributor to sentinel events. Our aim was to determine whether handoff standardization led to improvements in caregiver involvement and communication. METHODS: A prospective intervention study was designed to observe thirty one patient handoffs from OR to SICU for 49 critical parameters including caregiver presence, peri-operative details, and time required to complete key steps. Following a six month implementation period, thirty one handoffs were observed to determine improvement. RESULTS: A significant improvement in presence of physician providers including intensivists and surgeons was observed (p = 0.0004 and p < 0.0001, respectively). Critical details were communicated more consistently, including procedure performed (p = 0.0048), complications (p < 0.0001), difficult airways (p < 0.0001), ventilator settings (p < 0.0001) and pressor requirements (p = 0.0134). Conversely, handoff duration did not increase significantly (p = 0.22). CONCLUSIONS: Implementation of a standardized protocol for handoffs between OR and SICU significantly improved caregiver involvement and reduced information omission without affecting provider time commitment.

Modular use of human body models of varying levels of complexity: Validation of head kinematics.

OBJECTIVE: The significant computational resources required to execute detailed human body finite-element models has motivated the development of faster running, simplified models (e.g., GHBMC M50-OS). Previous studies have demonstrated the ability to modularly incorporate the validated GHBMC M50-O brain model into the simplified model (GHBMC M50-OS+B), which allows for localized analysis of the brain in a fraction of the computation time required for the detailed model. The objective of this study is to validate the head and neck kinematics of the GHBMC M50-O and M50-OS (detailed and simplified versions of the same model) against human volunteer test data in frontal and lateral loading. Furthermore, the effect of modular insertion of the detailed brain model into the M50-OS is quantified. METHODS: Data from the Navy Biodynamics Laboratory (NBDL) human volunteer studies, including a 15g frontal, 8g frontal, and 7g lateral impact, were reconstructed and simulated using LS-DYNA. A five-point restraint system was used for all simulations, and initial positions of the models were matched with volunteer data using settling and positioning techniques. Both the frontal and lateral simulations were run with the M50-O, M50-OS, and M50-OS+B with active musculature for a total of nine runs. RESULTS: Normalized run times for the various models used in this study were 8.4 min/ms for the M50-O, 0.26 min/ms for the M50-OS, and 0.97 min/ms for the M50-OS+B, a 32- and 9-fold reduction in run time, respectively. Corridors were reanalyzed for head and T1 kinematics from the NBDL studies. Qualitative evaluation of head rotational accelerations and linear resultant acceleration, as well as linear resultant T1 acceleration, showed reasonable results between all models and the experimental data. Objective evaluation of the results for head center of gravity (CG) accelerations was completed via ISO TS 18571, and indicated scores of 0.673 (M50-O), 0.638 (M50-OS), and 0.656 (M50-OS+B) for the 15g frontal impact. Scores at lower g levels yielded similar results, 0.667 (M50-O), 0.675 (M50-OS), and 0.710 (M50-OS+B) for the 8g frontal impact. The 7g lateral simulations also compared fairly with an average ISO score of 0.565 for the M50-O, 0.634 for the M50-OS, and 0.606 for the M50-OS+B. The three HBMs experienced similar head and neck motion in the frontal simulations, but the M50-O predicted significantly greater head rotation in the lateral simulation. CONCLUSION: The greatest departure from the detailed occupant models were noted in lateral flexion, potentially indicating the need for further study. Precise modeling of the belt system however was limited by available data. A sensitivity study of these parameters in the frontal condition showed that belt slack and muscle activation have a modest effect on the ISO score. The reduction in computation time of the M50-OS+B reduces the burden of high computational requirements when handling detailed HBMs. Future work will focus on harmonizing the lateral head response of the models and studying localized injury criteria within the brain from the M50-O and M50-OS+B.

Development and Full Body Validation of a 5th Percentile Female Finite Element Model.

To mitigate the societal impact of vehicle crash, researchers are using a variety of tools, including finite element models (FEMs). As part of the Global Human Body Models Consortium (GHBMC) project, comprehensive medical image and anthropometrical data of the 5th percentile female (F05) were acquired for the explicit purpose of FEM development. The F05-O (occupant) FEM model consists of 981 parts, 2.6 million elements, 1.4 million nodes, and has a mass of 51.1 kg. The model was compared to experimental data in 10 validation cases ranging from localized rigid hub impacts to full body sled cases. In order to make direct comparisons to experimental data, which represent the mass of an average male, the model was compared to experimental corridors using two methods: 1) post-hoc scaling the outputs from the baseline F05-O model and 2) geometrically morphing the model to the body habitus of the average male to allow direct comparisons. This second step required running the morphed full body model in all 10 simulations for a total of 20 full body simulations presented. Overall, geometrically morphing the model was found to more closely match the target data with an average ISO score for the rigid impacts of 0.76 compared to 0.67 for the scaled responses. Based on these data, the morphed model was then used for model validation in the vehicle sled cases. Overall, the morphed model attained an average weighted score of 0.69 for the two sled impacts. Hard tissue injuries were also assessed and the baseline F05-O model was found to predict a greater occurrence of pelvic fractures compared to the GHBMC average male model, but predicted fewer rib fractures.

