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Background Superior labrum lesion from anterior to posterior (SLAP) often presents together with other shoulder pathologies such as rotator cuff tear (RCT), but it is uncertain if repairing both SLAP and RCT has superior clinical outcomes over isolated repairs of SLAP and RCT. Materials and methods This was a retrospective cohort study with prospectively collected data, reviewing 157 patients who underwent arthroscopic repair of either RCT, SLAP (type II lesion), or both. Before surgery and after 6 weeks, 12 weeks, and 24 weeks, shoulder objective range of motion and strength were measured, patient-reported function and pain was assessed by the modified L’Insalata questionnaire with a Likert scale, and complications after each repair were examined. Results At 24 weeks after surgery, the combined group (n = 22) and SLAP group (n = 47) had significantly higher forward flexion (165° ± 4° and 167° ± 4° vs. 154° ± 3°, P = .01 and P = .01), external rotation strength (82 ± 6 N, 81 ± 6 N vs. 61 ± 3 N, P = .01 and P = .01), and abduction strength (94 ± 14 N, 78 ± 8 N vs. 53 ± 3 N, P = .001 and P = .02) compared with the rotator cuff tear repair (RCR) group (n = 88). The combined group also had stronger internal rotation than the RCR group (107 ± 12 N vs. 72 ± 4 N, P = .02). Function and pain improved from “severe-moderate” to “moderate-mild” in all groups after surgery. Conclusion Repairing RCT and SLAP tears together results in significant clinical benefits compared to repairing just RCT and analogous results against SLAP-only repair.

Summary Objectives This study was conducted to closely examine the effects of representative types of lower limb flexion and extension exercises (unilateral and bilateral exercises) and the combined exercise using a ski simulator on lower limb joint and muscle activities. Equipment and methods In the experiments of this study performed on 20 participants, lower limb joint angles and muscle activities were measured during unilateral (lunge), bilateral (squat), and combine (ski simulator) using a 3D motion capture and electromyography analysis system. Results Analysis of the measurement results revealed that unilateral exercises required more time and exhibited greater angular displacements of the lower limb joints (P Conclusion Research approaches adopted by such studies are easy to apply and may be applicable in many fields involving rehabilitation and improvement of muscle strength and balance.

Despite efforts to simulate the in vivo environment, post-mortem degradation and lack of blood perfusion complicate the use of ex vivo derived material models in computational studies of spinal cord injury. In order to quantify the mechanical changes that manifest ex vivo, the viscoelastic behavior of in vivo and ex vivo porcine spinal cord samples were compared. Stress-relaxation data from each condition were fit to a non-linear viscoelastic model using a novel characterization technique called the direct fit method. To validate the presented material models, the parameters obtained for each condition were used to predict the respective dynamic cyclic response. Both ex vivo and in vivo samples displayed non-linear viscoelastic behavior with a significant increase in relaxation with applied strain. However, at all three strain magnitudes compared, ex vivo samples experienced a higher stress and greater relaxation than in vivo samples. Significant differences between model parameters also showed distinct relaxation behaviors, especially in non-linear relaxation modulus components associated with the short-term response (0.1–1 s). The results of this study underscore the necessity of utilizing material models developed from in vivo experimental data for studies of spinal cord injury, where the time-dependent properties are critical. The ability of each material model to accurately predict the dynamic cyclic response validates the presented methodology and supports the use of the in vivo model in future high-resolution finite element modeling efforts. Statement of Significance Neural tissues (such as the brain and spinal cord) display time-dependent, or viscoelastic, mechanical behavior making it difficult to model how they respond to various loading conditions, including injury. Methods that aim to characterize the behavior of the spinal cord almost exclusively use ex vivo cadaveric or animal samples, despite evidence that time after death affects the behavior compared to that in a living animal (in vivo response). Therefore, this study directly compared the mechanical response of ex vivo and in vivo samples to quantify these differences for the first time. This will allow researchers to draw more accurate conclusions about spinal cord injuries based on ex vivo data (which are easier to obtain) and emphasizes the importance of future in vivo experimental animal work.

Background Biodegradable suture anchors are associated with higher redislocation rates. This study examined whether the biocompatibility and/or biomechanical properties of suture anchors contribute to the increase in complications. Methods Human glenohumeral capsule cells were cultured with 4 types of suture anchors, Opus LabraFix (titanium alloy; ArthroCare, Austin, TX, USA), PushLock (poly-ether-ether-ketone; Arthrex, Naples, FL, USA), BioKnotless (poly-l-lactic acid; DePuy Mitek, Warsaw, IN, USA), and Suretac II (polyglycolic acid; Smith & Nephew, London, UK), to measure cell viability and pH. Four groups of 6 ovine shoulders were used to repair the labrum, which was completely detached from the glenoid rim anteroinferiorly and reattached with 2 suture anchors and subject to failure load testing. Results In cell culture, BioKnotless at 48 and 72 hours (85.2% ± 2.1% and 84.5% ± 3.6%) and Suretac II groups (33.9% ± 3.1% and 42.8% ± 6.4%) had fewer viable cells compared with control ( P = .048). The pH of Suretac II was lower than control (7.51 to 7.65) at 24 hours (7.31 ± 0.08, P = .049), 48 hours (7.25 ± 0.02, P = .046), and 72 hours (7.29 ± 0.04, P = .04). During mechanical testing, 83% of repairs failed by the capsule tearing. Among the anchors, the BioKnotless repair group had a significantly lower failure load (37 ± 5 N) compared with the PushLock (61 ± 7 N), Opus (60 ± 6 N), and Suretac II (57 ± 7 N) groups ( P = .038). Conclusion BioKnotless and Suretac II anchors are cytotoxic. The BioKnotless biodegradable anchor has significantly lower failure load. Absorbable suture anchors may cause higher redislocation of arthroscopic Bankart repair.

