Correction to: A suite of automated tools to quantify hand and wrist motor function after cervical spinal cord injury.

The original article [1] contains several errors which the authors would like to rectify.

A suite of automated tools to quantify hand and wrist motor function after cervical spinal cord injury.

BACKGROUND: Cervical spinal cord injury (cSCI) often causes chronic upper extremity disability. Reliable measurement of arm function is critical for development of therapies to improve recovery after cSCI. In this study, we report a suite of automated rehabilitative tools to allow simple, quantitative assessment of hand and wrist motor function. METHODS: We measured range of motion and force production using these devices in cSCI participants with a range of upper limb disability and in neurologically intact participants at two time points separated by approximately 4 months. Additionally, we determined whether measures collected with the rehabilitative tools correlated with standard upper limb assessments, including the Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) and the Jebsen Hand Function Test (JHFT). RESULTS: We find that the rehabilitative devices are useful to provide assessment of upper limb function in physical units over time in SCI participants and are well-correlated with standard assessments. CONCLUSIONS: These results indicate that these tools represent a reliable system for longitudinal evaluation of upper extremity function after cSCI and may provide a framework to assess the efficacy of strategies aimed at improving recovery of upper limb function.

Vagus Nerve Stimulation Paired With Upper Limb Rehabilitation After Chronic Stroke.

Background and Purpose- We assessed safety, feasibility, and potential effects of vagus nerve stimulation (VNS) paired with rehabilitation for improving arm function after chronic stroke. Methods- We performed a randomized, multisite, double-blinded, sham-controlled pilot study. All participants were implanted with a VNS device and received 6-week in-clinic rehabilitation followed by a home exercise program. Randomization was to active VNS (n=8) or control VNS (n=9) paired with rehabilitation. Outcomes were assessed at days 1, 30, and 90 post-completion of in-clinic therapy. Results- All participants completed the course of therapy. There were 3 serious adverse events related to surgery. Average FMA-UE scores increased 7.6 with active VNS and 5.3 points with control at day 1 post-in-clinic therapy (difference, 2.3 points; CI, -1.8 to 6.4; P=0.20). At day 90, mean scores increased 9.5 points from baseline with active VNS, and the control scores improved by 3.8 (difference, 5.7 points; CI, -1.4 to 11.5; P=0.055). The clinically meaningful response rate of FMA-UE at day 90 was 88% with active VNS and 33% with control VNS ( P<0.05). Conclusions- VNS paired with rehabilitation was acceptably safe and feasible in participants with upper limb motor deficit after chronic ischemic stroke. A pivotal study of this therapy is justified. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02243020.

Paper-Based Surface-Enhanced Raman Scattering Lateral Flow Strip for Detection of Neuron-Specific Enolase in Blood Plasma.

An inexpensive and disposable paper-based lateral flow strip (PLFS) has been developed as an immunoassay, in which surface-enhanced Raman scattering (SERS) is utilized for sensing signal transduction. The Au nanostar@Raman Reporter@silica sandwich nanoparticles are developed as the SERS probes, which is the key to the high sensitivity of the device. Compared with a colorimetric PLFS, the SERS-PLFS exhibits superior performance in terms of sensitivity and limit of detection (LOD) in a blood plasma-containing sample matrix. In addition, the SERS-PLFS has been successfully used for detection of neuron-specific enolase (NSE), a traumatic brain injury (TBI) protein biomarker, in diluted blood plasma samples, achieving a LOD of 0.86 ng/mL. Moreover, the SERS-PLFS was successfully employed to measure the NSE level in clinical blood plasma samples taken from deidentified TBI patients. This work demonstrates that the SERS-PLFS has great potential in assisting screening of TBI patients in the point-of-care setting.

Estrogen-provided cardiac protection following burn trauma is mediated through a reduction in mitochondria-derived DAMPs.

