One and two-year clinical outcomes for a polyethylene glenoid with a fluted peg: one thousand two hundred seventy individual patients from eleven centers.

PURPOSE: Clinical shoulder science lacks a benchmark against which the early clinical value of new glenoid components can be compared; such a benchmark may be derived from a multicenter study of patients receiving an established, internationally used design of glenoid component. METHODS: We obtained data from 11 centers on 1270 patients having total shoulder arthroplasty using an all-polyethylene component with a fluted central peg. We analyzed individual patient outcomes at 1 and 2 years after surgery. We compared the improvement for each patient to the minimal clinically important difference (MCID) and calculated each patient's improvement as a percent of maximal possible improvement (MPI). RESULTS: The preoperative scores improved from SST 3 ± 2, ASES 37 ± 15, Constant score 36 ± 16, and Penn score 30 ± 19 to SST 10 ± 2, ASES 90 ± 12, Constant 76 ± 13, and Penn 80 ± 24 (p < 0.001 for each). A high percentage of patients improved by more than the MCID (SST 96%, ASES 98%, Constant 94%, Penn 93%) and obtained improvement of at least 30% of the MPI (SST 95%, ASES 98%, Constant 91%, Penn 87%). The clinical outcomes realized with this glenoid design were not worse for the 41% of shoulders with preoperative type B glenoids or for the 30% of shoulders with more than 15 degrees of glenoid retroversion. CONCLUSIONS: Individual patients from 11 international practices having total shoulder arthroplasty using a basic glenoid component design obtained highly significant clinical outcomes, providing a benchmark against which the early outcomes of new designs can be compared to determine whether they provide increased clinical value.

Hepatic acute phase response protects the brain from focal inflammation during postnatal window of susceptibility.

Perinatal inflammation is known to contribute to neurodevelopmental diseases. Animal models of perinatal inflammation have revealed that the inflammatory response within the brain is age dependent, but the regulators of this variation remain unclear. In the adult, the peripheral acute phase response (APR) is known to be pivotal in the downstream recruitment of leukocytes to the injured brain. The relationship between perinatal brain injury and the APR has not been established. Here, we generated focal inflammation in the brain using interleukin (IL)-1ß at postnatal day (P)7, P14, P21 and P56 and studied both the central nervous system (CNS) and hepatic inflammatory responses at 4 h. We found that there is a significant window of susceptibility in mice at P14, when compared to mice at P7, P21 and P56. This was reflected in increased neutrophil recruitment to the CNS, as well as an increase in blood-brain barrier permeability. To investigate phenomena underlying this window of susceptibility, we performed a dose response of IL-1ß. Whilst induction of endogenous IL-1ß or intercellular adhesion molecule (ICAM)-1 in the brain and induction of a hepatic APR were dose dependent, the recruitment of neutrophils and associated blood-brain barrier breakdown was inversely proportional. Furthermore, in contrast to adult animals, an additional peripheral challenge (intravenous IL-1ß) reduced the degree of CNS inflammation, rather than exacerbating it. Together these results suggest a unique window of susceptibility to CNS injury, meaning that suppressing systemic inflammation after brain injury may exacerbate the damage caused, in an age-dependent manner.

Cardiovascular Risk Assessment in Patients with Hypertriglyceridemia.

PURPOSE OF REVIEW: Assessing the cardiovascular risk associated with hypertriglyceridemia can be challenging due to frequent confounding conditions such as hypertension, diabetes mellitus, and hyperlipidemia. We sought to quantify this risk by examining several meta-analyses as well as subgroup analyses of previously published major randomized controlled trials that focused on the treatment of hyperlipidemia. RECENT FINDINGS: Recent trials measuring the effects of PCSK9 inhibitors such as evolocumab and alirocumab on cardiovascular outcomes have demonstrated a high degree of residual cardiovascular risk even after profound reductions in low-density-lipoprotein cholesterol (LDL-C). Despite optimization of LDL-C through the use of statins, PCSK9 inhibitors and adjunctive therapies such as ezetimibe, bile acid sequestrants and niacin, residual cardiovascular risk remains significant. Several ongoing trials are assessing the efficacy of pemafibrate and omega-3 fatty acids for the treatment of hypertriglyceridemia and their effects on major cardiovascular outcomes.

