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.

Development of a capillary temperature control system for capillary electrophoresis instruments designed for spaceflight applications.

Capillary temperature control during capillary electrophoresis (CE) separations is key for achieving accurate and reproducible results with a broad array of potential methods. However, the difficulty of enabling typical fluid temperature control loops on portable instruments has meant that active capillary temperature control of in situ CE systems has frequently been overlooked. This work describes construction and test of a solid-state device for capillary temperature control that is suitable for inclusion with in situ instruments, including those designed for space missions. Two test articles were built, a thermal mass model (TMM) and a functional model (FM). The TMM demonstrated that temperature gradients could be limited using the proposed control scheme, and that our thermal modeling of the system can be relied on for future adaptations of physical geometries of the system. The FM demonstrated CE analytical performance while under active temperature control and that the device was compatible with the harsh thermal-vacuum environments that might be encountered during space flight.

Metatranscriptomic Comparison of Endophytic and Pathogenic Fusarium-Arabidopsis Interactions Reveals Plant Transcriptional Plasticity.

Plants are continuously exposed to beneficial and pathogenic microbes, but how plants recognize and respond to friends versus foes remains poorly understood. Here, we compared the molecular response of Arabidopsis thaliana independently challenged with a Fusarium oxysporum endophyte Fo47 versus a pathogen Fo5176. These two F. oxysporum strains share a core genome of about 46 Mb, in addition to 1,229 and 5,415 unique accessory genes. Metatranscriptomic data reveal a shared pattern of expression for most plant genes (about 80%) in responding to both fungal inoculums at all timepoints from 12 to 96 h postinoculation (HPI). However, the distinct responding genes depict transcriptional plasticity, as the pathogenic interaction activates plant stress responses and suppresses functions related to plant growth and development, while the endophytic interaction attenuates host immunity but activates plant nitrogen assimilation. The differences in reprogramming of the plant transcriptome are most obvious in 12 HPI, the earliest timepoint sampled, and are linked to accessory genes in both fungal genomes. Collectively, our results indicate that the A. thaliana and F. oxysporum interaction displays both transcriptome conservation and plasticity in the early stages of infection, providing insights into the fine-tuning of gene regulation underlying plant differential responses to fungal endophytes and pathogens.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

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.

The Cauda Scale - Validation for Clinical Practice.

Purpose: The purpose of this study was to validate the cauda scale (TCS) in an external population. TCS was proposed as a tool to be used to predict the likelihood of cauda equina compression.Methods: We analysed the presenting condition of consecutive patients attending the emergency department undergoing a magnetic resonance scan with a clinical suspicion of cauda equina syndrome (CES). The findings were graded according to TCS for those with and without radiological compression of the cauda equina. Logistic regression was applied to the data in accordance with the original paper.Results: Patients were included over a 14 month period (n = 313), subsequent imaging revealed CES compression in 34 cases and no CES compression in 279. The TCS proposed that small values meant a more likely diagnosis of CES, the data showed the opposite of this with the highest number of patients with CES scoring a maximal 9 on TCS (mildest symptoms).Conclusions: Our data suggests that TCS has potential limitations in identifying patients with CES and needs further work prior to implementation.

Recognizing Rosacea: Tips on Differential Diagnosis

Rosacea is a common chronic inflammatory dermatosis with a variety of clinical manifestations. Rosacea primarily affects the central face, and includes papules, pustules, erythema, telangiectasias, perilesional redness, phymatous changes, and even ocular involvement. Symptoms may vary among different patients and even vary over time in an individual patient. Central facial redness affects many adults and can be an indicator of the chronic inflammatory disease rosacea. Rosacea is a clinical diagnosis based on the patient's history, physical examination, and exclusion of other disorders. It is under-diagnosed, particularly in individuals with skin of color. The goal of this article is to provide clinicians with the tools and understanding needed to correctly identify rosacea and differentiate it from other conditions that have overlapping signs and symptoms. J Drugs Dermatol. 2019;18(9):888-894

Overexpression of ShCYP51B and ShatrD in Sclerotinia homoeocarpa isolates exhibiting practical field resistance to a demethylation inhibitor fungicide.