Mitochondria-derived danger-associated molecular patterns (DAMPs) play important roles in sterile inflammation after acute injuries. This study was designed to test the hypothesis that 17ß-estradiol protects the heart via suppressing myocardial mitochondrial DAMPs after burn injury using an animal model. Sprague-Dawley rats were given a third-degree scald burn comprising 40% total body surface area (TBSA). 17ß-Estradiol, 0.5 mg/kg, or control vehicle was administered subcutaneously 15 min following burn. The heart was harvested 24 h postburn. Estradiol showed significant inhibition on the productivity of H2O2 and oxidation of lipid molecules in the mitochondria. Estradiol increased mitochondrial antioxidant defense via enhancing the activities and expression of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Estradiol also protected mitochondrial respiratory function and structural integrity. In parallel, estradiol remarkably decreased burn-induced release of mitochondrial cytochrome c and mitochondrial DNA (mtDNA) into cytoplasm. Further, estradiol inhibited myocardial apoptosis, shown by its suppression on DNA laddering and downregulation of caspase 1 and caspase 3. Estradiol's anti-inflammatory effect was demonstrated by reduction in systemic and cardiac cytokines (TNF-α, IL-1ß, and IL-6), decrease in NF-κB activation, and attenuation of the expression of inflammasome component ASC in the heart of burned rats. Estradiol-provided cardiac protection was shown by reduction in myocardial injury marker troponin-I, amendment of heart morphology, and improvement of cardiac contractility after burn injury. Together, these data suggest that postburn administration of 17ß-estradiol protects the heart via an effective control over the generation of mitochondrial DAMPs (mtROS, cytochrome c, and mtDNA) that incite cardiac apoptosis and inflammation.

Bulk derivatization and direct injection of human cerebrospinal fluid for trace-level quantification of endogenous estrogens using trap-and-elute liquid chromatography with tandem mass spectrometry.

Although there are existing methods for determining estrogen in human bodily fluids including blood plasma and serum, very little information is available regarding estrogen levels in human cerebrospinal fluid (CSF), which is critical to assess in studies of neuroprotective functions and diffusion of neuroprotective estrogens across the blood-brain barrier. To address this problem, a liquid chromatography with tandem mass spectrometry method for the simultaneous quantification of four endogenous estrogens (estrone, 17α-estradiol, 17ß-estradiol, and estriol) in human CSF was developed. An aliquot (300 µL) of human CSF was bulk derivatized using dansyl chloride in the sample and 10 µL was directly injected onto a restricted-access media trap column for protein removal. No off-line sample extraction or cleanup was needed. The limits of detection of estrone, 17α-estradiol, 17ß-estradiol, and estriol were 17, 28, 13, and 30 pg/mL, respectively, which is in the parts-per-trillion regime. The method was then applied to human CSF collected from ischemic trauma patients. Endogenous estrogens were detected and quantified, demonstrating the effectiveness of this method.

17ß-Estradiol reappropriates mass lost to the hypermetabolic state in thermally injured rats.

BACKGROUND: The hypermetabolic response to severe thermal injury is unlike any physiologic response seen in medicine. While some parallels can be drawn to shock and sepsis states, this response is typified by its intensity and duration. Our group has been interested in the myriad effects of estrogens after injury, specifically the ability of estrogens to reduce inflammatory responses. Given this, and the known link between severe inflammation and the hypermetabolic response, we examined the effects of a single dose of 17ß estradiol administered after a severe thermal injury in rats. METHODS: Twelve male Sprague-Dawley rats were subject to either a sham burn or a 40% total body surface area burn, followed by fluid resuscitation. Burned animals were divided into a vehicle and treatment group, with injections given 15 min after the injury. Animals were monitored for a period of 45 d, with markers of hypermetabolism (weight, fecal output, food intake, and serum insulin and glucose) measured daily. RESULTS: We identified a significant difference in daily measured weights between the burned groups. We observed a sparing of body mass during the acute phase lasting 2 wk after the injury and an improved recovery phase during the remainder of the study. Glucose and insulin levels during the first week of the study did not differ between the treatment groups. CONCLUSION: Estrogen may have a role in preserving body mass after severe thermal injury. Further studies are required to determine if this spared body mass composition.

Usage of RePlay as a Take-Home System to Support High-Repetition Motor Rehabilitation After Neurological Injury.

