Fetal-derived trophoblast use the apoptotic cytokine tumor necrosis factor-alpha-related apoptosis-inducing ligand to induce smooth muscle cell death.

Remodeling of the uterine spiral arteries during pregnancy transforms them from high to low resistance vessels that lack vasoconstrictive properties. This process is essential to meet the demand for increased blood flow imposed by the growing fetus. Loss of endothelial and smooth muscle cells (SMC) is evident in remodeled arteries but the mechanisms underlying this transformation remain unknown. This study investigated the hypothesis that fetal trophoblast invading from the placenta instigate remodeling by triggering cell death in vascular SMC. Specifically, a role for trophoblast-derived death inducing cytokine tumor necrosis factor-α–related apoptosis-inducing ligand (TRAIL) was investigated. Expression of the activating TRAIL receptors R1 and R2 was detected by flow cytometry on human aortic SMC and by immunohistochemistry on spiral artery SMC. Recombinant human TRAIL induced human aortic SMC apoptosis, which was inhibited by antibodies against TRAIL-R1 or -R2. Perfusion of denuded spiral artery segments with recombinant human TRAIL also induced SMC apoptosis. Trophoblasts isolated from first trimester placenta expressed membrane-associated TRAIL and induced apoptosis of human aortic SMC; apoptosis was significantly inhibited by a recombinant human TRAIL-R1:Fc construct. Trophoblast within the first trimester placental bed also expressed TRAIL. These data show that: 1) TRAIL causes SMC death; 2) trophoblast produce the apoptotic cytokine TRAIL; and 3) trophoblast induce SMC apoptosis via a TRAIL-dependent mechanism. We conclude that TRAIL produced by trophoblast causes apoptosis of SMC and thus may contribute to SMC loss during spiral artery remodeling in pregnancy

The ocrelizumab phase II extension trial suggests the potential to improve the risk: Benefit balance in multiple sclerosis.

OBJECTIVE: Ocrelizumab inhibits relapsing multiple sclerosis when administered every six months. Based on potential similar memory B cell depletion mechanisms with cladribine and alemtuzumab, we hypothesised that CD20-depletion of B cells by ocrelizumab may exhibit a duration of response exceeding the current licenced treatment interval. METHODS: Internet-located information from regulatory submissions and meeting reports relating to the unpublished open-label, phase II ocrelizumab extension trial (NCT00676715) were reviewed. This followed people (54-55/arm) with MS, who switched from placebo or interferon-beta to ocrelizumab for three 600 mg treatment cycles (week 24, 48, 72) or people treated with ocrelizumab for four 600 mg treatment cycles (week 0-72), followed by an 18 month treatment-free period. RESULTS: CD19+ B cells were rapidly depleted within 2 weeks and slow CD19+ B cell repopulation began about 6 months after the last infusion with median-repletion of over 15 months. The reduced annualized relapse rate during the published efficacy study appeared to be maintained in the extension study and there were no new T1 gadolinium-enhancing or T2 lesions detected in the treatment-free period. Importantly, within these extension cohorts, there appeared to be fewer adverse events and infections events. CONCLUSIONS: Ocrelizumab appears to induce durable relapsing disease inhibition, within 3 treatment cycles Therefore, it may be possible to reduce the frequency of dosing to maintain efficacy, whilst limiting infection and other risks associated with continuous immunosuppression and could allow more effective vaccination against new pathogens. Further studies are now clearly required to determine whether this data is robust

Il tema del “doppio” nel romanzo di A. Skaldin Stranstvia i priključenija Nikodima Staršego

L’«inspiegabile divisione» (неизъяснимое разделение) psicofisica della personalità sperimentata dal giovane barin Nikodim Michajlovič Ipat’ev, protagonista del romanzo filosofico di Aleksej Skaldin Stranstvija i priključenija Nikodima Staršego [Peregrinazioni e avventure di Nikodim il Vecchio]4, va certamente letta come un tributo dell’ultimo (in ordine cronologico) dei simbolisti russi ad un tema di antica memoria, caro alla mitologia e alla classicità – quello del “doppio” –, che, a partire da Pogorel’skij, passando per Puškin, Odoevskij, Gogol’ e Dostoevskij, aveva imperversato nell’Ottocento russo e, prima ancora, nell’ambiente letterario europeo barocco e romantico, confermandosi nel Novecento, secolo del relativismo e della crisi dell’io, come il tratto distintivo della modernità. Eppure lo sdoppiamento, a detta di Pasolini «la più grande delle invenzioni letterarie», se ricollega Skaldin alla grande tradizione culturale otto-novecentesca, è un Leitmotiv che l’autore desume non da fonti esterne ma dall’intimo della propria esperienza personale. La mia analisi della scissione identitaria del Nikodim skaldiniano si basa appunto sull’ipotesi di una totale o parziale identificazione dello scrittore con il suo personaggio, nella convinzione che solo un accurato esame del substratum autobiografico dell’opera ci possa restituire il significato e la funzione che in essa riveste il topos della destrutturazione e moltiplicazione dell’io