Health Literacy: Readability of ACC/AHA Online Patient Education Material.

OBJECTIVES: To determine whether the online patient education material offered by the American College of Cardiology (ACC) and the American Heart Association (AHA) is written at a higher level than the 6th-7th grade level recommended by the National Institute of Health (NIH). METHODS: Online patient education material from each website was subjected to reading grade level (RGL) analysis using the Readability Studio Professional Edition. One-sample t testing was used to compare the mean RGLs obtained from 8 formulas to the NIH-recommended 6.5 grade level and 8th grade national mean. RESULTS: In total, 372 articles from the ACC website and 82 from the AHA were studied. Mean (±SD) RGLs for the 454 articles were 9.6 ± 2.1, 11.2 ± 2.1, 11.9 ± 1.6, 10.8 ± 1.6, 9.7 ± 2.1, 10.8 ± 0.8, 10.5 ± 2.6, and 11.7 ± 3.5 according to the Flesch-Kincaid grade level (FKGL), Simple Measure of Gobbledygook (SMOG Index), Coleman-Liau Index (CLI), Gunning-Fog Index (GFI), New Dale-Chall reading level formula (NDC), FORCAST, Raygor Readability Estimate (RRE), and Fry Graph (Fry), respectively. All analyzed articles had significantly higher RGLs than both the NIH-recommended grade level of 6.5 and the national mean grade level of 8 (p < 0.00625). CONCLUSIONS: Patient education material provided on the ACC and AHA websites is written above the NIH-recommended 6.5 grade level and 8th grade national mean reading level. Additional studies are required to demonstrate whether lowering the RGL of this material improves outcomes among patients with cardiovascular disease.

Interobserver and intraobserver variability of glenoid track measurements.

BACKGROUND: A method of assessing combined glenoid and humeral bone loss in traumatic shoulder instability with an associated treatment protocol was recently published. The aim of this study was to investigate its reliability and reproducibility. METHODS: Seventy-one patients with unilateral anteroinferior shoulder instability underwent computed tomography scans, from which 3-dimensional images were derived. En face views of both glenoid fossae and with 3 views of the humeral head were provided to 4 assessors to determine interobserver reliability. From these measurements, the shoulder was assigned a treatment classification. Two observers repeated their assessments 1 month later to determine intraobserver reliability. For each measurement, the mean coefficient of variability was calculated. RESULTS: Assessment of glenoid bone loss showed good interobserver (4 observers agreeing in 90.1% of cases) and also good intraobserver agreement (94% and 96%). There was a poor level of interobserver reliability regarding the on-track or off-track classification (72%). Intraobserver reliability for this measurement was less variable (90% and 80%). There was a poor level of agreement between observers (65%) regarding treatment classification. The coefficient of variability for the Hill-Sachs lesion measured 19.2%, indicating a high level of variability for this measurement compared with <4% for all other measures. CONCLUSION: Linear bone loss on the glenoid can be measured reliably and reproducibly; however, evaluation of Hill-Sachs lesions demonstrates a high level of variability, and poor interobserver reliability.

The Shoulder Function Index (SFInX): evaluation of its measurement properties in people recovering from a proximal humeral fracture.