Stroke is a leading cause of chronic motor disability. While physical rehabilitation can promote functional recovery, several barriers prevent patients from receiving optimal rehabilitative care. Easy access to at-home rehabilitative tools could increase patients' ability to participate in rehabilitative exercises, which may lead to improved outcomes. Toward achieving this goal, we developed RePlay: a novel system that facilitates unsupervised rehabilitative exercises at home. RePlay leverages available consumer technology to provide a simple tool that allows users to perform common rehabilitative exercises in a gameplay environment. RePlay collects quantitative time series force and movement data from handheld devices, which provide therapists the ability to quantify gains and individualize rehabilitative regimens. RePlay was developed in C# using Visual Studio. In this feasibility study, we assessed whether participants with neurological injury are capable of using the RePlay system in both a supervised in-office setting and an unsupervised at-home setting, and we assessed their adherence to the unsupervised at-home rehabilitation assignment. All participants were assigned a set of 18 games and exercises to play each day. Participants produced on average 698 ± 36 discrete movements during the initial 1 hour in-office visit. A subset of participants who used the system at home produced 1593 ± 197 discrete movements per day. Participants demonstrated a high degree of engagement while using the system at home, typically completing nearly double the number of assigned exercises per day. These findings indicate that the open-source RePlay system may be a feasible tool to facilitate access to rehabilitative exercises and potentially improve overall patient outcomes.

Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model.

Using a mitochondria-targeted vitamin E (Mito-Vit-E) in a rat pneumonia-related sepsis model, we examined the role of mitochondrial reactive oxygen species in sepsis-mediated myocardial inflammation and subsequent cardiac contractile dysfunction. Sepsis was produced in adult male Sprague-Dawley rats via intratracheal injection of S. pneumonia (4 × 10(6) colony formation units per rat). A single dose of Mito-Vit-E, vitamin E, or control vehicle, at 21.5 µmol/kg, was administered 30 min postinoculation. Blood was collected, and heart tissue was harvested at various time points. Mito-Vit-E in vivo distribution was confirmed by mass spectrometry. In cardiac mitochondria, Mito-Vit-E improved total antioxidant capacity and suppressed H(2)O(2) generation, whereas vitamin E offered little effect. In cytosol, both antioxidants decreased H(2)O(2) levels, but only vitamin E strengthened antioxidant capacity. Mito-Vit-E protected mitochondrial structure and function in the heart during sepsis, demonstrated by reduction in lipid and protein oxidation, preservation of mitochondrial membrane integrity, and recovery of respiratory function. While both Mito-Vit-E and vitamin E suppressed sepsis-induced peripheral and myocardial production of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1ß, and interleukin-6), Mito-Vit-E exhibited significantly higher efficacy (P < 0.05). Stronger anti-inflammatory action of Mito-Vit-E was further shown by its near-complete inhibition of sepsis-induced myeloperoxidase accumulation in myocardium, suggesting its effect on neutrophil infiltration. Echocardiography analysis indicated that Mito-Vit-E ameliorated cardiac contractility of sepsis animals, shown by improved fractional shortening and ejection fraction. Together, our data suggest that targeted scavenging of mitochondrial reactive oxygen species protects mitochondrial function, attenuates tissue-level inflammation, and improves whole organ activities in the heart during sepsis.

A "hot Spot"-Enhanced paper lateral flow assay for ultrasensitive detection of traumatic brain injury biomarker S-100ß in blood plasma.

Currently colorimetric paper lateral flow strips (PLFS) encounter two major limitations, that is, low sensitivity and severe interference from complex sample matrices such as blood. These shortcomings limit their application in detection of low-concentration analytes in complex samples. To solve these problems, a PLFS has been developed by utilizing surface-enhanced Raman scattering (SERS) for sensing signal transduction. In particular, a hierarchical three-dimensional nanostructure has been designed to create "hot spots", which can significantly amplify the SERS sensing signal, leading to high sensitivity. As a result, this PLFS has demonstrated a limit of detection (LOD) of 5.0 pg mL-1 toward detection of S-100ß, a traumatic brain injury (TBI) protein biomarker in blood plasma. The PLFS has been successfully used for rapid measurement of S-100ß in clinical TBI patient samples taken in the emergency department. Availability of PLFS for blood testing would shift the paradigm of TBI patient management and clinical outcome in emergency departments. It is expected that this type of PLFS can be adapted for rapid detection of various human diseases due to its capability of measuring a low level of protein blood biomarkers in complex human fluids.