We investigated genetic factors that govern the reduced propiconazole sensitivity of Sclerotinia homoeocarpa field isolates collected during a 2-year field efficacy study on dollar spot disease of turf in five New England sites. These isolates displayed a >50-fold range of in vitro sensitivity to a sterol demethylation inhibitor (DMI) fungicide, propiconazole, making them ideal for investigations of genetic mechanisms of reduced DMI sensitivity. The CYP51 gene homolog in S. homoeocarpa (ShCYP51B), encoding the enzyme target of DMIs, is likely a minor genetic factor for reduced propiconazole sensitivity, since there were no differences in constitutive relative expression (RE) values and only 2-fold-higher induced RE values for insensitive than for sensitive isolate groups. Next, we mined RNA-Seq transcriptome data for additional genetic factors and found evidence for the overexpression of a homolog of Botrytis cinerea atrD (BcatrD), ShatrD, a known efflux transporter of DMI fungicides. The ShatrD gene showed much higher constitutive and induced RE values for insensitive isolates. Several polymorphisms were found upstream of ShatrD but were not definitively linked to overexpression. The screening of constitutive RE values of ShCYP51B and ShatrD in isolates from two golf courses that exhibited practical field resistance to propiconazole uncovered evidence for significant population-specific overexpression of both genes. However, linear regression demonstrated that the RE of ShatrD displays a more significant relationship with propiconazole sensitivity than that of ShCYP51B. In summary, our results suggest that efflux is a major determinant of the reduced DMI sensitivity of S. homoeocarpa genotypes in New England, which may have implications for the emergence of practical field resistance in this important turfgrass pathogen.

Allopurinol augmentation in the outpatient treatment of bipolar mania: a pilot study.

BACKGROUND: Allopurinol promotes the salvage of purines, possibly increasing endogenous adenosine levels. Recent studies suggest that adenosine has neuroprotective and inhibitory effects. Two previous inpatient trials demonstrated that allopurinol has anti-manic activity. Our objective was to test allopurinol as an adjunct to standard medications in bipolar disorder manic outpatients. METHODS: In this double-blind, placebo-controlled trial, 27 subjects who met DSM-IV criteria for bipolar disorder and scored ≥ 14 on the Young Mania Rating Scale (YMRS) were randomized to augmentation with allopurinol or placebo for six weeks. The primary efficacy measure was the YMRS. The primary safety measure was the Treatment Emergent Symptom Scale. RESULTS: The effect of allopurinol augmentation in decreasing mean YMRS scores was modest, with an overall effect size of -0.25 (Cohen's d). Allopurinol-treated individuals who abstained from caffeine (n = 4) had a greater decrease in YMRS scores (-15.3 ± 1.8) than subjects using caffeine (n = 5) (-9.6 ± 3.4, p = 0.219), with an effect size of -0.86. CONCLUSION: In this small outpatient pilot study, allopurinol augmentation did not show a statistically significant improvement over placebo in attenuating manic symptoms. Subjects with restricted caffeine use showed a greater effect size compared to caffeine users. This finding may be interpreted as corroborating the hypothesized mechanism of action of allopurinol's anti-manic effect in previous studies.

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.

A pilot study to assess the influence of infiltrated stormwater on groundwater: Hydrology and trace organic contaminants.

Underground infiltration basins (UIBs) mimic the natural hydrologic cycle by allowing stormwater to recharge local groundwater aquifers. However, little is known about the potential transport of organic contaminants to receiving groundwater. We conducted a pilot study in which we collected paired grab samples of stormwater runoff flowing into two UIBs (inflow) and shallow groundwater adjacent to the UIBs. Samples were collected coincident with three rain events and analyzed for volatile organic compounds, semi-volatile organic compounds, pharmaceuticals, and pesticides. Few contaminants were detected in groundwater, compared with inflow, and groundwater concentrations were typically an order of magnitude less. With one exception (trichloroethene), all groundwater concentrations were at least two orders of magnitude below available guidance or screening values. This short communication highlights information gaps in understanding the hydrologic connectivity between UIBs and receiving groundwater and potential consequent contaminant transport to the subsurface from varying climatic conditions. PRACTITIONER POINTS: Urban stormwater contains organic contaminants including pharmaceuticals, pesticides, and semi-volatile organic compounds that may be transported to groundwater via infiltration. In general, fewer contaminants were detected in groundwater and at lower concentrations, compared with urban stormwater runoff. Trace organic contaminant concentrations in groundwater were much lower than drinking water guidance/screening values.

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.

Managing Rosacea in the Clinic: From Pathophysiology to Treatment-A Review of the Literature.

Rosacea is a chronic skin disease characterized by a waxing and waning course. It can encompass different symptoms including erythema, papules/pustules, telangiectasia, and phymata and sometimes secondary manifestations, such as itching, burning, or stinging. This article reviews recent changes in rosacea management. Discussion of relevant medical literature augmented with clinical expertise is also provided. Notably, while patients report that rosacea negatively impacts their emotional and overall well-being, they also tend to have low satisfaction with treatment and are prone to discontinuing therapy and/or using rosacea medications on an intermittent basis, thereby undermining treatment efficacy. Fortunately, the therapeutic armamentarium for rosacea is expanding, and experts now recommend a treatment approach that targets the presenting signs and/or symptoms, with the goal of achieving the greatest possible clearance. More so than in the past, several treatments can be used concurrently to best address the overall presentation of rosacea in an individual patient.

