Acute intranasal osteopontin treatment in male rats following TBI increases the number of activated microglia but does not alter lesion characteristics.

Intranasal recombinant osteopontin (OPN) has been shown to be neuroprotective in different models of acquired brain injury but has never been tested after traumatic brain injury (TBI). We used a model of moderate-to-severe controlled cortical impact in male adult Sprague Dawley rats and tested our hypothesis that OPN treatment would improve neurological outcomes, lesion and brain tissue characteristics, neuroinflammation, and vascular characteristics at 1 day post-injury. Intranasal OPN administered 1 hr after the TBI did not improve neurological score, lesion volumes, blood-brain barrier, or vascular characteristics. When assessing neuroinflammation, we did not observe any effect of OPN on the astrocyte reactivity but discovered an increased number of activated microglia within the ipsilateral hemisphere. Moreover, we found a correlation between edema and heme oxygenase-1 (HO-1) expression which was decreased in OPN-treated animals, suggesting an effect of OPN on the HO-1 response to injury. Thus, OPN may increase or accelerate the microglial response after TBI, and early response of HO-1 in modulating edema formation may limit the secondary consequences of TBI at later time points. Additional experiments and at longer time points are needed to determine if intranasal OPN could potentially be used as a treatment after TBI where it might be beneficial by activating protective signaling pathways.

Single-Stage Revision Arthroplasty for Infection-An Underutilized Treatment Strategy.

BACKGROUND: The burden of revision arthroplasty surgery for infection is rising as the rate of primary arthroplasty surgery increases. Infected arthroplasty rates are now relatively low, but the sheer increase in volume is leading to considerable patient morbidity and significant increases in costs to the health care system. Single-stage revision for infection is one of the several accepted treatment options, but the indications and results are debated. This review aims to clarify the current evidence. METHODS: MEDLINE/PubMed databases were reviewed for studies that looked at single- or one-stage revision knee or hip arthroplasty for infection. RESULTS: There is increasing evidence that single-stage revision for infection can control infection and with decreased morbidity, mortality, and health care costs compared with a staged approach. However, the indications are still debated. Recently, there has been a determined effort to define an infected arthroplasty in a manner that will allow for standardization of reporting in the literature. The evidence supporting single stage for knee arthroplasty is catching up with the result with hip arthroplasty. High-quality data from randomized controlled trials are now pending. CONCLUSION: After the gradual evolution of using the single-stage approach, with the widespread acceptance of this definition, we can now standardize comparisons across the world and move toward a refined definition of the ideal patient population for single-stage arthroplasty revision in both the hip and the knee population.

Psychosocial Stress and Age Influence Depression and Anxiety-Related Behavior, Drive Tumor Inflammatory Cytokines and Accelerate Prostate Cancer Growth in Mice.

Prostate cancer (PCa) prevalence is higher in older men and poorer coping with psychosocial stressors effect prognosis. Yet, interactions between age, stress and PCa progression are underexplored. Therefore, we characterized the effects of age and isolation combined with restraint (2 h/day) for 14 days post-tumor inoculation on behavior, tumor growth and host defense in the immunocompetent, orthotopic RM-9 murine PCa model. All mice were tumor inoculated. Isolation/restraint increased sympathetic and hypothalamic-pituitary-adrenal cortical activation, based on elevated serum 3-methoxy-4-hydroxyphenylglycol/norepinephrine ratios and corticosterone levels, respectively. Elevated zero maze testing revealed age-related differences in naïve C57Bl/6 mice, and increased anxiety-like behavior in tumor-bearing mice. In open field testing, old stressed mice were less active throughout the 30-min test than young non-stressed and stressed, and old non-stressed mice, suggesting greater anxiety in old stressed mice. Old (18 month) mice demonstrated more depression-like behavior than young mice with tail suspension testing, without effects of isolation/restraint stress. Old mice developed larger tumors, despite similar tumor expression of tumor vascular endothelial growth factor or transforming growth factor-beta1 across age. Tumor chemokine/cytokine expression, commonly prognostic for poorer outcomes, were uniquely age- and stress-dependent, underscoring the need for PCa research in old animals. Macrophages predominated in RM-9 tumors. Macrophages, and CD4+ and CD4+FoxP3+ T-cell tumor infiltration were greater in young mice than in old mice. Stress increased macrophage infiltration in old mice. Conversely, stress reduced intratumoral CD4+ and CD4+FoxP3+ T-cell numbers in young mice. CD8+ T-cell infiltration was similar across treatment groups. Our findings support that age- and psychological stress interacts to affect PCa outcomes by interfering with neural-immune mechanisms and affecting behavioral responses.