BACKGROUND: Concerns about test administration, reliability estimations, content and internal structure (dimensionality) of available shoulder measures for people with proximal humeral facture led to the development of a new clinician-observed outcome measure: the Shoulder Function Index (SFInX). The SFInX measures shoulder function by judgement of actual ability to perform daily tasks in which the shoulder is involved. Patients and health professionals had input into the instrument development, and Rasch analysis was used to create a unidimensional, interval-level scale. This study comprehensively evaluated the measurement properties of the SFInX in people recovering from a proximal humeral fracture. METHODS: Data were collected on 92 people [79 women, mean age 63.5 years (SD13.9)] who sustained a proximal humeral fracture within the previous year on three occasions to allow for evaluation of the following measurement properties: construct validity (convergent, discriminant and known-groups validity), longitudinal validity (responsiveness), intra-rater reliability (one week retest interval), and inter-rater reliability (n = 20 subgroup; two independent raters). Comparative measures were Constant Score and Disabilities of the Arm Shoulder and Hand (DASH) and discriminative measure was a mental status questionnaire. Minimal clinically important difference, floor and ceiling effects and feasibility of the SFInX were also evaluated. A priori hypotheses were formulated where applicable. RESULTS: Results for construct validity testing supported hypothesised relationships (convergent validity r = 0.75-0.89 (Constant Score and DASH); discriminant validity r = -0.08 (mental status); known-groups validity r = 0.50). For longitudinal validity, lower correlations (r = 0.40-0.49) than hypothesised (r = 0.50-0.70) were found. The SFInX scores changed more (10.3 points) than other scales, which could indicate that the SFInX is more responsive than the comparative measures. Intra-rater and inter-rater reliability found ICCs of 0.96 (95 % CI 0.94-0.97) and 0.91 (95 % CI 0.63-0.97) respectively, with low measurement error (SEM = 3.9-5.8/100). A change of 11-12 points (out of 100) was indicative of a clinically important difference. CONCLUSIONS: The SFInX is a feasible outcome measure which clinicians can use to reliably measure and detect clinically important changes in the construct of 'shoulder function', the ability to perform activities in which the shoulder is involved, in people recovering from a proximal humeral fracture.

The Shoulder Function Index (SFInX): a clinician-observed outcome measure for people with a proximal humeral fracture.

BACKGROUND: Proximal humeral fractures are amongst the most common fractures. Functional recovery is often slow and many people have ongoing disability during activities of daily life. Unidimensional measurement of activity limitations is required to monitor functional progress during rehabilitation. However, current shoulder measures are multidimensional incorporating constructs such as activities, range of motion and pain into a single scale. Psychometric information of these measures is scarce in this population, and indicate measurement issues with reliability. Therefore, the aim was to develop the clinician-observed Shoulder Function Index (SFInX), a unidimensional, interval-level measure of 'shoulder function' based on actual performance of activities, reflecting activity limitations following a proximal humeral fracture. METHODS: An outcome measure development study was performed including item generation (existing shoulder measures, focus groups) and item selection (selection criteria, importance and feasibility ratings, pilot testing, Rasch analysis). Clinicians (n=15) and people with a proximal humeral fracture (n=13) participated in focus groups. Items were pilot tested (n=12 patients) and validated in a Rasch study. The validation study sample (n=92, 86% female) were recruited between 5 and 52 weeks post-fracture and had a mean age of 63.5 years (SD13.9). Measurements at recruitment and 6 and 7 weeks later were taken in three public metropolitan hospitals or during home visits. Raw SFInX data were analysed with WINSTEPS v3.74 using polytomous Rasch models. RESULTS: From 282 generated items, 42 items were selected to be rated by clinicians and patients; 34 items were pilot tested and 16 items were included for Rasch analysis. The final SFInX, developed with the Partial Credit Model, contains 13 items and has the response categories: 'unable', 'partially able' and 'able'. It is unidimensional measuring 'shoulder function', and can measure from early functional use (drinking from a cup) to independence around the house (lifting items above head, carrying heavy items). CONCLUSIONS: The SFInX is a promising outcome measure of shoulder function for people with a proximal humeral fracture. It has content relevant to patients and clinicians, is unidimensional and feasible for use in clinical and home settings. In its current form, the SFInX is ready for further psychometric evaluation, and for subsequent use in clinical settings and research.

Cholesterol dependent cytolysins and the brain: Revealing a potential therapeutic avenue for bacterial meningitis.

Bacterial meningitis is a catastrophic nervous system disorder with high mortality and wide range of morbidities. Some of the meningitis-causing bacteria occupy cholesterol dependent cytolysins (CDCs) to increase their pathogenicity and arrange immune-evasion strategy. Studies have observed that the relationship between CDCs and pathogenicity in these meningitides is complex and involves interactions between CDC, blood-brain barrier (BBB), glial cells and neurons. In BBB, these CDCs acts on capillary endothelium, tight junction (TJ) proteins and neurovascular unit (NVU). CDCs also observed to elicit intriguing effects on brain inflammation which involves microglia and astrocyte activations, along with neuronal damage as the end-point of pathological pathways in bacterial meningitis. As some studies mentioned potential advantage of CDC-targeted therapeutic mechanisms to combat CNS infections, it might be a fruitful avenue to deepen our understanding of CDC as a candidate for adjuvant therapy to combat bacterial meningitis.