In the military environment, injured soldiers undergoing medical evacuation via helicopter or mine-resistant ambush-protected vehicle (MRAP) are subjected to vibration and shock inherent to the transport vehicle. We conducted the present study to assess the consequences of such vibration on the acutely injured spinal cord. We used a porcine model of spinal cord injury (SCI). After a T10 contusion-compression injury, animals were subjected to 1) no vibration (n = 7-8), 2) whole body vibration at frequencies and amplitudes simulating helicopter transport (n = 8), or 3) whole body vibration simulating ground transportation in an MRAP ambulance (n = 7). Hindlimb locomotor function (using Porcine Thoracic Injury Behavior Scale [PTIBS]), Eriochrome Cyanine histochemistry and biochemical analysis of inflammatory and neural damage markers were analyzed. Cerebrospinal fluid (CSF) expression levels for monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, IL-8, and glial fibrillary acidic protein (GFAP) were similar between the helicopter or MRAP group and the unvibrated controls. Spared white/gray matter tended to be lower in the MRAP-vibrated animals than in the unvibrated controls, especially rostral to the epicenter. However, spared white/gray matter in the helicopter-vibrated group appeared normal. Although there was a relationship between the extent of sparing and the extent of locomotor recovery, no significant differences were found in PTIBS scores between the groups. In summary, exposures to vibration in the context of ground (MRAP) or aeromedical (helicopter) transportation did not significantly impair functional outcome in our large animal model of SCI. However, MRAP vibration was associated with increased tissue damage around the injury site, warranting caution around exposure to vehicle vibration acutely after SCI.

We have previously reported that administration of a CD11d monoclonal antibody (mAb) improves recovery in a clip-compression model of SCI. In this model the CD11d mAb reduces the infiltration of activated leukocytes into the injured spinal cord (as indicated by reduced intraspinal MPO). However not all anti-inflammatory strategies have reported beneficial results, suggesting that success of the CD11d mAb treatment may depend on the type or severity of the injury. We therefore tested the CD11d mAb treatment in a rat hemi-contusion model of cervical SCI. In contrast to its effects in the clip-compression model, the CD11d mAb treatment did not improve forelimb function nor did it significantly reduce MPO levels in the hemi-contused cord. To determine if the disparate results using the CD11d mAb were due to the biomechanical nature of the cord injury (compression SCI versus contusion SCI) or to the spinal level of the injury (12th thoracic level versus cervical) we further evaluated the CD11d mAb treatment after a T12 contusion SCI. In contrast to the T12 clip compression SCI, the CD11d mAb treatment did not improve locomotor recovery or significantly reduce MPO levels after T12 contusion SCI. Lesion analyses revealed increased levels of hemorrhage after contusion SCI compared to clip-compression SCI. SCI that is accompanied by increased intraspinal hemorrhage would be predicted to be refractory to the CD11d mAb therapy as this approach targets leukocyte diapedesis through the intact vasculature. These results suggest that the disparate results of the anti-CD11d treatment in contusion and clip-compression models of SCI are due to the different pathophysiological mechanisms that dominate these two types of spinal cord injuries.

Because of the complex, multifaceted nature of spinal cord injury (SCI), it is widely believed that a combination of approaches will be superior to individual treatments. Therefore, we employed a rat model of cervical SCI to evaluate the combination of four noninvasive treatments that individually have been reported to be effective for acute SCI during clinically relevant therapeutic time windows. These treatments included ghrelin, ibuprofen, C16, and ketogenic diet (KD). These were selected not only because of their previously reported efficacy in SCI models but also for their potentially different mechanisms of action. The administration of ghrelin, ibuprofen, C16, and KD several hours to days postinjury was based on previous observations by others that each treatment had profound effects on the pathophysiology and functional outcome following SCI. Here we showed that, with the exception of a modest improvement in performance on the Montoya staircase test at 8-10 weeks postinjury, the combinatorial treatment with ghrelin, ibuprofen, C16, and KD did not result in any significant improvements in the rearing test, grooming test, or horizontal ladder. Histologic analysis of the spinal cords did not reveal any significant differences in tissue sparing between treatment and control groups. Although single approaches of ghrelin, ibuprofen, C16, and KD have been reported to be beneficial after SCI, our results show that the combination of the four interventions did not confer significant functional or histological improvements in a cervical model of SCI. Possible interactions among the treatments may have negated their beneficial effects, emphasizing the challenges that have to be addressed when considering combinatorial drug therapies for SCI.