Burn serum causes a CD14-dependent mitochondrial damage in primary cardiomyocytes.

Studies from animal models suggest that myocardial mitochondrial damage contributes to cardiac dysfunction after burn injury. In this report, we used an ex vivo model of primary cardiomyocyte culture to investigate the mechanisms of burn-induced mitochondrial impairment. Briefly, blood serum was collected from Sprague-Dawley (SD) rats subjected to 40% total body surface area burn and added (10% vol/vol) to primary cardiomyocytes prepared from SD rats. The effect of the burn serum on mitochondrial function and membrane integrity in the myocytes was analyzed. Exposure of myocytes to burn serum doubled the mitochondrial membrane damage measured by two independent assays. This treatment also significantly elevated mitochondrial oxidative stress, indicated by a more than 30% increase in lipid oxidation. Downregulation of mitochondrial antioxidant defense was also evident since the activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase were reduced by about 30% and 50%, respectively. Burn serum also induced deficiency of mitochondrial metabolism, indicated by a 30% decrease in the activity of cytochrome c oxidase. These mitochondrial dysfunctions appear to be generated by oxidative stress because burn serum induced a significant increase of mitochondrial oxygen species (mtROS) in cardiomyocytes, and pretreatment of cardiomyocytes with the antioxidant N-acetyl-cysteine prevented the mitochondrial damages induced by burn serum. Remarkably, the increase in mtROS was abolished by an antibody-mediated blockade of CD14. Furthermore, burn injury-induced mitochondrial damage in cardiomyocytes was prevented in CD14 knockout mice. Taken together, these data suggested that burn injury produces CD14-dependent mitochondrial damage via oxidative stress in myocardium.

Rationale for routine and immediate administration of intravenous estrogen for all critically ill and injured patients.

In addition to a number of very compelling clinical observations, an extensive body of extremely supportive experimental data has generated a very persuasive argument that intravenous estrogen should be routinely administered, as soon as possible, to all persons identified as having a critical illness or injury. Although, to date, definitive gold-standard clinical trials are lacking, what has made this provocative argument even more convincing is the longstanding, documented safety of intravenous estrogen for various illnesses and conditions as well as the relative ease and inexpensive cost of treatment. As such, even routine prehospital administration becomes extremely feasible for a myriad of conditions. More importantly, the worldwide magnitude of potential patients who could benefit is profound. Even if estrogen only changes the outcome in a relatively small percentage of applicable cases, the potential impact may still be of dramatic proportions in terms of the absolute number of lives saved and the resources spared worldwide. Resources may be spared not only in terms of diminishing the economic impact of death and long-term disability, but also in terms of preventing extended intensive care unit stays and treatment of preventable complications that result in longer recovery.

Intravenous fluid resuscitation for the trauma patient.

PURPOSE OF REVIEW: Although longstanding practice in trauma care has been to provide immediate, aggressive intravenous fluid resuscitation to injured patients with presumed internal hemorrhage, recent experimental and clinical data suggest a more discriminating approach that first considers concurrent head injury, hemodynamic stability, and the presence of potentially uncontrollable hemorrhage (e.g., deep truncal injury) versus a controllable source (e.g., distal extremity wound). RECENT FINDINGS: The data suggest that rapid intravenous fluid infusions could be used for patients with isolated extremity, thermal or head injury. However, intravenous fluids should be limited in conditions with potentially uncontrollable internal hemorrhage, and particularly in patients with penetrating truncal injury being transported immediately to a trauma center. Likewise, positive pressure ventilatory support should be limited with severe hemorrhage due to the secondary reductions in venous return off-setting the effects of the fluids. For trauma patients with severe bleeding, there is growing evidence for the increased use of plasma and factor VIIa, as well as tourniquets, intra-osseus devices, and evolving monitoring techniques. SUMMARY: Future research efforts in trauma should focus on the timing and rate of infusions as well as the concept of infusing alternative intravenous resuscitative fluids such as hemoglobin-based oxygen carriers (HBOCs) and the use of hemostatic agents and special blood products.

