Current outcomes of valvular surgery for Indigenous Australians with Rheumatic Heart Disease: a single-centre experience

Purpose: Rheumatic heart disease (RHD) remains a problem amongst Indigenous Australians, with many presenting for surgery at a young age. Long-term outcomes of RHD surgery amongst Indigenous Australians remain unreported. Hence, this study aimed to describe outcomes of valvular surgery for RHD in Indigenous Australians at a single centre. Methods: Indigenous Australian patients with RHD and who underwent valvular surgery (n = 112) between 2008 and 2016 were reviewed. Data were prospectively collected, and follow-up was obtained fromcardiologists. Multivariate analysis was performed to determine predictors of mortality. Results: Mean age was 43±16 years (range 13–73) with 82 (73%) being females. Surgery was performed on the mitral valve in 93 (83%), aortic valve in 51 (46%), and tricuspid valve in 28 (25%) patients. In patients aged ≤50 years (n = 73), there were 45 bioprosthetic (62%) valves implanted. Operative mortality was 2.7%. Nine (8%) patients had reoperation for infective endocarditis (n = 3), bioprosthetic valve degeneration (n = 4), mechanical valve thrombus (n = 1), and progression of RHD in other valves (n = 1). There were 18 (16%) late deaths, and survival at 5 years was 83±4.1 (95% CI 73–89%). Risk factors for mortality were concomitant coronary artery bypass grafting (p = 0.008) and preoperative left ventricular ejection fraction (LVEF) ≤40% (p = 0.043). The mean follow-up for survivors was 5 years (2 months–9 years) with 97% of patients in New York Heart Association class I or II. Conclusions: Valvular surgery forRHD in Indigenous Australians can be performed with low operative mortality. In patients aged ≤50 years, bioprostheses were the valve of choice. Concomitant coronary artery disease and LVEF ≤40% were predictors of mortality

Septin/anillin filaments scaffold central nervous system myelin to accelerate nerve conduction

Myelination of axons facilitates rapid impulse propagation in the nervous system. The axon/myelin-unit becomes impaired in myelin-related disorders and upon normal aging. However, the molecular cause of many pathological features, including the frequently observed myelin outfoldings, remained unknown. Using label-free quantitative proteomics, we find that the presence of myelin outfoldings correlates with a loss of cytoskeletal septins in myelin. Regulated by phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2)-levels, myelin septins (SEPT2/SEPT4/SEPT7/SEPT8) and the PI(4,5)P2-adaptor anillin form previously unrecognized filaments that extend longitudinally along myelinated axons. By confocal microscopy and immunogold-electron microscopy, these filaments are localized to the non-compacted adaxonal myelin compartment. Genetic disruption of these filaments in Sept8-mutant mice causes myelin outfoldings as a very specific neuropathology. Septin filaments thus serve an important function in scaffolding the axon/myelin-unit, evidently a late stage of myelin maturation. We propose that pathological or aging-associated diminishment of the septin/anillin-scaffold causes myelin outfoldings that impair the normal nerve conduction velocity

Cocapture of cognate and bystander antigens can activate autoreactive B cells

Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) are associated with autoimmune central nervous system diseases like acute disseminated encephalomyelitis (ADEM). For ADEM, it is speculated that a preceding infection is the trigger of the autoimmune response, but the mechanism connecting the infection to the production of MOG antibodies remains a mystery. We reasoned that the ability of B cells to capture cognate antigen from cell membranes, along with small quantities of coexpressed “bystander” antigens, might enable B-cell escape from tolerance. We tested this hypothesis using influenza hemagglutinin as a model viral antigen and transgenic, MOG-specific B cells. Using flow cytometry and live and fixed cell microscopy, we show that MOG-specific B cells take up large amounts of MOG from cell membranes. Uptake of the antigen from the membrane leads to a strong activation of the capturing B cell. When influenza hemagglutinin is also present in the membrane of the target cell, it can be cocaptured with MOG by MOG-specific B cells via the B-cell receptor. Hemagglutinin and MOG are both presented to T cells, which in turn are activated and proliferate. As a consequence, MOG-specific B cells get help from hemagglutinin-specific T cells to produce anti-MOG antibodies. In vivo, the transfer of MOG-specific B cells into recipient mice after the cocapture of MOG and hemagglutinin leads to the production of class-switched anti-MOG antibodies, dependent on the presence of hemagglutinin-specific T cells. This mechanism offers a link between infection and autoimmunity. Keywords: tolerance; autoantibodies; antigen capture; antigen presentation; influenz

