Glial Sphingosine-Mediated Epigenetic Regulation Stabilizes Synaptic Function in Drosophila Models of Alzheimer's Disease.

Destabilization of neural activity caused by failures of homeostatic regulation has been hypothesized to drive the progression of Alzheimer's Disease (AD). However, the underpinning mechanisms that connect synaptic homeostasis and the disease etiology are yet to be fully understood. Here, we demonstrated that neuronal overexpression of amyloid ß (Aß) causes abnormal histone acetylation in peripheral glia and completely blocks presynaptic homeostatic potentiation (PHP) at the neuromuscular junction in Drosophila The synaptic deficits caused by Aß overexpression in motoneurons are associated with motor function impairment at the adult stage. Moreover, we found that a sphingosine analog drug, Fingolimod, ameliorates synaptic homeostatic plasticity impairment, abnormal glial histone acetylation, and motor behavior defects in the Aß models. We further demonstrated that perineurial glial sphingosine kinase 2 (Sk2) is not only required for PHP, but also plays a beneficial role in modulating PHP in the Aß models. Glial overexpression of Sk2 rescues PHP, glial histone acetylation, and motor function deficits that are associated with Aß in Drosophila Finally, we showed that glial overexpression of Sk2 restores PHP and glial histone acetylation in a genetic loss-of-function mutant of the Spt-Ada-Gcn5 Acetyltransferase complex, strongly suggesting that Sk2 modulates PHP through epigenetic regulation. Both male and female animals were used in the experiments and analyses in this study. Collectively, we provided genetic evidence demonstrating that abnormal glial epigenetic alterations in Aß models in Drosophila are associated with the impairment of PHP and that the sphingosine signaling pathway displays protective activities in stabilizing synaptic physiology.SIGNIFICANCE STATEMENT Fingolimod, an oral drug to treat multiple sclerosis, is phosphorylated by sphingosine kinases to generate its active form. It is known that Fingolimod enhances the cognitive function in mouse models of Alzheimer's disease (AD), but the role of sphingosine kinases in AD is not clear. We bridge this knowledge gap by demonstrating the relationship between impaired homeostatic plasticity and AD. We show that sphingosine kinase 2 (Sk2) in glial cells is necessary for homeostatic plasticity and that glial Sk2-mediated epigenetic signaling has a protective role in synapse stabilization. Our findings demonstrate the potential of the glial sphingosine signaling as a key player in glia-neuron interactions during homeostatic plasticity, suggesting it could be a promising target for sustaining synaptic function in AD.

Evaluation of the role of anal tone and perianal sensation examination in the assessment of suspected cauda equina syndrome.

PURPOSE: Cauda equina syndrome (CES) can present with a varied constellation of clinical signs and symptoms, which together with the time-sensitive nature of the condition and risk of catastrophic clinical outcome, presents a significant challenge to those assessing patients with this suspected diagnosis. Anal tone is commonly tested during initial assessment using a digital rectal examination (DRE). This study aims to evaluate the diagnostic value of anal tone and perianal sensation assessment in patients with suspected CES and report modern prevalence data on CES within a neurosciences centre. MATERIALS AND METHODS: Consecutive patients with suspected CES presenting over three years to the Emergency Department (ED) of a busy tertiary centre were included in the study. History and examination findings, documented in the ED notes, were assessed and these variables were correlated with the presence or absence of cauda equina compression on subsequent magnetic resonance imaging (MRI). RESULTS: Out of 1005 patients with suspected CES, 117 (11.6%) had MRI confirmed cauda equina compression (MRI + ve CES). 35% of MRI + ve patients and 31% of MRI -ve patients had reduced anal tone. Using univariate and multivariable logistic regression analyses, no associations were found between abnormal anal tone and MRI + ve CES for patients of all ages. The univariate logistic regression analysis identified altered perianal sensation to be significantly associated with MRI + ve CES in patients ≤42 years old. This association was no longer present when an adjusted multivariable logistic regression was performed. CONCLUSION: The prevalence of MRI + ve CES was 11.6%. Our findings suggest that the clinical finding of reduced anal tone has no demonstrable diagnostic value for those with suspected CES, either in itself or in combination with other clinical findings. Further studies are needed to confirm the diagnostic efficacy of assessing perianal sensation in this context.

Post-operative Horner's Syndrome: A Rare Complication Following Posterior Scoliosis Surgery in a Patient With Syringomyelia.