Role of NADPH Oxidase as a Mediator of Oxidative Damage in Low-Dose Irradiated and Hindlimb-Unloaded Mice.

The purpose of this study was to determine whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived stress can account for unloading- and radiation-induced endothelial damage and neurovascular remodeling in a mouse model. Wild-type (WT, Nox2+/+) C57BL/6 mice or Nox2-/- (B6.129S6-CYBBM) knockout (KO) mice were placed into one of the following groups: age-matched control; hindlimb unloading (HLU); low-dose/low-dose-rate radiation (LDR); or HLU with LDR simultaneously for 21 days. The mice were then sacrificed one month later. Anti-orthostatic tail suspension was used to model the unloading, fluid shift and physiological stress aspects of microgravity. The LDR was delivered using 57Co plates (0.04 Gy at 0.01 cGy/h) to the simulate whole-body irradiation, similar to that experienced while in space. Brains were isolated for characterization of various oxidative stress markers and vascular topology. The level of 4-hydroxynonenal (4-HNE) protein, a specific marker for lipid peroxidation, was measured. Expression of aquaporin-4 (AQP4), a water channel protein expressed in astrocyte end-feet, was quantified. Thirty days after simulated spaceflight, KO mice showed decreased apoptosis (P < 0.05) in the brain compared to WT counterparts. The HLU-dependent increase in apoptosis in WT mice was not observed in KO mice. The level of 4-HNE protein was significantly elevated in the hippocampus of the LDR with HLU treatment group compared to WT controls (P < 0.05). However, there were no significant differences among groups of Nox2-KO mice at the one-month time point. In contrast to findings in the WT animals, superoxide dismutase (SOD) level and expression of AQP4 were similar among all KO groups. In summary, for most of the parameters, the oxidative response to HLU and LDR was suppressed in Nox2-KO mice. This suggests that Nox2-containing NADPH oxidase may contribute to spaceflight environment-induced oxidative stress.

Long-term effects of simulated microgravity and/or chronic exposure to low-dose gamma radiation on behavior and blood-brain barrier integrity.

Astronauts on lengthy voyages will be exposed to an environment of microgravity and ionizing radiation that may have adverse effects on physical abilities, mood, and cognitive functioning. However, little is known about the long-term effects of combined microgravity and low-dose radiation. We exposed mice to gamma radiation using a cobalt-57 plate (0.01 cGy/h for a total dose of 0.04 Gy), hindlimb unloading to simulate microgravity, or a combination of both for 3 weeks. Mice then underwent a behavioral test battery after 1 week, 1 month, 4 months, and 8 months to assess sensorimotor coordination/balance (rotarod), activity levels (open field), learned helplessness/depression-like behavior (tail suspension test), risk-taking (elevated zero maze), and spatial learning/memory (water maze). Aquaporin-4 (AQP4) expression was assessed in the brain after behavioral testing to determine blood-brain barrier (BBB) integrity. Mice that received unloading spent significantly more time in the exposed portions of the elevated zero maze, were hypoactive in the open field, and spent less time struggling on the tail suspension test than mice that did not receive unloading. Mice in the combination group expressed more AQP4 immunoactivity than controls. Elevated zero maze and AQP4 data were correlated. No differences were seen on the water maze or rotarod, and no radiation-only effects were observed. These results suggest that microgravity may lead to changes in exploratory/risk-taking behaviors in the absence of other sensorimotor or cognitive deficits and that combined microgravity and a chronic, low dose of gamma radiation may lead to BBB dysfunction.