An Objective Evaluation of Mass Scaling Techniques Utilizing Computational Human Body Finite Element Models.

Biofidelity response corridors developed from post-mortem human subjects are commonly used in the design and validation of anthropomorphic test devices and computational human body models (HBMs). Typically, corridors are derived from a diverse pool of biomechanical data and later normalized to a target body habitus. The objective of this study was to use morphed computational HBMs to compare the ability of various scaling techniques to scale response data from a reference to a target anthropometry. HBMs are ideally suited for this type of study since they uphold the assumptions of equal density and modulus that are implicit in scaling method development. In total, six scaling procedures were evaluated, four from the literature (equal-stress equal-velocity, ESEV, and three variations of impulse momentum) and two which are introduced in the paper (ESEV using a ratio of effective masses, ESEV-EffMass, and a kinetic energy approach). In total, 24 simulations were performed, representing both pendulum and full body impacts for three representative HBMs. These simulations were quantitatively compared using the International Organization for Standardization (ISO) ISO-TS18571 standard. Based on these results, ESEV-EffMass achieved the highest overall similarity score (indicating that it is most proficient at scaling a reference response to a target). Additionally, ESEV was found to perform poorly for two degree-of-freedom (DOF) systems. However, the results also indicated that no single technique was clearly the most appropriate for all scenarios.

Computed tomography to operating room in less than 3 hours minimizes complications from appendicitis.

BACKGROUND: The aim of our study is to select patients with nonperforated appendicitis verified by computed tomography (CT) scan and to determine if there is a temporal component to perforation. METHODS: A retrospective cohort study of patients with CT scan evidence of nonperforated appendicitis from 2007 to 2012. RESULTS: 411 patients, aged 39.7 ± 16.25 years (47.5% male) were included in the study. 330 patients (80.3%) were nonperforated at surgery. Analysis of 3-hour intervals from CT scan to operating room (OR) revealed an absolute reduction in the rate of perforation from 27% at the 6- to 9-hour interval, to 17% and 10% at the 3- to 6-hour and 0- to 3-hour intervals, respectively, (P < .04). All organ space infections occurred in patients who were delayed to the OR greater than 3 hours. Mean length of hospitalization was .93 days and 2.81 days, respectively, in nonperforated and perforated appendicitis patients (P < .001). CONCLUSIONS: Delays to the OR were associated with increased risk of perforation. Patients with uncomplicated appendicitis had shorter hospitalization and fewer postoperative wound infections.

Melatonin Preserves Blood-Brain Barrier Integrity and Permeability via Matrix Metalloproteinase-9 Inhibition.

Microvascular hyperpermeability that occurs at the level of the blood-brain barrier (BBB) often leads to vasogenic brain edema and elevated intracranial pressure following traumatic brain injury (TBI). At a cellular level, tight junction proteins (TJPs) between neighboring endothelial cells maintain the integrity of the BBB via TJ associated proteins particularly, zonula occludens-1 (ZO-1) that binds to the transmembrane TJPs and actin cytoskeleton intracellularly. The pro-inflammatory cytokine, interleukin-1ß (IL-1ß) as well as the proteolytic enzymes, matrix metalloproteinase-9 (MMP-9) are key mediators of trauma-associated brain edema. Recent studies indicate that melatonin a pineal hormone directly binds to MMP-9 and also might act as its endogenous inhibitor. We hypothesized that melatonin treatment will provide protection against TBI-induced BBB hyperpermeability via MMP-9 inhibition. Rat brain microvascular endothelial cells grown as monolayers were used as an in vitro model of the BBB and a mouse model of TBI using a controlled cortical impactor was used for all in vivo studies. IL-1ß (10 ng/mL; 2 hours)-induced endothelial monolayer hyperpermeability was significantly attenuated by melatonin (10 µg/mL; 1 hour), GM6001 (broad spectrum MMP inhibitor; 10 µM; 1 hour), MMP-9 inhibitor-1 (MMP-9 specific inhibitor; 5 nM; 1 hour) or MMP-9 siRNA transfection (48 hours) in vitro. Melatonin and MMP-9 inhibitor-1 pretreatment attenuated IL-1ß-induced MMP-9 activity, loss of ZO-1 junctional integrity and f-actin stress fiber formation. IL-1ß treatment neither affected ZO-1 protein or mRNA expression or cell viability. Acute melatonin treatment attenuated BBB hyperpermeability in a mouse controlled cortical impact model of TBI in vivo. In conclusion, one of the protective effects of melatonin against BBB hyperpermeability occurs due to enhanced BBB integrity via MMP-9 inhibition. In addition, acute melatonin treatment provides protection against BBB hyperpermeability in a mouse model of TBI indicating its potential as a therapeutic agent for brain edema when established in humans.