In animal models, spinal cord injury (SCI) is typically imparted by contusion alone (e.g., weight drop) or by compression alone (e.g., clip compression). In humans, however, the cord is typically injured by a combination of violent contusion followed by varying degrees of ongoing mechanical compression. Understanding how the combination of contusion and compression influences the early pathophysiology of SCI is important for the pre-clinical development of neuroprotective therapies that are applicable to the human condition. Disturbances in the metabolism of energy-related substrates such as lactate, pyruvate, and glucose are important aspects of secondary damage. In this study, we used a porcine model of traumatic SCI to determine the extent to which these metabolites were influenced by contusion followed by sustained compression, using the microdialysis technique. Following contusion injury, lactate and pyruvate levels near the epicenter both increased, while glucose remained quite stable. When the contusion injury was followed by sustained compression, we observed a transient rise in lactate, while pyruvate and glucose levels dropped rapidly, which may reflect decreased regional spinal cord blood flow. Furthermore, contusion with sustained compression produced a prolonged and dramatic increase in the lactate-pyruvate (L/P) ratio as a marker of tissue hypoxia, whereas after contusion injury alone, a transient and less significant elevation of the L/P ratio was observed. In this study, we demonstrate that disturbances in energy metabolism within the injured spinal cord vary greatly depending upon the biomechanical nature of the injury. Such differences are likely to be relevant to the applicability of novel therapies targeting specific aspects of the early secondary injury cascade after acute human SCI.

Spinal cord injury (SCI) researchers have predominately utilized rodents and mice for in vivo SCI modeling and experimentation. From these small animal models have come many insights into the biology of SCI, and a growing number of novel treatments that promote behavioral recovery. It has, however, been difficult to demonstrate the efficacy of such treatments in human clinical trials. A large animal SCI model that is an intermediary between rodent and human SCI may be a valuable translational research resource for pre-clinically evaluating novel therapies, prior to embarking upon lengthy and expensive clinical trials. Here, we describe the development of such a large animal model. A thoracic spinal cord injury at T10/11 was induced in Yucatan miniature pigs (20-25 kg) using a weight drop device. Varying degrees of injury severity were induced by altering the height of the weight drop (5, 10, 20, 30, 40, and 50 cm). Behavioral recovery over 12 weeks was measured using a newly developed Porcine Thoracic Injury Behavior Scale (PTIBS). This scale distinguished locomotor recovery among animals of different injury severities, with strong intra-observer and inter-observer reliability. Histological analysis of the spinal cords 12 weeks post-injury revealed that animals with the more biomechanically severe injuries had less spared white matter and gray matter and less neurofilament immunoreactivity. Additionally, the PTIBS scores correlated strongly with the extent of tissue sparing through the epicenter of injury. This large animal model of SCI may represent a useful intermediary in the testing of novel pharmacological treatments and cell transplantation strategies.

A porcine model of spinal cord injury (SCI) was used to evaluate the neuroprotective effects of magnesium chloride (MgCl2) within a polyethylene glycol (PEG) formulation, called "AC105" (Acorda Therapeutics Inc., Ardsley, NY). Specifically, we tested the hypothesis that AC105 would lead to greater tissue sparing at the injury site and improved behavioral outcome when delivered in a clinically realistic time window post-injury. Four hours after contusion/compression injury, Yucatan minipigs were randomized to receive a 30-min intravenous infusion of AC105, magnesium sulfate (MgSO4), or saline. Animals received 4 additional infusions of the same dose at 6-h intervals. Behavioral recovery was tested for 12 weeks using two-dimensional (2D) kinematics during weight-supported treadmill walking and the Porcine Injury Behavior Scale (PTIBS), a 10-point locomotion scale. Spinal cords were evaluated ex vivo by diffusion-weighted magnetic resonance imaging (MRI) and subjected to histological analysis. Treatment with AC105 or MgSO4 did not result in improvements in locomotor recovery on the PTIBS or in 2D kinematics on weight-supported treadmill walking. Diffusion weighted imaging (DWI) showed severe loss of tissue integrity at the impact site, with decreased fractional anisotropy and increased mean diffusivity; this was not improved with AC105 or MgSO4 treatment. Histological analysis revealed no significant increase in gray or white matter sparing with AC105 or MgSO4 treatment. Finally, AC105 did not result in higher Mg2+ levels in CSF than with the use of standard MgSO4. In summary, when testing AC105 in a porcine model of SCI, we were unable to reproduce the promising therapeutic benefits observed previously in less-severe rodent models of SCI.

Spinal cord injury (SCI) often results in a loss of motor and sensory function. Currently there are no validated effective clinical treatments. Previously we found in rats that dietary restriction, in the form of every-other-day fasting (EODF), started prior to (pre-EODF), or after (post-EODF) an incomplete cervical SCI was neuroprotective, increased plasticity, and promoted motor recovery. Here we examined if EODF initiated prior to, or after, a T10 thoracic contusion injury would similarly lead to enhanced functional recovery compared to ad libitum feeding. Additionally, we tested if a group fed every day (pair-fed), but with the same degree of restriction as the EODF animals (∼25% calorie restricted), would also promote functional recovery, to examine if EODF's effect is due to overall calorie restriction, or is specific to alternating sequences of 24-h fasts and ad libitum eating periods. Behaviorally, both pre- and post-EODF groups exhibited better functional recovery in the regularity indexed BBB ambulatory assessment, along with several parameters of their walking pattern measured with the CatWalk device, compared to both the ad-libitium-fed group as well as the pair-fed group. Several histological parameters (intensity and symmetry of serotonin immunostaining caudal to the injury and gray matter sparing) correlated with functional outcome; however, no group differences were observed. Thus besides the beneficial effects of EODF after a partial cervical SCI, we now report that alternating periods of fasting (but not pair-fed) also promotes improved hindlimb locomotion after thoracic spinal cord contusion, demonstrating its robust effect in two different injury models.

