The Effects of Mild Concussions and Pomegranates on Behavior

The neuropathological effects of mild concussions can accumulate, leading to the development of motor and cognitive deficits. Although there are currently no treatments that can restore lost function after repetitive concussion, our laboratory has shown that dietary supplementation with pomegranate polyphenols can improve Alzheimer’s-like pathology, protect mice from the effects of proton irradiation, and protect humans from post-operative cognitive deficits. This study investigated the behavioral and neuropathological effects of repetitive concussions in mice and the use of dietary supplementation with pomegranate to ameliorate these effects. Adult mice were given dilute pomegranate juice or control water for 1 week, followed by anesthesia, repeated anesthesia (3 days apart), or repeated concussive injury (a single closed-head injury to each hemisphere 3 days apart). They were then maintained on the pomegranate juice or control water for 2 additional weeks. Behavioral testing was administered 1, 3, 5, and 7-11 days post injury to assess cognitive, motor, and affective functions. Repeated concussion, but not repeated anesthesia, induced motor and learning deficits, some of which were significantly reduced by pomegranate juice. These data suggest that the model of mild repeated concussive injury in mice might be used to test neuroprotective treatment in future studies

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Cortical and trabecular bone are equally affected in rats with renal failure and secondary hyperparathyroidism

Abstract Background Changes in mineral metabolism and bone structure develop early in the course of chronic kidney disease and at end-stage are associated with increased risk of fragility fractures. The disruption of phosphorus homeostasis leads to secondary hyperparathyroidism, a common complication of chronic kidney disease. However, the molecular pathways by which high phosphorus influences bone metabolism in the early stages of the disease are not completely understood. We investigated the effects of a high phosphorus diet on bone and mineral metabolism using a 5/6 nephrectomy model of chronic kidney disease. Methods Four-week old rats were randomly assigned into groups: 1) Control with standard diet, 2) Nephrectomy with standard rodent diet, and 3) Nephrectomy with high phosphorus diet. Rats underwent in vivo imaging at baseline, day 14, and day 28, followed by ex vivo imaging. Results Cortical bone density at the femoral mid-diaphysis was reduced in nephrectomy-control and nephrectomy-high phosphorus compared to control rats. In contrast, trabecular bone mass was reduced at both the lumbar vertebrae and the femoral secondary spongiosa in nephrectomy-high phosphorus but not in nephrectomy-control. Reduced trabecular bone volume adjusted for tissue volume was caused by changes in trabecular number and separation at day 35. Histomorphometry revealed increased bone resorption in tibial secondary spongiosa in nephrectomy-control. High phosphorus diet-induced changes in bone microstructure were accompanied by increased serum parathyroid hormone and fibroblast growth factor 23 levels. Conclusion Our study demonstrates that changes in mineral metabolism and hormonal dysfunction contribute to trabecular and cortical bone changes in this model of early chronic kidney disease

Long-term Consequences of Traumatic Brain Injury in Bone Metabolism

Traumatic brain injury (TBI) leads to long-term cognitive, behavioral, affective deficits, and increase neurodegenerative diseases. It is only in recent years that there is growing awareness that TBI even in its milder form poses long-term health consequences to not only the brain but to other organ systems. Also, the concept that hormonal signals and neural circuits that originate in the hypothalamus play key roles in regulating skeletal system is gaining recognition based on recent mouse genetic studies. Accordingly, many TBI patients have also presented with hormonal dysfunction, increased skeletal fragility, and increased risk of skeletal diseases. Research from animal models suggests that TBI may exacerbate the activation and inactivation of molecular pathways leading to changes in both osteogenesis and bone destruction. TBI has also been found to induce the formation of heterotopic ossification and increased callus formation at sites of muscle or fracture injury through increased vascularization and activation of systemic factors. Recent studies also suggest that the disruption of endocrine factors and neuropeptides caused by TBI may induce adverse skeletal effects. This review will discuss the long-term consequences of TBI on the skeletal system and TBI-induced signaling pathways that contribute to the formation of ectopic bone, altered fracture healing, and reduced bone mass

Inhibition of microRNA-210 provides neuroprotection in hypoxic-ischemic brain injury in neonatal rats

