Thromboprophylaxis in atrial fibrillation and association with cognitive decline: systematic review

Objective:Atrial Fibrillation (AF) is associated with dementia. If AF-related cognitive decline is driven by cerebral embolic events, thromboprophylaxis may impact on this. This systematic review assessed the association between cognitive impairment and AF thromboprophylaxis. Methods:Two independent reviewers searched CINAHL, EMBASE, MEDLINE, PsycINFO, Web of Science Core Collection, and Cochrane Library from inception until 12th November 2014. Eligible studies compared AF thromboprophylaxis to control with an outcome measure of cognition or dementia. Where data allowed, meta-analyses describing between-group differences in cognitive test scores or rates of incident dementia were performed. Results:Nineteen studies were eligible. For two prospective studies (one RCT) comparing anticoagulation against antiplatelet therapy, change in Mini-Mental State Examination score from baseline to last follow-up (maximal duration:5.9 years) suggested a difference favouring anticoagulation (mean difference:0.90, 95% CI:0.29 to 1.51), in keeping with a trend seen in the single RCT (mean difference MMSE:0.80. 95% CI:-0.07 to 1.67). Pooled odds ratios suggested no association with incident dementia, comparing anticoagulant to antiplatelet therapy (two studies, OR:1.23, 95% CI:0.80 to 1.91) or no treatment (three studies, OR:0.89, 95%CI:0.47 to 1.69). Conclusions:Our analyses show no definitive evidence of cognitive benefit or harm from anticoagulation. We demonstrated a potential benefit of anticoagulation in comparison to antiplatelet over time. Larger-scale studies with longer follow-up are needed to determine the true cognitive impact of AF thromboprophylaxis

Novel fused arylpyrimidinone based allosteric modulators of the M1 muscarinic acetylcholine receptor

Benzoquinazolinone 1 is a positive allosteric modulator (PAM) of the M1 muscarinic acetylcholine receptor (mAChR), which is significantly more potent than the prototypical PAM, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid (BQCA). In this study, we explored the structural determinants that underlie the activity of 1 as a PAM of the M1 mAChR. We paid particular attention to the importance of the tricyclic scaffold of compound 1, for the activity of the molecule. Complete deletion of the peripheral fused benzene ring caused a significant decrease in affinity and binding cooperativity with acetylcholine (ACh). This loss of affinity was rescued with the addition of either one or two methyl groups in the 7- and/or 8-position of the quinazolin-4(3H)-one core. These results demonstrate that the tricyclic benzo[h]quinazolin-4(3H)-one core could be replaced with a quinazolin-4(3H)-one core and maintain functional affinity. As such, the quinazolin-4(3H)-one core represents a novel scaffold to further explore M1 mAChR PAMs with improved physicochemical properties

First record of verticillium wilt (Verticillium longisporum) in winter oilseed rape in the UK

Verticillium longisporum is an important pathogen of oilseed rape (OSR) and vegetable brassicas in several European countries, but has not been reported previously in the UK (Karapapa et al., 1997; Steventon et al., 2002). In 2007, Verticillium wilt was suspected in UK crops of winter OSR (W-OSR) on cv. Castille in Romney Marsh, Kent and on cv. Barrel near Hereford. At these two locations, 32 and 10% of the plants, respectively, appeared to be affected, but the presence of stem canker may have masked some infections. Symptoms were first seen as the crops began to ripen (seeds green-brown to brown, Growth Stage: 6,4-6,5) and included brown and dark grey vertical bands on the stems from soil level into the branches, and premature ripening of some branches (Fig. 1). Microsclerotia were observed on stem samples collected in the field (Fig. 2), suggesting V. longisporum as the causal agent. Cultures were prepared from field samples by immersing stem pieces in 5% sodium hypochlorite solution for one minute, washing twice in sterile distilled water and plating onto potato dextrose agar containing 25 mg/l streptomycin sulphate. Isolates from three plants per outbreak were identified morphologically as V. longisporum. Mean conidial dimensions (25 spores per isolate) were 8.80-9.65 μm (length) and 2.50-2.85 μm (width) and all isolates produced elongated microsclerotia, characters typical of V. longisporum (Karapapa et al., 1997). The identity was confirmed by PCR using species-specific primers (Steventon et al., 2002) and, as a member of the α sub-group, by direct sequencing of the amplicons from primer pairs ITS4-ITS5 and DB19-DB22 (Collins et al., 2003; 2005). Sequences for isolate 003 from Kent were deposited in GenBank (Accession Nos. HQ702376 and HQ702377). All isolates tested from 2008 and 2009 were identical with previously deposited sequences for European OSR isolates (e.g. AF363992 and AF363246 respectively). Pathogenicity was confirmed by inoculating three OSR cv. Castille seedlings per isolate using the root dip technique with 1 x 106 spores/ml (Karapapa et al., 1997) under heated glasshouse conditions at 19°C. Leaf yellowing and blackening of the leaf veins were found 26 days after inoculation (Fig. 3). Yellowing affecting the three oldest leaves increased for seven to nine days. After five weeks the final mean leaf area affected was 63-78% with no differences between isolates. No leaf yellowing occurred in the controls. After five weeks, V. longisporum was re-isolated from all the inoculated seedlings, but not from the non-inoculated controls. In June 2008, infection of W-OSR crops in different fields on the same farms was found on cv. Es Astrid in Kent (56% incidence) and on cv. Lioness in Hereford (15% incidence). The Kent farm had been growing W-OSR alternating with winter wheat for at least 10 years whilst the Hereford farm had grown W-OSR one year in four. These short rotations of OSR may be contributing to the appearance of this disease. This study confirms the identification of V. longisporum on any host in the UK, through molecular studies and detailed spore measurements that were not reported in an earlier review (Gladders, 2009). This pathogen occurs in several European countries and, since OSR may be traded freely, following a Defra consultation, no statutory plant health action is to be taken