Magnetic resonance imaging of pathological processes in rodent models of amyotrophic lateral sclerosis.

Non-human models of neurodegenerative diseases have potential for the identification of key pathways in pathogenesis and for the more rapid assessment of therapeutic candidates. While there are legitimate concerns about the physiological differences between the rodent and human motor systems, mice expressing the 'G93A' superoxide dismutase-1 gene mutation are a predictable and robustly-characterized model for amyotrophic lateral sclerosis (ALS). This model has provided evidence for an important role of inflammatory processes during the pre-clinical phase, a stage currently inaccessible for human study in what is largely a sporadic disease. While magnetic resonance imaging is now an established and leading modality for the identification of ALS biomarkers in humans, it can also be increasingly applied to rodent models to probe structural, functional and biochemical changes throughout the course of the disease, with additional potential to generate surrogate markers for the efficacy of therapeutic interventions. Targeted MRI contrast agents, through tagging of various cell types and even individual molecules, will deliver an era of in vivo molecular neuroimaging, with greater specificity for the most relevant pathological processes. These are potentially important steps towards the ultimate goal of human therapeutic translation.

Differential regulation of the SMN2 gene by individual HDAC proteins.

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that is the leading genetic cause of infantile death. SMA is caused by homozygous deletion or mutation of the survival of motor neuron 1 gene (SMN1). The SMN2 gene is nearly identical to SMN1, however is alternatively spliced. The close relationship to SMN1 results in SMN2 being a very power genetic modifier of SMA disease severity and a target for therapies. We sought to identify the regulatory role individual HDAC proteins use to control expression of full length protein from the SMN2 genes. We used quantitative PCR to determine the effects shRNA silencing of individual HDACs on the steady state levels of a SMN2-luciferase reporter transcripts. We determined that reduction of individual HDAC proteins was sufficient to increase SMN protein levels in a transgenic reporter system. Knockdown of class I HDAC proteins preferentially activated the reporter by increased promoter transcription. Silencing of class II HDAC proteins maintained transcriptional activity; however silencing of HDAC 5 and 6 also appeared to enhance inclusion of an alternatively spliced exon. This work highlights HDAC proteins 2 and 6 as excellent investigative targets. These data are important to the basic understanding of SMN expression regulation and the refinements of current therapeutic compounds as well as the development of novel SMA therapeutics.

Aspiration Thrombectomy.

Distal embolization of thrombus can lead to impairment of microvascular perfusion, and measures of abnormal microvascular perfusion have been associated with increased mortality and worsened clinical outcomes. Large multicenter randomized controlled trials and multiple meta-analyses have failed to demonstrate an improvement in clinical outcomes with the routine use of manual aspiration thrombectomy, with some studies suggesting an increased incidence of stroke, likely owing to thrombus dislodgement during retrieval leading to cerebral vessel embolization. In patients with high thrombus burden who do not respond to balloon predilation, the use of manual aspiration thrombectomy as a bailout treatment strategy can be considered.

Medium-Term Clinical and Radiographic Results of an All-Polyethylene, Pegged, Bone-Ingrowth Glenoid Component: A Concise Follow-up of a Previous Report.

ABSTRACT: We previously reported the mean 4-year outcomes of anatomic total shoulder replacement using an all-polyethylene, pegged, hybrid-fixation (bone ingrowth and cement) glenoid component. In the present study, we report on that patient cohort after another 4 years of follow-up (mean, 101 months; range, 77 to 146 months). At that time, the median American Shoulder and Elbow Surgeons (ASES) score was 92 points (interquartile range [IQR], 81.7 to 98.3) and the median Oxford Shoulder Score was 47 points (IQR, 41 to 48). Osseointegration, demonstrated by bone ingrowth between the flanges on the central peg as seen on coronal computed tomography (CT), was complete in 75% of the shoulders, partial in 21%, and absent in 4%. There were radiolucent lines at the bone-prosthesis interface on CT, with a median Yian score of 1 (IQR, 0 to 2; range, 0 to 18). The conclusion in the present study was that shoulder arthroplasty with an all-polyethylene, hybrid-fixation (bone ingrowth and cement) pegged glenoid component has durable clinical and radiographic outcomes at medium-term follow-up. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Ventricular septal defect complicating delayed presentation of acute myocardial infarction during COVID-19 lockdown: a case report.