Perinatal hypoxic-ischemic encephalopathy (HIE) is associated with high neonatal mortality and severe long-term neurologic morbidity. Yet the mechanisms of brain injury in infants with HIE remain largely elusive. The present study determined a novel mechanism of microRNA-210 (miR-210) in silencing endogenous neuroprotection and increasing hypoxic-ischemic brain injury in neonatal rats. The study further revealed a potential therapeutic effect of miR-210 inhibition using complementary locked nucleic acid oligonucleotides (miR-210-LNA) in 10-day-old neonatal rats in the Rice-Vannucci model. The underlying mechanisms were investigated with intracerebroventricular injection (i.c.v) of miR-210 mimic, miR-210-LNA, glucocorticoid receptor (GR) agonist and antagonist. Luciferase reporter gene assay was conducted for identification of miR-210 targeting GR 3\u27untranslated region. The results showed that the HI treatment significantly increased miR-210 levels in the brain, and miR-210 mimic significantly decreased GR protein abundance and exacerbated HI brain injury in the pups. MiR-210-LNA administration via i.c.v. 4h after the HI insult significantly decreased brain miR-210 levels, increased GR protein abundance, reduced HI-induced neuronal death and brain infarct size, and improved long-term neurological function recovery. Of importance, the intranasal delivery of miR-210-LNA 4h after the HI insult produced similar effects in decreasing HI-induced neonatal brain injury and improving neurological function later in life. Altogether, the present study provides evidence of a novel mechanism of miR-210 in a neonatal HI brain injury model, and suggests a potential therapeutic approach of miR-210 inhibition in the treatment of neonatal HIE

Mild Concussion, but Not Moderate Traumatic Brain Injury, Is Associated with Long-Term Depression-Like Phenotype in Mice.

Mild traumatic brain injuries can lead to long-lasting cognitive and motor deficits, increasing the risk of future behavioral, neurological, and affective disorders. Our study focused on long-term behavioral deficits after repeated injury in which mice received either a single mild CHI (mCHI), a repeated mild CHI (rmCHI) consisting of one impact to each hemisphere separated by 3 days, or a moderate controlled cortical impact injury (CCI). Shams received only anesthesia. Behavioral tests were administered at 1, 3, 5, 7, and 90 days post-injury (dpi). CCI animals showed significant motor and sensory deficits in the early (1-7 dpi) and long-term (90 dpi) stages of testing. Interestingly, sensory and subtle motor deficits in rmCHI animals were found at 90 dpi. Most importantly, depression-like behaviors and social passiveness were observed in rmCHI animals at 90 dpi. These data suggest that mild concussive injuries lead to motor and sensory deficits and affective disorders that are not observed after moderate TBI

Turn bias was most evident in the mice with CCI.

<p><b>(A)</b> At 1 dpi, CCI mice made significantly fewer left turns (contralateral to the injury) on the balance beam than sham (^≠<i>p</i><0.05) and mCHI (^∂∂<i>p</i> < .01) mice. <b>(B)</b> Both rmCHI and CCI mice exhibited more turns to the right throughout balance beam testing than shams, though these results did not reach statistical significance. <b>(C)</b> CCI mice made more left-sided slips on the balance beam than other animals. These deficits were most prominent at 7 dpi compared to shams and other injury groups (^aaa<i>p</i><0.001) and persisted up to 90+ dpi (^≠≠<i>p</i><0.01 vs. sham, ^≠≠≠<i>p</i><0.001 vs. sham, ^ø<i>p</i><0.05 vs. rmCHI, ^øø<i>p</i><0.01 vs. rmCHI, ^∂<i>p</i><0.05 vs. mCHI, ^∂∂<i>p</i><0.01 vs. mCHI, ^∂∂∂<i>p</i><0.001 vs. mCHI). <b>(D)</b> In the water maze, rmCHI and CCI mice tended to swim to the left (contralateral to the injury) compared to sham and mCHI animals (*<i>p</i><0.05, **<i>p</i><0.01; mean +/- 95% CI). 95% confidence intervals show that the left turn biases in rmCHI and CCI mice are statistically significant (<i>p</i><0.05), whereas no significant turn bias is observed in the sham and mCHI mice. (The clock graphic above shows variance markings of the relative angular velocity of each injury group with each mark on the clock representing a separation of 6° in relation to 12 o’clock. Flag symbol marks zero degrees).</p