Horner's syndrome following posterior spinal instrumentation for scoliosis has been rarely reported. We describe the case of a 15-year-old male who presented with right-sided ptosis, miosis, and anhidrosis after scoliosis correction. This is the first reported case of first-order Horner's syndrome developing after scoliosis repair via posterior fixation in a patient known to have asymptomatic syringomyelia. The impression was that Horner's syndrome developed secondary to increased traction of the syringomyelia after scoliosis repair. This is significant as a diagnosis of Horner's syndrome can be distressing to patients and chronic cases cause cosmetic defects that might require surgical correction. We suggest that similar patients should be warned pre-operatively given the psychological distress associated with chronic Horner's syndrome. This case also illustrates the importance of an appropriate workup to rule out other sinister pathologies that can cause Horner's syndrome.

Spontaneous Posterior Subdural Pyogenic Escherichia coli Abscess Secondary to Lumbar Spondylodiscitis.

Pyogenic subdural spinal collections are rare but an important pathology to recognise and manage appropriately. We report the case of a 56-year-old female who developed a posterior subdural spinal collection associated with local discitis. There was no direct communication between the infected disc and subdural space, and the collection was located posteriorly within the subdural space which makes this case all the more unusual. We discuss the need for spinal subdural collections to be considered as a differential in patients with back pain and lower limb neurology (especially when there is a known spinal infective focus), the importance of careful interpretation of imaging, and the pathophysiological mechanisms and organisms known to cause spinal subdural collections.

Cement-in-cement revision with the Exeter Short Revision Stem: A review of 50 consecutive hips.

Revision of a well-fixed cemented femoral stem is technically challenging. The Exeter Short Revision Stem (SRS) was developed to facilitate cement-in-cement revision mitigating some of these challenges. We present the short to mid-term results of 50 cement-in-cement revisions performed with this implant. A retrospective review of all cement-in-cement revision with the Exeter SRS, at our institution, over a seven-year period between 2007 and 2014 was conducted. Records were assessed for radiological and clinical component loosening at greater than 12 months follow-up and for revision and complications at all time points. An Oxford Hip Score (OHS) and Numeric Rating Scale (NRS) for groin and thigh pain at rest and initial mobilisation were obtained. 50 implants in 46 patients were identified. Radiographic and clinical follow-up was available for 42 and 38 implants respectively at greater than 12 months. Mean radiographic follow-up was 5.1 years and clinical 4.9 years. There was no radiographic or clinical evidence of loosening. 3 revisions were performed, one for each of recurrent dislocation, infection and stem breakage. Median OHS was 39 (IQR 12) and mean NRS for groin pain at rest and initial mobilisation was 1.7 and 1.7 respectively and NRS for thigh pain at rest and initial mobilisation was 1.3 and 1.6 respectively with mean follow-up of 6.9 years. The Exeter SRS provides a viable option for cement-in-cement stem revision, with low revision, complication and loosening rates and good patient reported outcomes at short to mid-term follow up.

The Boyd-McLeod procedure for tennis elbow: mid- to long-term results.

BACKGROUND: Tennis elbow is a common condition that usually responds to conservative measures. In refractory cases, surgical intervention is indicated. A plethora of surgical techniques have been described. We report the mid- to long-term outcomes of the Boyd-McLeod procedure for refractory tennis elbow. METHODS: A retrospective analysis and current review of patients that had undergone the Boyd-McLeod procedure over a 12-year period was undertaken. Demographics, time to discharge, length of follow-up and outcome scores were collected. RESULTS: Seventy patients underwent surgery. Mean time to discharge was 15.35 weeks, with 88% successful outcomes. Fifty-four patients were available for current follow-up at mean of 5.52 years (range 1.17 years to 11.49 years). Range of motion in all patients was unchanged. There were no revision procedures. Mean (SD) Mayo Elbow Performance Score was 90.85 (13.11), with 75.5% returning a good or excellent score and 24.5% a fair outcome. The mean (SD) Oxford Elbow Score was 44.04 (6.92); mean (SD) pain score was 89.5 (17.58); mean (SD) function score was 95.34 (9.59) and mean (SD) socio-psychological score was 91.50 (17.01). Overall, 83% of patients had an Oxford Elbow Score of 43 or greater, suggesting excellent outcome. CONCLUSIONS: We show that the Boyd-McLeod procedure is an excellent option over both the short- and long-term for refractory tennis elbow.