Biologic Treatment Options for Pediatric Psoriasis and Atopic Dermatitis-A Review.

Background and Objectives: Severe, recalcitrant cases of pediatric psoriasis or atopic dermatitis may necessitate treatment with biological agents; however, this may be difficult due to lack of treatment options and standardized treatment guidelines. This review evaluates the biological treatment options available, including off-label uses, and provides a basic therapeutic guideline for pediatric psoriasis and atopic dermatitis. Materials and Methods: A PubMed review of biological treatments for pediatric psoriasis and atopic dermatitis with information regarding age, efficacy, dosing, contra-indications, adverse events, and off-label treatments. Results: Currently there are three European Medicines Agency (EMA)-approved biological treatment options for pediatric psoriasis: etanercept, ustekinumab, and adalimumab. While dupilumab was recently Food and Drug Administration (FDA)- and EMA-approved for adult atopic dermatitis, it is still not yet approved for pediatric atopic dermatitis. Conclusion: Given the high morbidity associated with pediatric atopic dermatitis and psoriasis, there is a need for more treatment options. Further research and post-marketing registries are needed to extend the use of biologics into pediatric patients.

The prevalence of lumbar disc degeneration in symptomatic younger patients: A study of MRI scans.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVE: Low back pain (LBP) and radiculopathy present a significant burden to patients and healthcare systems. Lumbar disc degeneration (LDD) is associated with LBP. While the prevalence of LDD in older, symptomatic, patients has been extensively documented there has been little describing the prevalence in younger patients. METHODS: 1011 patients aged 20-30 years, who had undergone Magnetic Resonance Imaging (MRI), for investigation of LBP and or radiculopathy, over a 9-year period were identified. Those who had previous surgery, congenital deformities or unavailable imaging were excluded. A single surgeon evaluated the MRI images of 730 patients and classified each lumbar disc according to the Pfirrmann classification. 105 randomly selected patient's imaging was reviewed again by the primary reviewer and by a consultant musculoskeletal radiologist with the kappa coefficients for inter-rater and intra-rater agreement calculated. RESULTS: Of the 730 patients, 428 (58.6%) had MRI evidence of LDD (Pfirrmann III, IV, V). 255 (59.6%) demonstrated single level pathology and 173 (41.4%) multilevel involvement. There was very high intra/inter observer agreement with kappa coefficients for intra-observer agreement from 0.65 to 0.98 and inter-observer agreement from 0.51 to 0.88. CONCLUSIONS: This is the largest study to document the prevalence of LDD in a symptomatic young cohort. A large prospective study including non-symptomatic patients and information on associated factors would add further information. Given the considerably higher than anticipated prevalence identified in this study and the significant burden associated with LBP this study should encourage such further research.

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.

Single incision lateral release for hallux valgus using a cervical biopsy blade: A cadaveric study.

The role of lateral release is widely accepted and regarded as a key step in the management of hallux valgus. There remains however debate in the literature in regards to which structures should be divided and the method of approach. As such, a technique of lateral release using a curved blade placed inferior to the metatarsal head to divide the lateral metatarsosesamoid suspensory ligament and incise the lateral joint capsule has been developed. This technique was performed on fourteen fresh frozen cadaveric specimens which were then dissected. In all cases the lateral metatarsosesamoid suspensory ligament was divided and the lateral capsule incised to the joint line. One case of iatrogenic injury to the oblique head of adductor hallucis tendon was noted. No cases of neurovascular injury were noted. The authors conclude that this method of lateral release to be safe and reproducible in a cadaveric model in achieving lateral release for the management of hallux valgus.

Bicycle helmet use to reduce the impact of head injuries in ladder users.

BACKGROUND: The aim of this study was to determine if wearing a bicycle helmet during ladder use could reduce the incidence and severity of head injury in the event of a fall. METHODS: A headform model with inbuilt accelerometers was used to determine the Head Injury Criterion (HIC) score of head impact by dropping 41 helmeted and unhelmeted headforms from eight heights. These results were compared. RESULTS: There was a statistically significant difference between averaged HIC scores in helmeted and unhelmeted drops (P < 0.001). Unhelmeted HIC scores ranged from 387 at 0.25 m to 2121 at 0.6 m. Helmeted HIC scores ranged from 29 at 0.25 m to 1199 at 2.5 m. At a height of 0.5 m, the risk of severe brain injury (AIS ≥4) from direct frontal head impact is predicted to reduce from >50% to <5% with helmet use. CONCLUSION: There was a significant decrease in the HIC scores when helmets are used and it is likely that the benefits would be seen in the clinical setting. These results provide an argument for the use of a bicycle helmets by all ladder users, in particular those over age 50 who are at increased risk of head injuries. We recommend that bicycle helmet use be incorporated into ladder injury prevention strategies.