The impact of sphingosine-1-phosphate receptor modulators on COVID-19 and SARS-CoV-2 vaccination.

BACKGROUND: Sphingosine-one phosphate receptor (S1PR) modulation inhibits S1PR1-mediated lymphocyte migration, lesion formation and positively-impacts on active multiple sclerosis (MS). These S1PR modulatory drugs have different: European Union use restrictions, pharmacokinetics, metabolic profiles and S1PR receptor affinities that may impact MS-management. Importantly, these confer useful properties in dealing with COVID-19, anti-viral drug responses and generating SARS-CoV-2 vaccine responses. OBJECTIVE: To examine the biology and emerging data that potentially underpins immunity to the SARS-CoV-2 virus following natural infection and vaccination and determine how this impinges on the use of current sphingosine-one-phosphate modulators used in the treatment of MS. METHODS: A literature review was performed, and data on infection, vaccination responses; S1PR distribution and functional activity was extracted from regulatory and academic information within the public domain. OBSERVATIONS: Most COVID-19 related information relates to the use of fingolimod. This indicates that continuous S1PR1, S1PR3, S1PR4 and S1PR5 modulation is not associated with a worse prognosis following SARS-CoV-2 infection. Whilst fingolimod use is associated with blunted seroconversion and reduced peripheral T-cell vaccine responses, it appears that people on siponimod, ozanimod and ponesimod exhibit stronger vaccine-responses, which could be related notably to a limited impact on S1PR4 activity. Whilst it is thought that S1PR3 controls B cell function in addition to actions by S1PR1 and S1PR2, this may be species-related effect in rodents that is not yet substantiated in humans, as seen with bradycardia issues. Blunted antibody responses can be related to actions on B and T-cell subsets, germinal centre function and innate-immune biology. Although S1P1R-related functions are seeming central to control of MS and the generation of a fully functional vaccination response; the relative lack of influence on S1PR4-mediated actions on dendritic cells may increase the rate of vaccine-induced seroconversion with the newer generation of S1PR modulators and improve the risk-benefit balance IMPLICATIONS: Although fingolimod is a useful asset in controlling MS, recently-approved S1PR modulators may have beneficial biology related to pharmacokinetics, metabolism and more-restricted targeting that make it easier to generate infection-control and effective anti-viral responses to SARS-COV-2 and other pathogens. Further studies are warranted

Active Region Modulation of Coronal Hole Solar Wind

Active regions (ARs) are a candidate source of the slow solar wind (SW), the origins of which are a topic of ongoing research. We present a case study that examines the processes by which SW is modulated in the presence of an AR in the vicinity of the SW source. We compare properties of SW associated with a coronal hole (CH)–quiet Sun boundary to SW associated with the same CH but one Carrington rotation later, when this region bordered the newly emerged NOAA AR 12532. Differences found in a range of in situ parameters are compared between these rotations in the context of source region mapping and remote sensing observations. Marked changes exist in the structure and composition of the SW, which we attribute to the influence of the AR on SW production from the CH boundary. These unique observations suggest that the features that emerge in the AR-associated wind are consistent with an increased occurrence of interchange reconnection during SW production, compared with the initial quiet Sun case

Isotopic and chromatographic fingerprinting of the sources of dissolved organic carbon in a shallow coastal aquifer