BACKGROUND: Post-myocardial infarction ventricular septal defects (VSDs) have become rare in the reperfusion era but remain associated with very high morbidity and mortality. As patients defer prompt evaluation and management of acute coronary syndromes during the COVID-19 global pandemic, the incidence of these and other post-infarction mechanical complications is expected to increase. CASE SUMMARY: A 37-year-old gentleman with multiple coronary artery disease risk factors presented with intermittent chest discomfort and 1 week of heart failure symptoms. An echocardiogram demonstrated a large muscular VSD and coronary angiography confirmed the presence of an anterior wall infarction. He was subsequently referred for transcatheter VSD repair and showed rapid clinical improvement in his symptoms. DISCUSSION: Post-infarction VSDs remain associated with a high degree of morbidity and mortality. Surgical repair of acutely ruptured myocardium can be technically challenging, and transcatheter repair has emerged as a safe and effective alternative.

Magnetic Resonance Imaging as a Biomarker in Diabetic and HIV-Associated Peripheral Neuropathy: A Systematic Review-Based Narrative.

Background: Peripheral neuropathy can be caused by diabetes mellitus and HIV infection, and often leaves patients with treatment-resistant neuropathic pain. To better treat this condition, we need greater understanding of the pathogenesis, as well as objective biomarkers to predict treatment response. Magnetic resonance imaging (MRI) has a firm place as a biomarker for diseases of the central nervous system (CNS), but until recently has had little role for disease of the peripheral nervous system. Objectives: To review the current state-of-the-art of peripheral nerve MRI in diabetic and HIV symmetrical polyneuropathy. We used systematic literature search methods to identify all studies currently published, using this as a basis for a narrative review to discuss major findings in the literature. We also assessed risk of bias, as well as technical aspects of MRI and statistical analysis. Methods: Protocol was pre-registered on NIHR PROSPERO database. MEDLINE, Web of Science and EMBASE databases were searched from 1946 to 15th August 2020 for all studies investigating either diabetic or HIV neuropathy and MRI, focusing exclusively on studies investigating symmetrical polyneuropathy. The NIH quality assessment tool for observational and cross-sectional cohort studies was used for risk of bias assessment. Results: The search resulted in 18 papers eligible for review, 18 for diabetic neuropathy and 0 for HIV neuropathy. Risk of bias assessment demonstrated that studies generally lacked explicit sample size justifications, and some may be underpowered. Whilst most studies made efforts to balance groups for confounding variables (age, gender, BMI, disease duration), there was lack of consistency between studies. Overall, the literature provides convincing evidence that DPN is associated with larger nerve cross sectional area, T2-weighted hyperintense and hypointense lesions, evidence of nerve oedema on Dixon imaging, decreased fractional anisotropy and increased apparent diffusion coefficient compared with controls. Analysis to date is largely restricted to the sciatic nerve or its branches. Conclusions: There is emerging evidence that various structural MR metrics may be useful as biomarkers in diabetic polyneuropathy, and areas for future direction are discussed. Expanding this technique to other forms of peripheral neuropathy, including HIV neuropathy, would be of value. Systematic Review Registration: (identifier: CRD 42020167322) https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=167322.

Volume changes in Alzheimer's disease and mild cognitive impairment: cognitive associations.