Functional recovery after spinal cord injury (SCI) is limited, and the injury results in a dramatic reduction in long-term lifespan. Prophylactic dietary restriction (DR) robustly extends animal lifespan, and is beneficial in models of neuronal insult. In rats, we found that one form of DR, every-other-day-fasting (EODF), which started 1 month prior to a cervical SCI improved functional recovery, resulted in greater numbers of neurons surrounding the injury site, and a approximately 45% reduction in lesion size compared to the control group. In the light of the low-risk implementation of prophylactic EODF, the clinical translation as a treatment prior to elective subacute or chronic interventions is attractive. There are numerous secondary complications after human SCI, including a 13- to 25-year reduction in lifespan. DR consistently increases median and maximal lifespan in a large range of organisms, including non-human primates. Animal research suggests that EODF might reduce many of the secondary complications people with SCI suffer from. Dietary interventions may provide the possibility to improve the quality and span of life for individuals with SCI.

Although much progress has been made in the clinical care of patients with acute spinal cord injuries, there are no reliably effective treatments, which minimize secondary damage and improve neurologic outcome. The time and expense needed to establish de novo pharmacologic or biologic therapies for acute SCI has encouraged the development of neuroprotective treatments based on drugs that are already in clinical use and, therefore, have the advantage of a well-characterized safety and pharmacokinetic profile in humans. Statins are the most commonly prescribed class of lipid-lowering drugs, and recently, it has been recognized that statins also have powerful immunomodulatory and anti-inflammatory effects. This paper describes a series of experiments that were performed to evaluate the comparative neuroprotective effects of simvastatin and atorvastatin. We observed a promising signal of neurologic benefit with simvastatin in our first experiment, but in repeated attempts to replicate that effect in three subsequent experiments, we failed to reveal any behavioral or histologic improvements. We would conclude that simvastatin given orally or subcutaneously at doses previously reported by other investigators to be effective in different neurologic conditions does not confer a significant neurologic benefit in a thoracic contusion injury model (OSU Impactor) when administered with a 1-h delay in intervention. We contend that further preclinical investigation of atorvastatin and simvastatin is warranted before considering their translation into human SCI.

Spinal cord injury typically results in limited functional recovery. Here we investigated whether therapeutic dietary restriction, a multi-faceted, safe, and clinically-feasible treatment, can improve outcome from cervical spinal cord injury. The well-established notion that dietary restriction increases longevity has kindled interest in its potential benefits in injury and disease. When followed for several months prior to insult, prophylactic dietary restriction triggers multiple molecular responses and improves outcome in animal models of stroke and myocardial infarction. However, the efficacy of the clinically-relevant treatment of post-injury dietary restriction is unknown. Here we report that “every-other-day fasting” (EODF), a form of dietary restriction, implemented after rat cervical spinal cord injury was neuroprotective, promoted plasticity, and improved behavioral recovery. Without causing weight loss, EODF improved gait-pattern, forelimb function during ladder-crossing, and vertical exploration. In agreement, EODF preserved neuronal integrity, dramatically reduced lesion volume by > 50%, and increased sprouting of corticospinal axons. As expected, blood β-hydroxybutyrate levels, a ketone known to be neuroprotective, were increased by 2–3 fold on the fasting days. In addition, we found increased ratios of full-length to truncated trkB (receptor for brain-derived neurotrophic factor) in the spinal cord by 2–6 folds at both 5 days (lesion site) and 3 weeks after injury (caudal to lesion site) which may further enhance neuroprotection and plasticity. Because EODF is a safe, non-invasive, and low-cost treatment, it could be readily translated into the clinical setting of spinal cord injury and possibly other insults.

Whole-body vibration has been identified as a potential stressor to spinal cord injury (SCI) patients during pre-hospital transportation. However, the effect that such vibration has on the acutely injured spinal cord is largely unknown, particularly in the frequency domain of 5 Hz in which resonance of the spine occurs. The objective of the study was to investigate the consequences of resonance vibration on the injured spinal cord. Using our previously characterized porcine model of SCI, we subjected animals to resonance vibration (5.7±0.46 Hz) or no vibration for a period of 1.5 or 3.0 h. Locomotor function was assessed weekly and cerebrospinal fluid (CSF) samples were collected to assess different inflammatory and injury severity markers. Spinal cords were evaluated histologically to quantify preserved white and gray matter. No significant differences were found between groups for CSF levels of monocyte chemotactic protein-1, interleukin 6 (IL-6) and lL-8. Glial fibrillary acidic protein levels were lower in the resonance vibration group, compared with the non-vibrated control group. Spared white matter tissue was increased within the vibrated group at 7 d post-injury but this difference was not apparent at the 12-week time-point. No significant difference was observed in locomotor recovery following resonance vibration of the spine. Here, we demonstrate that exposure to resonance vibration for 1.5 or 3 h following SCI in our porcine model is not detrimental to the functional or histological outcomes. Our observation that a 3.0-h period of vibration at resonance frequency induces modest histological improvement at one week post-injury warrants further study.