Generation of both cortical and Aire(+) medullary thymic epithelial compartments from CD205(+) progenitors

In the adult thymus, the development of self-tolerant thymocytes requires interactions with thymic epithelial cells (TECs). Although both cortical and medullary TECs (cTECs/mTECs) are known to arise from common bipotent TEC progenitors, the phenotype of these progenitors and the timing of the emergence of these distinct lineages remain unclear. Here, we have investigated the phenotype and developmental properties of bipotent TEC progenitors during cTEC/mTEC lineage development. We show that TEC progenitors can undergo a stepwise acquisition of first cTEC and then mTEC hallmarks, resulting in the emergence of a progenitor population simultaneously expressing the cTEC marker CD205 and the mTEC regulator Receptor Activator of NF-κB (RANK). In vivo analysis reveals the capacity of CD205(+) TECs to generate functionally competent cortical and medullary microenvironments containing both cTECs and Aire(+) mTECs. Thus, TEC development involves a stage in which bipotent progenitors can co-express hallmarks of the cTEC and mTEC lineages through sequential acquisition, arguing against a simple binary model in which both lineages diverge simultaneously from bipotent lineage negative TEC progenitors. Rather, our data reveal an unexpected overlap in the phenotypic properties of these bipotent TECs with their lineage-restricted counterparts

Confirmatory factor analysis of the Test of Performance Strategies (TOPS) among adolescent athletes

The aim of the present study was to examine the factorial validity of the Test of Performance Strategies (TOPS; Thomas et al., 1999) among adolescent athletes using confirmatory factor analysis. The TOPS was designed to assess eight psychological strategies used in competition (i.e. activation, automaticity, emotional control, goal-setting, imagery, negative thinking, relaxation and self-talk,) and eight used in practice (the same strategies except negative thinking is replaced by attentional control). National-level athletes (n = 584) completed the 64-item TOPS during training camps. Fit indices provided partial support for the overall measurement model for the competition items (robust comparative fit index = 0.92, Tucker-Lewis index = 0.88, root mean square error of approximation = 0.05) but minimal support for the training items (robust comparative fit index = 0.86, Tucker-Lewis index = 0.81, root mean square error of approximation = 0.06). For the competition items, the automaticity, goal-setting, relaxation and self-talk scales showed good fit, whereas the activation, emotional control, imagery and negative thinking scales did not. For the practice items, the attentional control, emotional control, goal-setting, imagery and self-talk scales showed good fit, whereas the activation, automaticity and relaxation scales did not. Overall, it appears that the factorial validity of the TOPS for use with adolescents is questionable at present and further development is required

Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor

We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D2 receptor (D2R) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3, placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g. aromatic/aliphatic carbocycles). We identify analogues with diverse pharmacology at the D2R including NAMs (19fc) with sub-?M affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i)

Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, primarily affecting lower motor neurons. Recent evidence from SMA and related conditions suggests that glial cells can influence disease severity. Here, we investigated the role of glial cells in the peripheral nervous system by creating SMA mice selectively overexpressing SMN in myelinating Schwann cells (Smn(−/−);SMN2(tg/0);SMN1(SC)). Restoration of SMN protein levels restricted solely to Schwann cells reversed myelination defects, significantly improved neuromuscular function and ameliorated neuromuscular junction pathology in SMA mice. However, restoration of SMN in Schwann cells had no impact on motor neuron soma loss from the spinal cord or ongoing systemic and peripheral pathology. This study provides evidence for a defined, intrinsic contribution of glial cells to SMA disease pathogenesis and suggests that therapies designed to include Schwann cells in their target tissues are likely to be required in order to rescue myelination defects and associated disease symptoms

Exploring the limit of metazoan thermal tolerance via comparative proteomics: thermally induced changes in protein abundance by two hydrothermal vent polychaetes

Temperatures around hydrothermal vents are highly variable, ranging from near freezing up to 300°C. Nevertheless, animals thrive around vents, some of which live near the known limits of animal thermotolerance. Paralvinella sulfincola, an extremely thermotolerant vent polychaete, and Paralvinella palmiformis, a cooler-adapted congener, are found along the Juan de Fuca Ridge in the northwestern Pacific. We conducted shipboard high-pressure thermotolerance experiments on both species to characterize the physiological adaptations underlying P. sulfincola's pronounced thermotolerance. Quantitative proteomics, expressed sequence tag (EST) libraries and glutathione assays revealed that P. sulfincola (i) exhibited an upregulation in the synthesis and recycling of glutathione with increasing temperature, (ii) downregulated nicotinamide adenine dinucleotide (NADH) and succinate dehydrogenases (key enzymes in oxidative phosphorylation) with increasing temperature, and (iii) maintained elevated levels of heat shock proteins (HSPs) across all treatments. In contrast, P. palmiformis exhibited more typical responses to increasing temperatures (e.g. increasing HSPs at higher temperatures). These data reveal differences in how a mesotolerant and extremely thermotolerant eukaryote respond to thermal stress, and suggest that P. sulfincola's capacity to mitigate oxidative stress via increased synthesis of antioxidants and decreased flux through the mitochondrial electron transport chain enable pronounced thermotolerance. Ultimately, oxidative stress may be the key factor in limiting all metazoan thermotolerance.Organismic and Evolutionary Biolog

Surviving the Journey for Doctoral Students and Jr. Faculty: Panel Presentation and Discussion

Abbreviated presentations will be made by the four panelists that will focus on a range of topics of special interest to doctoral students and untenured junior faculty. The panelists’ presentations will serve as discussion starters for the session with the primary focus on the interaction among the conference attendees and the panelists