OBJECTIVE: To assess the relationship between MRI-derived changes in whole-brain and ventricular volume with change in cognitive scores in Alzheimer's disease (AD), mild cognitive impairment (MCI) and control subjects. MATERIAL AND METHODS: In total 131 control, 231 MCI and 99 AD subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort with T1-weighted volumetric MRIs from baseline and 12-month follow-up were used to derive volume changes. Mini mental state examination (MMSE), Alzheimer's disease assessment scale (ADAS)-cog and trails test changes were calculated over the same period. RESULTS: Brain atrophy rates and ventricular enlargement differed between subject groups (p < 0.0005) and in MCI and AD were associated with MMSE changes. Both measures were additionally associated with ADAS-cog and trails-B in MCI patients, and ventricular expansion was associated with ADAS-cog in AD patients. Brain atrophy (p < 0.0005) and ventricular expansion rates (p = 0.001) were higher in MCI subjects who progressed to AD within 12 months of follow-up compared with MCI subjects who remained stable. MCI subjects who progressed to AD within 12 months had similar atrophy rates to AD subjects. CONCLUSION: Whole-brain atrophy rates and ventricular enlargement differed between patient groups and healthy controls, and tracked disease progression and psychological decline, demonstrating their relevance as biomarkers.

Acromioclavicular Joint Stabilization: A Biomechanical Study of Bidirectional Stability and Strength.

BACKGROUND: It is important to restore horizontal and vertical stability to the acromioclavicular (AC) joint when treating dislocations of this joint. Most surgical stabilization techniques of the AC joint have primarily addressed the coracoclavicular ligament complex; however, these techniques may not satisfactorily restore horizontal stability to the AC joint. PURPOSE: To evaluate the strength and bidirectional stability of 3 AC joint stabilizing techniques in a cadaveric model. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 24 cadaveric shoulders were randomly allocated to 3 treatment groups. For each group, a standardized AC joint stabilizing procedure was performed, and the specimens were potted for mechanical testing. The following reconstruction techniques were used: a single clavicular tunnel for group A, a double clavicular tunnel for group B, and a double clavicular tunnel plus suture fixation across the AC joint for group C. The specimens underwent cyclic loading in the horizontal and vertical planes and then load to failure. Eight control specimens also underwent cyclic loading in both planes. Construct stiffness during cyclic loading, change in displacement after cyclic loading in both planes, load to failure in the vertical plane, and mode of failure were evaluated, and stiffness was compared among the treatment groups as well as with a control group. RESULTS: There was a decrease in joint stiffness for all groups, including controls, during the cyclic loading. Compared with controls, all 3 treatment groups demonstrated equivalent stiffness and displacement in the vertical plane. In the horizontal plane, all 3 treatment groups demonstrated decreased stiffness, increased displacement, or both when compared with controls. When groups were compared, no treatment arm proved superior regarding stiffness or displacement in either plane. Load-to-failure testing of the 3 treatment groups in the vertical plane demonstrated construct strength and stiffness comparable with reports for the native AC joint. The mode of failure was predominantly fracture at the point of fixation to the testing apparatus. CONCLUSION: There was no difference in bidirectional strength and stability between the single- and double-clavicular tunnel techniques of coracoclavicular reconstruction. The addition of a stabilizing suture across the AC joint does not improve horizontal stability in the absence of repair of the AC joint capsule and deltotrapezial fascia. CLINICAL RELEVANCE: This laboratory study provides further evidence of the importance of the AC joint capsule and associated soft tissues in affording horizontal stability to that joint. Information from this and subsequent studies utilizing a bidirectional model can influence the choice of surgical procedure in the clinical treatment of AC joint dislocations.

Temporal evolution of the microbiome, immune system and epigenome with disease progression in ALS mice.

Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease. Genetic predisposition, epigenetic changes, aging and accumulated life-long environmental exposures are known ALS risk factors. The complex and dynamic interplay between these pathological influences plays a role in disease onset and progression. Recently, the gut microbiome has also been implicated in ALS development. In addition, immune cell populations are differentially expanded and activated in ALS compared to healthy individuals. However, the temporal evolution of both the intestinal flora and the immune system relative to symptom onset in ALS is presently not fully understood. To better elucidate the timeline of the various potential pathological factors, we performed a longitudinal study to simultaneously assess the gut microbiome, immunophenotype and changes in ileum and brain epigenetic marks relative to motor behavior and muscle atrophy in the mutant superoxide dismutase 1 (SOD1G93A) familial ALS mouse model. We identified alterations in the gut microbial environment early in the life of SOD1G93A animals followed by motor dysfunction and muscle atrophy, and immune cell expansion and activation, particularly in the spinal cord. Global brain cytosine hydroxymethylation was also altered in SOD1G93A animals at disease end-stage compared to control mice. Correlation analysis confirmed interrelationships with the microbiome and immune system. This study serves as a starting point to more deeply comprehend the influence of gut microorganisms and the immune system on ALS onset and progression. Greater insight may help pinpoint novel biomarkers and therapeutic interventions to improve diagnosis and treatment for ALS patients.This article has an associated First Person interview with the joint first authors of the paper.