Combinatory multifactor treatment effects on primary nanofiber oligodendrocyte cultures

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system. Neurological deficits are attributed to inflammatory demyelination, which compromises axonal function and survival. These are mitigated in experimental models by rapid and often complete remyelination of affected axons, but in MS this endogenous repair mechanism frequently fails, leaving axons increasingly vulnerable to the detrimental effects of inflammatory and metabolic stress. Understanding the molecular basis of remyelination and remyelination failure is essential to develop improved therapies for this devastating disease. However, recent studies suggest that this is not due to a single dominant mechanism, but rather represents the biological outcome of multiple changes in the lesion microenvironment that combine to disrupt oligodendrocyte differentiation. This identifies a pressing need to develop technical platforms to investigate combinatory and/or synergistic effects of factors differentially expressed in MS lesions on oligodendrocyte proliferation and differentiation. Here we describe protocols using primary oligodendrocyte cultures from Bl6 mice on 384-well nanofiber plates to model changes affecting oligodendrogenesis and differentiation in the complex signaling environment associated with multiple sclerosis lesions. Using platelet-derived growth factor (PDGF–AA), fibroblast growth factor 2 (FGF2), bone morphogenetic protein 2 (BMP2) and bone morphogenetic protein 4 (BMP4) as representative targets, we demonstrate that we can assess their combinatory effects across a wide range of concentrations in a single experiment. This in vitro model is ideal for assessing the combinatory effects of changes in availability of multiple factors, thus more closely modelling the situation in vivo and furthering high-throughput screening possibilities

The direct drivers of recent global anthropogenic biodiversity loss

Effective policies to halt biodiversity loss require knowing which anthropogenic drivers are the most important direct causes. Whereas previous knowledge has been limited in scope and rigor, here we statistically synthesize empirical comparisons of recent driver impacts found through a wide-ranging review. We show that land/sea use change has been the dominant direct driver of recent biodiversity loss worldwide. Direct exploitation of natural resources ranks second and pollution third; climate change and invasive alien species have been significantly less important than the top two drivers. The oceans, where direct exploitation and climate change dominate, have a different driver hierarchy from land and fresh water. It also varies among types of biodiversity indicators. For example, climate change is a more important driver of community composition change than of changes in species populations. Stopping global biodiversity loss requires policies and actions to tackle all the major drivers and their interactions, not some of them in isolation.Fil: Jaureguiberry, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Titeux, Nicolas. German Centre For Integrative Biodiversity Research (idiv) Halle-Jena-Leipzig; Alemania. Luxembourg Institute Of Science And Technology; Luxemburgo. Helmholtz Zentrum Für Umweltforschung; AlemaniaFil: Wiemers, Martin. Helmholtz Zentrum Für Umweltforschung; Alemania. Senckenberg Gesellschaft Für Naturforschung; AlemaniaFil: Bowler, Diana E.. German Centre For Integrative Biodiversity Research (idiv) Halle-Jena-Leipzig; Alemania. Universitat Jena; Alemania. Helmholtz Zentrum Für Umweltforschung; AlemaniaFil: Coscieme, Luca. Hot Or Cool Institute; AlemaniaFil: Golden, Abigail S.. University of Washington; Estados Unidos. German Centre For Integrative Biodiversity Research (idiv) Halle-Jena-Leipzig; Alemania. Department Of Marine And Coastal Sciences; Estados UnidosFil: Guerra, Carlos A.. German Centre For Integrative Biodiversity Research (idiv) Halle-Jena-Leipzig; Alemania. Martin Luther University Halle Wittenberg; AlemaniaFil: Jacob, Ute. Universität Oldenburg; Alemania. Alfred-Wegener-Institut Helmholtz-Zentrum Für Polar- Und Meeresforschung; AlemaniaFil: Takahashi, Yasuo. Institute For Global Environmental Strategies; JapónFil: Settele, Josef. German Centre For Integrative Biodiversity Research (idiv) Halle-Jena-Leipzig; Alemania. University Of The Philippines, Los Baños; Filipinas. Helmholtz Zentrum Für Umweltforschung; AlemaniaFil: Díaz, Sandra Myrna. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Molnár, Zsolt. Institute Of Ecology And Botany; HungríaFil: Purvis, Andy. Imperial College London; Reino Unido. Natural History Museum; Reino Unid