Simulated Microgravity and Low-Dose/Low-Dose-Rate Radiation Induces Oxidative Damage in the Mouse Brain.

Microgravity and radiation are stressors unique to the spaceflight environment that can have an impact on the central nervous system (CNS). These stressors could potentially lead to significant health risks to astronauts, both acutely during the course of a mission or chronically, leading to long-term, post-mission decrements in quality of life. The CNS is sensitive to oxidative injury due to high concentrations of oxidizable, unsaturated lipids and low levels of antioxidant defenses. The purpose of this study was to evaluate oxidative damage in the brain cortex and hippocampus in a ground-based model for spaceflight, which includes prolonged unloading and low-dose radiation. Whole-body low-dose/low-dose-rate (LDR) gamma radiation using (57)Co plates (0.04 Gy at 0.01 cGy/h) was delivered to 6 months old, mature, female C57BL/6 mice (n = 4-6/group) to simulate the radiation component. Anti-orthostatic tail suspension was used to model the unloading, fluid shift and physiological stress aspects of the microgravity component. Mice were hindlimb suspended and/or irradiated for 21 days. Brains were isolated 7 days or 9 months after irradiation and hindlimb unloading (HLU) for characterization of oxidative stress markers and microvessel changes. The level of 4-hydroxynonenal (4-HNE) protein, an oxidative specific marker for lipid peroxidation, was significantly elevated in the cortex and hippocampus after LDR + HLU compared to controls (P < 0.05). The combination group also had the highest level of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression compared to controls (P < 0.05). There was a significant decrease in superoxide dismutase (SOD) expression in the animals that received HLU only or combined LDR + HLU compared to control (P < 0.05). In addition, 9 months after LDR and HLU exposure, microvessel densities were the lowest in the combination group, compared to age-matched controls in the cortex (P < 0.05). Our data provide the first evidence that prolonged exposure to simulated microgravity and LDR radiation is associated with increased oxidative stress biomarkers that may increase the likelihood of brain injury and reduced antioxidant defense. NOX2-containing nicotinamide adenosine dinucleotide phosphate (NADPH oxidase) may contribute to spaceflight environment-induced oxidative stress.

The tibiofibular line: an anatomical feature to diagnose syndesmosis malposition.

BACKGROUND: Medical imaging of the distal tibiofibular joint requires reliable and simple tools to identify disruption of the syndesmosis. We present an anatomical feature, the "tibiofibular line," which appears on axial computed tomography (CT) images of normal ankles. This feature is a straight line that connects the anterolateral surface of the fibula with the anterolateral tubercle of the tibia at the level of the ankle syndesmosis. The purpose of this study was, first, to demonstrate that this line is a reliable anatomical feature in normal ankles and, second, to demonstrate that this line is displaced with diastasis or malrotation of the syndesmosis. METHODS: A series of 150 normal ankle CTs were collected, negative for history of ankle injury with a normal tibiofibular overlap and clear space. Thirty ankles with a displaced syndesmosis were identified by history, CT, and abnormal tibiofibular overlap and clear space parameters. The tibiofibular line was applied to both groups and measured for its distance displaced from the anterior tibial tubercle. RESULTS: All CT images in the normal ankle group had a tibiofibular line within 2 mm of the anterior tibial tubercle (77% of the tibiofibular lines were within 0 mm, 19% were within 1 mm, and 4% were within 2 mm). The tibiofibular line in the injured group was displaced anteriorly by 4 to 19 mm (minimum to maximum) from the tibial tubercle (P < .0001). CONCLUSION: The tibiofibular line was a normal anatomical feature that could be used to identify displacement of the distal tibiofibular syndesmosis. LEVEL OF EVIDENCE: Level III, comparative series.