This study was designed to investigate the in vitro developmental ability and apoptosis of bovine embryos nuclear- transferred (NT) with frozen-thawed or cooled donor cells. Cultured adult bovine ear cells were used as donor cells after sub-culturing to confluence (CC), cooling to 4°C for 48 h, or freezing-thawing (FT). Apoptotic cells in blastocysts were evaluated for apoptosis by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) method. Fusion, cleavage and blastocyst rates were 69.0 (167/242), 68.8 (115/167), and 29.9 (50/167) with CC cells, 70.4 (88/125), 69.3 (61/88), and 29.6 (26/88) with cooled cells and 66.1 (117/177), 70.1 (82/117), and 13.7 (16/117) with FT cells, respectively. Blastocyst rates of NT embryos derived from FT cells were significantly lower than those from CC or cooled cells (p

【The experiment was conducted to evaluate CM (Cell Mass from Lysine Fermentation), which is used to produce synthetic lysine in industry, as an alternative protein source in broiler diets. Three different production conditions were employed to produce CMs (CM I, II, III). Treatments were control, CM I -1 (1 % of CM in the diet), CM I -3 (3% of CM in the diet), CM I -5 (5% of CM in the diet), CM II (3% of CM in the diet), and CM III (3% of CM in the diet). It was found that CM products were all high in crude protein content and especially high in lysine and methionine contents, while very low in minerals. For the starter period, all CM groups showed better weight gain, chicks fed CM I -1 diets were especially high in weight gain (p】

Although quasi-static and quasi-linear viscoelastic properties of the spinal cord have been reported previously, there are no published studies that have investigated the fully (strain-dependent) nonlinear viscoelastic properties of the spinal cord. In this study, stress relaxation experiments and dynamic cycling were performed on six fresh porcine lumbar cord specimens to examine their viscoelastic mechanical properties. The stress relaxation data were fitted to a modified superposition formulation and a novel finite ramp time correction technique was applied. The parameters obtained from this fitting methodology were used to predict the average dynamic cyclic viscoelastic behavior of the porcine cord. The data indicate that the porcine spinal cord exhibited fully nonlinear viscoelastic behavior. The average weighted root mean squared error for a Heaviside ramp fit was 2.8 kPa, which was significantly greater (p < 0.001) than that of the nonlinear (comprehensive viscoelastic characterization method) fit (0.365 kPa). Further, the nonlinear mechanical parameters obtained were able to accurately predict the dynamic behavior, thus exemplifying the reliability of the obtained nonlinear parameters. These parameters will be important for future studies investigating various damage mechanisms of the spinal cord and studies developing high-resolution finite elements models of the spine.

High fat, low carbohydrate ketogenic diets (KD) are validated non-pharmacological treatments for some forms of drug-resistant epilepsy. Ketones reduce neuronal excitation and promote neuroprotection. Here, we investigated the efficacy of KD as a treatment for acute cervical spinal cord injury (SCI) in rats. Starting 4 hours following C5 hemi-contusion injury animals were fed either a standard carbohydrate based diet or a KD formulation with lipid to carbohydrate plus protein ratio of 3:1. The forelimb functional recovery was evaluated for 14 weeks, followed by quantitative histopathology. Post-injury 3:1 KD treatment resulted in increased usage and range of motion of the affected forepaw. Furthermore, KD improved pellet retrieval with recovery of wrist and digit movements. Importantly, after returning to a standard diet after 12 weeks of KD treatment, the improved forelimb function remained stable. Histologically, the spinal cords of KD treated animals displayed smaller lesion areas and more grey matter sparing. In addition, KD treatment increased the number of glucose transporter-1 positive blood vessels in the lesion penumbra and monocarboxylate transporter-1 (MCT1) expression. Pharmacological inhibition of MCTs with 4-CIN (α-cyano-4-hydroxycinnamate) prevented the KD-induced neuroprotection after SCI, In conclusion, post-injury KD effectively promotes functional recovery and is neuroprotective after cervical SCI. These beneficial effects require the function of monocarboxylate transporters responsible for ketone uptake and link the observed neuroprotection directly to the function of ketones, which are known to exert neuroprotection by multiple mechanisms. Our data suggest that current clinical nutritional guidelines, which include relatively high carbohydrate contents, should be revisited.

The majority of clinical spinal cord injuries (SCIs) are contusive and occur at the cervical level of the spinal cord. Most scientists and clinicians agree that the preclinical evaluation of novel candidate treatments should include testing in a cervical SCI contusion model. Because mice are increasingly used because of the availability of genetically engineered lines, we characterized a novel cervical hemicontusion injury in mice using the Infinite Horizon Spinal Cord Impactor (Precisions SystemsInstrumentation, Lexington, KY). In the current study, C57BL/6 mice received a hemicontusion injury of 75 kilodynes with or without dwell time in an attempt to elicit a sustained moderate-to-severe motor deficit. Hemicontusion injuries without dwell time resulted in sustained deficits of the affected forepaw, as revealed by a 3-fold decrease in usage during rearing, a ∼50% reduction in grooming scores, and retrieval of significantly fewer pellets on the Montoya staircase test. Only minor transient deficits were observed in grasping force. CatWalk analysis revealed reduced paw-print size and swing speed of the affected forelimb. Added dwell time of 15 or 30 sec significantly worsened behavioral outcome, and mice demonstrated minimal ability of grasping, paw usage, and overground locomotion. Besides worsening of behavioral deficits, added dwell time also reduced residual white and gray matter at the epicenter and rostral-caudal to the injury, including on the contralateral side of the spinal cord. Taken together, we developed and characterized a new hemicontusion SCI model in mice that produces sufficient and sustained impairments in gross and skilled forelimb function and produced primarily unilateral functional deficits.