Minimizing Propionibacterium acnes contamination in shoulder arthroplasty: use of a wound protector.

BACKGROUND: Propionibacterium acnes may be transmitted from the subdermal tissues to the deeper tissues during shoulder arthroplasty surgery, resulting in deep infection. The aim of this prospective, clinical study was to determine whether the use of a wound protector drape can lower the incidence of P. acnes in the wound during shoulder arthroplasty surgery. METHODS: For a consecutive series of 47 patients undergoing shoulder arthroplasty, a wound protector drape was used during surgery, to isolate the subdermal layer from the surgeons' hands, retractors and other instruments. Microbiological swabs were taken both from the subdermal layer and the exposed drape to determine the incidence of P. acnes at both sites. RESULTS: The overall incidence of P. acnes in the subdermal layer was 23%. A fivefold decrease in the incidence of P. acnes in the exposed superficial layer was demonstrated by use of the wound protector drape. CONCLUSION: Use of a wound protector drape to isolate the superficial tissue layer from the surgeons' gloves, instruments and retractors decreases the incidence of P. acnes in the surgical field. This may result in a decreased rate of transmission to the deeper tissues, and a decreased rate of P. acnes deep infection.

Positive and negative regulation of poly(A) nuclease.

PAN, a yeast poly(A) nuclease, plays an important nuclear role in the posttranscriptional maturation of mRNA poly(A) tails. The activity of this enzyme is dependent on its Pan2p and Pan3p subunits, as well as the presence of poly(A)-binding protein (Pab1p). We have identified and characterized the associated network of factors controlling the maturation of mRNA poly(A) tails in yeast and defined its relevant protein-protein interactions. Pan3p, a positive regulator of PAN activity, interacts with Pab1p, thus providing substrate specificity for this nuclease. Pab1p also regulates poly(A) tail trimming by interacting with Pbp1p, a factor that appears to negatively regulate PAN. Pan3p and Pbp1p both interact with themselves and with the C terminus of Pab1p. However, the domains required for Pan3p and Pbp1p binding on Pab1p are distinct. Single amino acid changes that disrupt Pan3p interaction with Pab1p have been identified and define a binding pocket in helices 2 and 3 of Pab1p's carboxy terminus. The importance of these amino acids for Pab1p-Pan3p interaction, and poly(A) tail regulation, is underscored by experiments demonstrating that strains harboring substitutions in these residues accumulate mRNAs with long poly(A) tails in vivo.

Circulating endothelial cell-derived extracellular vesicles mediate the acute phase response and sickness behaviour associated with CNS inflammation.

Brain injury elicits a systemic acute-phase response (APR), which is responsible for co-ordinating the peripheral immunological response to injury. To date, the mechanisms responsible for signalling the presence of injury or disease to selectively activate responses in distant organs were unclear. Circulating endogenous extracellular vesicles (EVs) are increased after brain injury and have the potential to carry targeted injury signals around the body. Here, we examined the potential of EVs, isolated from rats after focal inflammatory brain lesions using IL-1ß, to activate a systemic APR in recipient naïve rats, as well as the behavioural consequences of EV transfer. Focal brain lesions increased EV release, and, following isolation and transfer, the EVs were sequestered by the liver where they initiated an APR. Transfer of blood-borne EVs from brain-injured animals was also enough to suppress exploratory behaviours in recipient naïve animals. EVs derived from brain endothelial cell cultures treated with IL-1ß also activated an APR and altered behaviour in recipient animals. These experiments reveal that inflammation-induced circulating EVs derived from endothelial cells are able to initiate the APR to brain injury and are sufficient to generate the associated sickness behaviours, and are the first demonstration that EVs are capable of modifying behavioural responses.