Preventing severe hypoxia during emergent intubation: is nasopharyngeal oxygenation the answer?

Critically ill patients requiring emergent endotracheal intubation are at risk for life-threatening hypoxemia during the intubation procedure, particularly when the patient is apneic and not receiving any supplemental oxygen. In a current study, Engström and colleagues investigated the effect of nasopharyngeal oxygenation in eight anesthetized pigs with induced acute lung injury. The investigators confirmed, even in this model, that pharyngeal oxygenation significantly prolonged the time to desaturation during periods of apnea. Recognizing the limitations of directly extrapolating these experimental results to critically ill human subjects, the findings do support the contention that, until proven otherwise, nasopharyngeal oxygenation should at least be considered as one technique to diminish hypoxemic complications in very sick patients, particularly those with underlying pulmonary impairment.

Retention behavior of estrogen metabolites on hydrophilic interaction chromatography stationary phases.

Estrogens and estrogen metabolites are important biological mediators of the endocrine system. They have also been implicated in detrimental carcinogenesis and beneficial neuroprotective processes. The retention behavior of estrogen metabolites was investigated on five polar stationary phases, used for hydrophilic interaction chromatography, and coupled with ESI-MS. Data were fit to partitioning and surface adsorption models. Retention of the compounds, especially estrogen glucuronides, on the amide- and diol-bonded stationary phases, could be best described by the surface adsorption model; however, mixed modes of retention were observed on most stationary phases. Retention time increased while the peak efficiency decreased proportional to the number of hydroxyl groups in the analytes. The effects of salt concentration and salt type were also investigated. The presence of solvated salt ions, which interact with the stationary phase and the analyte, enhanced retention of the analytes. This was believed to be due to two effects. The increased ionic strength reduced the contribution of secondary electrostatic interactions (mixed-mode effects). It also enhanced hydrogen-bonding and partitioning (hydrophilic interaction) between the analyte and the stationary phase, likely facilitated by the associated solvated salt ions.

Estrogen treatment following severe burn injury reduces brain inflammation and apoptotic signaling.

BACKGROUND: Patients with severe burn injury experience a rapid elevation in multiple circulating pro-inflammatory cytokines, with the levels correlating with both injury severity and outcome. Accumulations of these cytokines in animal models have been observed in remote organs, however data are lacking regarding early brain cytokine levels following burn injury, and the effects of estradiol on these levels. Using an experimental animal model, we studied the acute effects of a full-thickness third degree burn on brain levels of TNF-alpha, IL-1beta, and IL-6 and the protective effects of acute estrogen treatment on these levels. Additionally, the acute administration of estrogen on regulation of inflammatory and apoptotic events in the brain following severe burn injury were studied through measuring the levels of phospho-ERK, phospho-Akt, active caspase-3, and PARP cleavage in the placebo and estrogen treated groups. METHODS: In this study, 149 adult Sprague-Dawley male rats received 3rd degree 40% total body surface area (TBSA) burns. Fifteen minutes following burn injury, the animals received a subcutaneous injection of either placebo (n = 72) or 17 beta-estradiol (n = 72). Brains were harvested at 0.5, 1, 2, 4, 6, 8, 12, 18, and 24 hours after injury from the control (n = 5), placebo (n = 8/time point), and estrogen treated animals (n = 8/time point). The brain cytokine levels were measured using the ELISA method. In addition, we assessed the levels of phosphorylated-ERK, phosphorylated-Akt, active caspase-3, and the levels of cleaved PARP at the 24 hour time-point using Western blot analysis. RESULTS: In burned rats, 17 beta-estradiol significantly decreased the levels of brain tissue TNF-alpha (approximately 25%), IL-1beta (approximately 60%), and IL-6 (approximately 90%) when compared to the placebo group. In addition, we determined that in the estrogen-treated rats there was an increase in the levels of phospho-ERK (p < 0.01) and Akt (p < 0.05) at the 24 hour time-point, and that 17 beta-estradiol blocked the activation of caspase-3 (p < 0.01) and subsequent cleavage of PARP (p < 0.05). CONCLUSION: Following severe burn injury, estrogens decrease both brain inflammation and the activation of apoptosis, represented by an increase in the levels of phospho-Akt and inhibition of caspase-3 activation and PARP cleavage. Results from these studies will help further our understanding of how estrogens protect the brain following burn injury, and may provide a novel, safe, and effective clinical treatment to combat remote secondary burn injury in the brain and to preserve cognition.