Study design In vivo large animal (pig) model study of cerebrospinal fluid (CSF) pressures after acute experimental spinal cord injury (SCI). Objective To determine how the CSF pressure (CSFP) and CSF pulse pressure amplitude (CSFPPA) cranial and caudal to the injury site change after an acute SCI with subsequent thecal occlusion and decompression. Summary of background data Lowering intrathecal pressure via CSF drainage is currently instituted to prevent ischemia-induced SCI during thoracoabdominal aortic aneurysm surgery and was recently investigated as a potential intervention for acute traumatic SCI. However, in SCI patients, persistent extradural compression commonly occludes the subarachnoid space. This may generate a CSFP differential across the injury site, which cannot be appreciated with lumbar catheter pressure measurements. Methods Anesthetized pigs were subjected to an acute contusive SCI at T11 and 8 hours of sustained compression (n = 12), or sham surgery (n = 2). CSFP was measured cranial and caudal to the injury site, using miniature pressure transducers, during compression and for 6 hours after decompression. Results The cranial-caudal CSFP differential increased (mean, 0.39 mm Hg/h), predominantly due to increased cranial pressure. On decompression, cranial CSFP decreased (mean, -1.16 mm Hg) and caudal CSFP increased (mean, 0.65 mm Hg). The CSFP differential did not change significantly after decompression. Cranial CSFPPA was greater than caudal CSFPPA, but this differential did not change during compression. On decompression, the caudal CSFPPA increased in some but not all animals. Conclusion Although extradural compression exists at the site of injury, lumbar CSFP may not accurately indicate CSFP cranial to the injury. Decompression may provide immediate, though perhaps partial, resolution of the pressure differential. CSFPPA was not a consistent indicator of decompression in this animal model. These findings may have implications for the design of future clinical protocols in which CSFP is monitored after acute SCI.

Despite considerable effort over the last four decades, research has failed to translate into consistently effective treatment options for spinal cord injury (SCI). This is partly attributed to differences between the injury response of humans and rodent models. Some of this difference could be because the cerebrospinal fluid (CSF) layer of the human spine is relatively large, while that of the rodents is extremely thin. We sought to characterize the fluid impulse induced in the CSF by experimental SCIs of moderate and high human-like severity, and to compare this with previous studies in which fluid impulse has been associated with neural tissue injury. We used a new in vivo pig model (n = 6 per injury group, mean age 124.5 days, 20.9 kg) incorporating four miniature pressure transducers that were implanted in pairs in the subarachnoid space, cranial, and caudal to the injury at 30 mm and 100 mm. Tissue sparing was assessed with Eriochrome Cyanine and Neutral Red staining. The median peak pressures near the injury were 522.5 and 868.8 mmHg (range 96.7–1430.0) and far from the injury were 7.6 and 36.3 mmHg (range 3.8–83.7), for the moderate and high injury severities, respectively. Pressure impulse (mmHg.ms), apparent wave speed, and apparent attenuation factor were also evaluated. The data indicates that the fluid pressure wave may be sufficient to affect the severity and extent of primary tissue damage close to the injury site. However, the CSF pressure was close to normal physiologic values at 100 mm from the injury. The high injury severity animals had less tissue sparing than the moderate injury severity animals; this difference was statistically significant only within 1.6 mm of the epicenter. These results indicate that future research seeking to elucidate the mechanical origins of primary tissue damage in SCI should consider the effects of CSF. This pig model provides advantages for basic and preclinical SCI research due to its similarities to human scale, including the existence of a human-like CSF fluid layer.

Object Spinal cord injury (SCI) often results in considerable permanent neurological impairment, and unfortunately, the successful translation of effective treatments from laboratory models to human patients is lacking. This may be partially attributed to differences in anatomy, physiology, and scale between humans and rodent models. One potentially important difference between the rodent and human spinal cord is the presence of a significant CSF volume within the intrathecal space around the human cord. While the CSF may “cushion” the spinal cord, pressure waves within the CSF at the time of injury may contribute to the extent and severity of the primary injury. The objective of this study was to develop a model of contusion SCI in a miniature pig and establish the feasibility of measuring spinal CSF pressure during injury. Methods A custom weight-drop device was used to apply thoracic contusion SCI to 17 Yucatan miniature pigs. Impact load and velocity were measured. Using fiber optic pressure transducers implanted in the thecal sac, CSF pressures resulting from 2 injury severities (caused by 50-g and 100-g weights released from a 50-cm height) were measured. Results The median peak impact loads were 54 N and 132 N for the 50-g and 100-g injuries, respectively. At a nominal 100 mm from the injury epicenter, the authors observed a small negative pressure peak (median −4.6 mm Hg [cranial] and −5.8 mm Hg [caudal] for 50 g; −27.6 mm Hg [cranial] and −27.2 mm Hg [caudal] for 100 g) followed by a larger positive pressure peak (median 110.5 mm Hg [cranial] and 77.1 mm Hg [caudal] for 50 g; 88.4 mm Hg [cranial] and 67.2 mm Hg [caudal] for 100 g) relative to the preinjury pressure. There were no significant differences in peak pressure between the 2 injury severities or the caudal and cranial transducer locations. Conclusions A new model of contusion SCI was developed to measure spinal CSF pressures during the SCI event. The results suggest that the Yucatan miniature pig is an appropriate model for studying CSF, spinal cord, and dura interactions during injury. With further development and characterization it may be an appropriate in vivo largeanimal model of SCI to answer questions regarding pathological changes, therapeutic safety, or treatment efficacy, particularly where humanlike dimensions and physiology are important.