Fiscal year 1995 laboratory scale studies of Cs elution in Tank 8D-1 and sludge dissolution in tank 8D-2

During Phase I of West Valley Demonstration project waste remediation, an estimated 95% of the zeolite currently in tank 8D-1 will be transferred to tank 8D-2, leaving behind residual Cs-loaded zeolite which will require treatment to remove the Cs. After phase I vitrification, tank 8D-2 will contain residual waste from PUREX and THOREX and spent Cs-loaded zeolite. The residual waste will require treatment. Oxalic acid has been proposed for eluting Cs from zeolite in tank 8D-1 and dissolving radionuclides in tank 8D-2. Laboratory tests were performed to determine optimum Cs elution and sludge dissolution conditions and to evaluate effects of multiple contacts, long-term contacts, presence of corrosion products, lack of agitation, temperature of tank contents, and oxalic acid concentration. Mild steel corrosion tests were also conducted

Identifying Insects with Incomplete DNA Barcode Libraries, African Fruit Flies (Diptera: Tephritidae) as a Test Case

We propose a general working strategy to deal with incomplete reference libraries in the DNA barcoding identification of species. Considering that (1) queries with a large genetic distance with their best DNA barcode match are more likely to be misidentified and (2) imposing a distance threshold profitably reduces identification errors, we modelled relationships between identification performances and distance thresholds in four DNA barcode libraries of Diptera (n = 4270), Lepidoptera (n = 7577), Hymenoptera (n = 2067) and Tephritidae (n = 602 DNA barcodes). In all cases, more restrictive distance thresholds produced a gradual increase in the proportion of true negatives, a gradual decrease of false positives and more abrupt variations in the proportions of true positives and false negatives. More restrictive distance thresholds improved precision, yet negatively affected accuracy due to the higher proportions of queries discarded (viz. having a distance query-best match above the threshold). Using a simple linear regression we calculated an ad hoc distance threshold for the tephritid library producing an estimated relative identification error <0.05. According to the expectations, when we used this threshold for the identification of 188 independently collected tephritids, less than 5% of queries with a distance query-best match below the threshold were misidentified. Ad hoc thresholds can be calculated for each particular reference library of DNA barcodes and should be used as cut-off mark defining whether we can proceed identifying the query with a known estimated error probability (e.g. 5%) or whether we should discard the query and consider alternative/complementary identification methods

Early Development of the Central and Peripheral Nervous Systems Is Coordinated by Wnt and BMP Signals

The formation of functional neural circuits that process sensory information requires coordinated development of the central and peripheral nervous systems derived from neural plate and neural plate border cells, respectively. Neural plate, neural crest and rostral placodal cells are all specified at the late gastrula stage. How the early development of the central and peripheral nervous systems are coordinated remains, however, poorly understood. Previous results have provided evidence that at the late gastrula stage, graded Wnt signals impose rostrocaudal character on neural plate cells, and Bone Morphogenetic Protein (BMP) signals specify olfactory and lens placodal cells at rostral forebrain levels. By using in vitro assays of neural crest and placodal cell differentiation, we now provide evidence that Wnt signals impose caudal character on neural plate border cells at the late gastrula stage, and that under these conditions, BMP signals induce neural crest instead of rostral placodal cells. We also provide evidence that both caudal neural and caudal neural plate border cells become independent of further exposure to Wnt signals at the head fold stage. Thus, the status of Wnt signaling in ectodermal cells at the late gastrula stage regulates the rostrocaudal patterning of both neural plate and neural plate border, providing a coordinated spatial and temporal control of the early development of the central and peripheral nervous systems