Risk Factors for Open Malleolar Fractures: An Analysis of the National Trauma Data Bank (2007 to 2011).

A limited number of studies have described the epidemiology of open fractures, and the epidemiology of open ankle fractures is not an exception. Therefore, the risk factors associated with open ankle fractures have not been extensively evaluated. The frequencies and proportions of open ankle fractures among all the recorded malleolar fractures in the US National Trauma Data Bank data set from January 2007 to December 2011 were analyzed. Clinically relevant variables captured in the data set were also used to evaluate the risk factors associated with open ankle fractures, adjusting for other covariates. The entire cohort was further subdivided into "lower" and "higher" energy trauma groups and the same analysis performed for each group separately. We found that a body mass index of >40 kg/m(2) and farm location were risk factors for open ankle fractures and impaired sensorium was protective against open ankle fractures. In the "lower energy" group, male gender, alcohol use, peripheral vascular disease, other injuries, and injury occurring at a farm location were risk factors for open fractures. In the "higher energy" group, female gender, work-related injury, and injury at a farm or industry location demonstrated statistically significantly associations with open fractures.

Tissue inhibitor of metalloproteinase-2 inhibits burn-induced derangements and hyperpermeability in microvascular endothelial cells.

BACKGROUND: Burns induce microvascular hyperpermeability. We hypothesize that this occurs partly through an imbalance between matrix metalloproteinases (MMPs) and endogenous MMP inhibitors such as tissue inhibitors of metalloproteinases (TIMPs), and that such derangements can be attenuated with the use of TIMP-2. METHOD: Rats underwent either sham or burn: serum and tissue were collected. Western blot was used to examine MMP-9 and TIMP-2 levels and MMP activity was assayed from lung tissue. Rat lung microvascular endothelial cells were used to assess monolayer permeability and evaluate the adherens junction proteins ß-catenin, vascular endothelial cadherin and filamentous actin after exposure to burn serum ± TIMP-2. RESULTS: Lung tissue from burn animals showed increased MMP activity, decreased levels of TIMP-2, and no difference in levels of active MMP-9 in burn vs control groups. Burn serum increased monolayer permeability, damaged adherens junction proteins, and incited actin stress fiber formation; TIMP-2 attenuated these derangements. CONCLUSIONS: Burns may lower TIMP-2 levels and increase MMP activity and that TIMP-2 application in vitro may attenuate burn-induced hyperpermeability and decreases damage to endothelial structural proteins. These links warrant further investigation.

Doxycycline Attenuates Lipopolysaccharide-Induced Microvascular Endothelial Cell Derangements.

INTRODUCTION: Lipopolysaccharide (LPS) is known to induce vascular derangements. The pathophysiology involved therein is unknown, but matrix metalloproteinases (MMPs) may be an important mediator. We hypothesized that in vitro LPS provokes vascular permeability, damages endothelial structural proteins, and increases MMP activity; that in vivo LPS increases permeability and fluid requirements; and that the MMP inhibitor doxycycline mitigates such changes. METHODS: Rat lung microvascular endothelial cells were divided into four groups: control, LPS, LPS plus doxycycline, and doxycycline. Permeability, structural proteins ß-catenin and Filamentous-actin, and MMP-9 activity were examined. Sprauge Dawley rats were divided into sham, IV LPS, and IV LPS plus IV doxycycline groups. Mesenteric postcapillary venules were observed. Blood pressure was measured as animals were resuscitated and fluid requirements were compared. Statistical analysis was conducted using Student's t-test and ANOVA. RESULTS: In vitro LPS increased permeability, damaged adherens junctions, induced actin stress fiber formation, and increased MMP-9 enzyme activity. In vivo, IV LPS administration induced vascular permeability. During resuscitation, significantly more fluid was necessary to maintain normotension in the IV LPS group. Doxycycline mitigated all derangements observed. CONCLUSIONS: We conclude that LPS increases permeability, damages structural proteins, and increases MMP-9 activity in endothelial cells. Additionally, endotoxemia induces hyperpermeability and increases the amount of IV fluid required to maintain normotension in vivo. Doxycycline mitigates such changes both in vitro and in vivo. Our findings illuminate the possible role of matrix metalloproteinases in the pathophysiology of lipopolysaccharide-induced microvascular hyperpermeability and pave the way for better understanding and treatment of this process.