Metal capture experiments were performed in a 76 mm (3″) ID fluidized-bed combustor with limestone, sand and alumina serving as both the fluidized medium and metal capture sorbents. Wood pellets spiked with metal solutions were used to simulate the metal-containing combustible fuel. The tested metals were nitrate and chloride species of lead and cadmium. The experimental parameters included metal species and concentration, sorbent type and size, combustor temperature, air flow rate and combustion duration. Experimental results indicated that the technology is highly promising. In-furnace lead capture by limestone was observed to be as high as 95%. The capture efficiency, however, varied with experimental parameters and chemical additives. Most of the captured metals were observed to be TCLP nonleachable.

One of the major challenges in management of spinal cord injury (SCI) is that the assessment of injury severity is often imprecise. Identification of reliable, easily quantifiable biomarkers that delineate the severity of the initial injury and that have prognostic value for the degree of functional recovery would significantly aid the clinician in the choice of potential treatments. To find such biomarkers we performed quantitative liquid chromatography-mass spectrometry (LC-MS/MS) analyses of cerebrospinal fluid (CSF) collected from rats 24 h after either a moderate or severe SCI. We identified a panel of 42 putative biomarkers of SCI, 10 of which represent potential biomarkers of SCI severity. Three of the candidate biomarkers, Ywhaz, Itih4, and Gpx3 were also validated by Western blot in a biological replicate of the injury. The putative biomarkers identified in this study may potentially be a valuable tool in the assessment of the extent of spinal cord damage.

Study Design. Experimental animal study. Objective. To investigate the neuroprotective efficacy of this magnesium in polyethylene glycol (PEG) formulation in a contusive model of cervical spinal cord injury (SCI). Summary of Background Data. Intravenously administered magnesium has been extensively investigated as a neuroprotective agent in animal models of SCI, stroke, and traumatic brain injuries, and has been evaluated in large scale clinical trials for the latter 2 indications. We have developed a novel formulation of magnesium chloride (MgCl2) within PEG, and have previously demonstrated the neuroprotective benefit of this formulation in animal models of thoracic SCI. Methods. Twenty-two Sprague Dawley rats underwent a unilateral cervical hemicontusion at C4–C5 and were randomized 2 hours later to either the MgCl2 in PEG formulation, or normal saline. Each treatment was administered in 5 intravenous infusions spaced 6 hours apart. Behavioral recovery was assessed over 6 weeks, after which the cord was analyzed to measure the extent of gray matter and white matter sparing through the injury site. Results. In the horizontal ladder test, the percentage of forelimb errors made by the animals treated with MgCl2 in PEG formulation was significantly lower than the saline-treated controls. Histologic analysis also revealed a significantly higher cumulative white matter sparing through the injury site in the MgCl2 in PEG group. Conclusion. MgCl2 in a PEG formulation reduced secondary damage and improved behavioral recovery when administered 2 hours after a unilateral cervical hemicontusion injury. These findings are consistent with the neurologic benefit observed when administering this magnesium formulation in contusive and compressive models of thoracic SCI. Demonstrating the robustness of this neuroprotective effect in multiple injury models (and in the cervical injury model in particular) is important when considering the applicability of such a therapy for human SCIs.

Minocycline, a commonly prescribed tetracycline antibiotic, has shown promise as a potential therapeutic agent in animal models of numerous neurologic disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Huntington's disease, stroke, and spinal cord injury (SCI). Simvastatin is one of many hydroxymethylglutaryl-coenzyme-A reductase inhibitors prescribed to lower cholesterol. These drugs are also known to reduce inflammation and oxidative stress, improve endothelial function, and modulate the immune system in stroke, traumatic brain injury, and SCI. As both drugs have translational potential, we evaluated their neuroprotective properties here in a clinically relevant model of contusive cervical spinal cord injury. Sprague-Dawley rats underwent a unilateral cervical contusion SCI at C5 and were randomized to receive: 1. Minocycline 90 mg/kg x 3 days, 2. Simvastatin 20 mg/kg x 7 days, 3. Simvastatin 20 mg/kg x 7 days then 5mg/kg x 35 days, or 4. Saline (Control). Behavioral recovery was assessed over 6 weeks using the horizontal ladder test, cylinder rearing test, modified Montoya staircase test and grooming test. Forepaw sensitivity was also assessed using the electronic von Frey Aesthesiometer. The corticospinal and rubrospinal tracts were traced and the spinal cords were harvested 7 weeks after injury. The extent of gray matter and white matter sparing and corticospinal and rubrospinal tract sprouting were evaluated in cross sections of the spinal cord. In the end, neither minocycline nor simvastatin treatment was associated with improved performance on the behavioral tests, as compared to saline controls. Performance on the horizontal ladder test, cylinder rearing test, and von Frey sensory test were similar among all groups. Animals treated for 42 days with simvastatin scored significantly higher in the grooming score compared to other groups, but retrieved significantly fewer pellets on the modified Montoya staircase test than control and minocycline treated animals. Histologically, there were no significant differences in white and gray matter sparing and in the extent of corticospinal and rubrospinal sprouting between the four groups. In conclusion, both minocycline and simvastatin failed to improve functional and histological recovery in our model of contusive cervical spinal cord injury.