Mechanical devices for cardiopulmonary resuscitation.

PURPOSE OF REVIEW: The most current practice guidelines for cardiopulmonary resuscitation published by the American Heart Association and European Resuscitation Council have placed the highest priority on achieving the most optimal circulation possible following sudden cardiac arrest through the delivery of early, consistent, high-quality and infrequently interrupted chest compressions during resuscitative efforts. The purpose of this review is to analyze the most recent trials involving adjunct mechanical devices designed to optimize blood flow to vital organs during cardiopulmonary resuscitation conditions. RECENT FINDINGS: Six devices show substantial promise based on the compelling results of numerous animal and small-scale clinical trials. All of these promising interventions, however, have yet to be validated in definitive clinical trials, particularly those examining long-term survival and neurological function. SUMMARY: Markedly enhanced circulation during cardiopulmonary resuscitation efforts has been found to be a critical element for effecting successful resuscitation. Preliminary studies of adjunct mechanical cardiopulmonary resuscitation devices have revealed significant increases in improved hemodynamics in both animal models and human studies, as well as improvements in short-term human survival in the clinical setting. Several of these devices are currently undergoing definitive clinical trials that hopefully will establish irrefutable efficacy and improved long-term neurological outcomes.

The association of maximum Troponin values post out-of-hospital cardiac arrest with electrocardiographic findings, cardiac reperfusion procedures and survival to discharge: A sub-study of ROC PRIMED.

BACKGROUND: The role of Troponin (Tn) levels in the management of patients post out-of-hospital cardiac arrest (OHCA) is unclear. METHODS: All OHCA patients enrolled in the Resuscitation Outcomes Consortium Prehospital Resuscitation using an IMpedance valve and Early versus Delayed analysis trial and admitted to hospital with a Tn level and a 12-lead electrocardiogram were stratified by ST elevation (STE) or no STE in a regression model for survival to discharge adjusted for Utstein predictors and site. RESULTS: Of the 15,617 enrolled OHCA patients, 4118 (26%) survived to admission to hospital; 17% (693) were STE and 77% (3188) were no STE with 6% unknown; 83% (3460) had at least one Tn level. Reperfusion rates were higher when Tn level >2ng/ml (p>0.1ng/ml) improved with a diagnostic cardiac catheterization (p<0.001). CONCLUSIONS: Elevated Tn levels >2ng/ml were associated with improved survival to discharge in patients post OHCA with STE. Survival in patients with no STE and Tn values >0.1ng/ml was higher when associated with diagnostic cardiac catheterization or treated with reperfusion or revascularization.

Key advances in critical care in the out-of-hospital setting: the evolving role of laypersons and technology.

During the past decade, critical care in the out-of-hospital setting has transcended the original emphasis on on-scene advanced life support interventions by doctors, paramedics, and nurses. Many of the life-saving efforts and advances in critical care situations have now begun to focus more and more on how, through evolving technology, the average person can save lives and perhaps even spare precious intensive care unit (ICU) resources. A striking example was the recent study conducted at the Chicago airports at which automated external defibrillators (AEDs) were deployed throughout the airline terminals for use by the public at large. Not only did random bystanders on the concourses save an extremely high percentage of cardiac arrest patients with the AEDs, most patients rapidly awakened, even before the arrival of professional rescuers. Thus, this technology-assisted intervention, performed by an average person, pre-empted the need for many other critical care interventions and prolonged care in the ICU. Equipped with automated prompts to improve performance, new technology also exists to help to monitor the inadequacies and too-frequent interruption of life-saving chest compressions during basic cardiopulmonary resuscitation. As a result of these technological advances, survival rates for cardiac arrest are now expected to improve significantly.