The terrestrial subsurface is the largest source of freshwater globally. The organic carbon contained within it and processes controlling its concentration remain largely unknown. The global median concentration of dissolved organic carbon (DOC) in groundwater is low compared to surface waters, suggesting significant processing in the subsurface. Yet the processes that remove this DOC in groundwater are not fully understood. The purpose of this study was to investigate the different sources and processes influencing DOC in a shallow anoxic coastal aquifer. Uniquely, this study combines liquid chromatography organic carbon detection with organic (δ13CDOC) carbon isotope geochemical analyses to fingerprint the various DOC sources that influence the concentration, carbon isotopic composition, and character with respect to distance from surface water sources, depth below surface, and inferred groundwater residence time (using 3H activities) in groundwater. It was found that the average groundwater DOC concentration was 5 times higher (5 mg L−1) than the global median concentration and that the concentration doubled with depth at our site, but the chromatographic character did not change significantly. The anoxic saturated conditions of the aquifer limited the rate of organic matter processing, leading to enhanced preservation and storage of the DOC sources from peats and palaeosols contained within the aquifer. All groundwater samples were more aromatic for their molecular weight in comparison to other lakes, rivers and surface marine samples studied. The destabilization or changes in hydrology, whether by anthropogenic or natural processes, could lead to the flux of up to 10 times more unreacted organic carbon from this coastal aquifer compared to deeper inland aquifers

Knee complaints and consequences on work status; a 10-year follow-up survey among floor layers and graphic designers

<p>Abstract</p> <p>Background</p> <p>The purpose of the study was to examine if knee complaints among floor layers predict exclusion from the trade.</p> <p>Methods</p> <p>In 1994/95 self-reported data were obtained from a cohort of floor layers and graphic designers with and without knee straining work activities, respectively. At follow-up in 2005 the questionnaire survey was repeated. The study population consisted of 81 floor layers and 173 graphic designers who were presently working in their trades at baseline (1995). All participants were men aged 36–70 years in 2005.</p> <p>We computed the risk of losing gainful employment in the trade according to occurrence of knee complaints at baseline, using Cox proportional hazard regression adjusted for a number of potential confounding variables. Moreover, the crude and adjusted odds risk ratio for knee complaints according to status of employment in the trade were computed, using graphic designers as reference.</p> <p>Results</p> <p>A positive but non-significant association between knee complaints lasting more than 30 days the past 12 months and exclusion from the trade was found among floor layers (Hazard Ratio = 1.4, 95% CI = 0.6–3.5).</p> <p>The frequency of self-reported knee complaints was lower among floor layers presently at work in the trade in year 2005 (26.3%) compared with baseline in 1995 (41.1%), while the opposite tendency was seen among graphic designers (20.7% vs. 10.7%).</p> <p>Conclusion</p> <p>The study suggests that knee complaints are a risk factor for premature exclusion from a knee demanding trade. However, low power of the study precludes strong conclusions. The study also indicates a healthy worker effect among floor layers and a survivor effect among graphic designers.</p

Development of an occupational advice intervention for patients undergoing lower limb arthroplasty (the OPAL study)

Background: There are an increasing number of patients of working age undergoing hip and knee replacements. Currently there is variation in the advice and support given about sickness absence, recovery to usual activities and return to work after these procedures. Earlier, sustainable, return to work improves the health of patients and benefits their employers and society. An intervention that encourages and supports early recovery to usual activities, including work, has the potential to reduce the health and socioeconomic burden of hip and knee replacements. Methods/design: A two-phase research programme delivered over 27 months will be used to develop and subsequently test the feasibility of an occupational advice intervention to facilitate return to work and usual activities in patients undergoing lower limb arthroplasty. The 2 phases will incorporate a six-stage intervention mapping process: Phase 1: Intervention mapping stages 1–3: 1 Needs assessment (including rapid evidence synthesis, prospective cohort analysis and structured stakeholder interviews) 2 Identification of intended outcomes and performance objectives 3 Selection of theory-based methods and practical strategies Phase 2: Intervention mapping stages 4–6: 4 Development of components and materials for the occupational advice intervention using a modified Delphi process 5 Adoption and implementation of the intervention 6 Evaluation and feasibility testing The study will be undertaken in four National Health Service (NHS) hospitals in the United Kingdom and two Higher Education Institution. Discussion: OPAL (Occupational advice for Patients undergoing Arthroplasty of the Lower limb) aims to develop an occupational advice intervention to support early recovery to usual activities including work, which is tailored to the requirements of patients undergoing hip and knee replacements. The developed intervention will then be assessed with a specific focus on evaluating its feasibility as a potential trial intervention to improve speed of recovery to usual activities including work