A number of drugs commonly used for a variety of clinical indications have been found recently to have substantial neuroprotective properties, raising the potential for rapid translation into human clinical trials of spinal cord injury (SCI). In this study we compared the neuroprotective efficacy of erythropoietin and a derivative of it, darbepoetin, in an acute model of thoracic SCI. Sprague–Dawley rats were randomized to receive erythropoietin (5000 IU/kg), darbepoetin (10 μg/kg), or saline, as a single intravenous injection 1 h after a thoracic contusion SCI. The animals were evaluated for behavioral recovery over 6 weeks, which included BBB locomotor testing, horizontal ladder testing, video-analysis of gait, and hindlimb monofilament sensory testing. At 6 week post-injury, the spinal cords were evaluated histologically to measure white and grey matter sparing at and around the epicenter of injury. We found that neither erythropoietin nor darbepoetin led to improved behavioral recovery over saline controls, with no significant differences observed in BBB scores, BBB subscores, footfall errors on horizontal ladder testing, width of hindlimb base of support, or threshold for paw withdrawal on sensory testing. Furthermore, no differences were observed in grey or white matter sparing between the three experimental groups. Using doses of erythropoietin and darbepoetin that other investigators have reported to be beneficial in SCI and stroke models, we were unable to demonstrate a neuroprotective effect when administered 1 h after injury. Further preclinical investigation is necessary to refine the treatment strategy of using erythropoietin or darbepoetin in acute spinal cord injury.

The beta-adrenoceptor blockers exhibit a well-characterized anti-apoptotic property in the heart and kidney while less is known about the effect of this class of drugs on neuronal apoptosis. We studied the effects of three beta-adrenoceptor blockers propranolol (1-(isoproplyamino)-3-(naphthalene-1-yloxy)propan-2-ol), atenolol (2-[4-[2-hydroxy-3-(1-methylethylamino)propoxyl]phenyl]ehanamide), and ICI 118551 (1-[2,3-(dihydro-7-methyl-1H-iden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol), against staurosporine-induced apoptosis in SH-SY5Y human neuroblastoma cells. Staurosporine increased caspase 3-like activity, DNA fragmentation, PARP cleavage, and the number of TUNEL positive cells consistent with the induction of apoptosis. Propranolol and ICI 118551, but not atenolol, demonstrated a concentration-dependent inhibition of caspase 3-like activity. Propranolol and ICI 118551 directly inhibited the enzymatic activity of recombinant caspase 9 while atenolol did not; however, none of the beta-adrenoceptor blockers that were examined directly blocked caspases 2 or 3 activity. In isolated mitochondria, propranolol and ICI 118551 inhibited staurosporine-induced cytochrome c release while atenolol did not. We conclude that propranolol and ICI 118551 protect SH-SY5Y cells against staurosporine-induced apoptosis through a dual action on the mitochondria and on caspase 9 in a cell type and an apoptotic paradigm where the conventional inhibitors of mitochondrial permeability transition such as cyclosporin A and bongkrekic acid demonstrate no protection.

We have shown that A1 adenosine receptors (A 1 ARs) are cytoprotective against renal tubular necrosis and apoptosis both in vivo and in vitro . To study the role of A 1 AR numbers on renal epithelial cell survival, we stably overexpressed the human A1 receptor in a porcine renal tubule cell line and utilized primary cultures of proximal tubules obtained from A 1 AR knockout mice. Receptor-overexpressing cells were protected against peroxide-induced necrosis and tumor necrosis factor- α /cycloheximide-induced apoptosis. Conversely, cultured proximal tubule cells from receptor knockout mice showed more necrotic and apoptotic cell loss than corresponding cells from wild-type mice. Overexpression of the receptor resulted in a significantly higher baseline expression of both total and phosphorylated heat-shock protein (HSP)27; the latter due to A1 receptor enhancement of p38 and AP2 mitogen-activated protein kinase activities. The resistance to cell death in the porcine cells was reversed by selective A1 receptor antagonism and by a selective inhibitor of HSP synthesis. Receptor activation in wild-type mice in vivo led to increased total and phosphorylated HSP27, whereas receptor knockout mice showed decreased baseline and adenosine-mediated HSP phosphorylation. These studies show that endogenous A 1 AR activation produces cytoprotective effects in renal proximal tubules by modulating HSP27 signaling pathways.