Neural adaptations associated with interlimb transfer in a ballistic wrist flexion task.

Cross education is the process whereby training of one limb gives rise to increases in the subsequent performance of its opposite counterpart. The execution of many unilateral tasks is associated with increased excitability of corticospinal projections from primary motor cortex (M1) to the opposite limb. It has been proposed that these effects are causally related. Our aim was to establish whether changes in corticospinal excitability arising from prior training of the opposite limb determine levels of interlimb transfer.

We used three vision conditions shown previously to modulate the excitability of corticospinal projections to the inactive (right) limb during wrist flexion movements performed by the training (left) limb. These were: mirrored visual feedback of the training limb; no visual feedback of either limb; and visual feedback of the inactive limb. Training comprised 300 discrete, ballistic wrist flexion movements executed as rapidly as possible. Performance of the right limb on the same task was assessed prior to, at the mid point of, and following left limb training.

There was no evidence that variations in the excitability of corticospinal projections (assessed by transcranial magnetic stimulation (TMS)) to the inactive limb were associated with, or predictive of, the extent of interlimb transfer that was expressed. There were however associations between alterations in muscle activation dynamics observed for the untrained limb, and the degree of positive transfer that arose from training of the opposite limb.

The results suggest that the acute adaptations that mediate the bilateral performance gains realised through unilateral practice of this ballistic wrist flexion task are mediated by neural elements other than those within M1 that are recruited at rest by single-pulse TMS.

Extravascular modified lipoproteins: a role in the propagation of diabetic retinopathy in a mouse model of type 1 diabetes

Aims/hypothesis: We aimed to determine whether plasma lipoproteins, after leakage into the retina and modification by glycation and oxidation, contribute to the development of diabetic retinopathy in a mouse model of type 1 diabetes.

Methods: To simulate permeation of plasma lipoproteins intoretinal tissues, streptozotocin-induced mouse models of diabetes and non-diabetic mice were challenged with intravitreal injection of human ‘highly-oxidised glycated’ low-density lipoprotein (HOG-LDL), native- (N-) LDL, or the vehicle PBS.Retinal histology, electroretinography (ERG) and biochemical markers were assessed over the subsequent 14 days.

Results: Intravitreal administration of N-LDL and PBS had noeffect on retinal structure or function in either diabetic or non-diabetic animals. In non-diabetic mice, HOG-LDL elicited a transient inflammatory response without altering retinal function,but in diabetic mice it caused severe, progressive retinal injury, with abnormal morphology, ERG changes, vascular leakage, vascular endothelial growth factor overexpression, gliosis, endoplasmic reticulum stress, and propensity to apoptosis.

Conclusions/interpretation: Diabetes confers susceptibility to retinal injury imposed by intravitreal injection of modified LDL. The data add to the existing evidence that extravasated, modified plasma lipoproteins contribute to the propagation of diabetic retinopathy. Intravitreal delivery of HOG-LDL simulates a stress known to be present, in addition to hyperglycaemia, in human diabetic retinopathy once blood retinal barriers are compromised.

Beneficial Effects of Berberine on Oxidized LDL-induced Cytotoxicity in Human Retinal Müller Cells

PURPOSE. Limited mechanistic understanding of diabetic retinopathy (DR) has hindered therapeutic advances. Berberine, an isoquinolone alkaloid, has shown favorable effects on glucose and lipid metabolism in animal and human studies, but effects on DR are unknown. We previously demonstrated intraretinal extravasation and modification of LDL in human diabetes, and toxicity of modified LDL to human retinal M¨uller cells. We now explore pathogenic effects of modified LDL on M¨uller cells, and the efficacy of berberine in mitigating this cytotoxicity. METHODS. Confluent human M¨uller cells were exposed to in vitro–modified ‘highly oxidized, glycated (HOG-) LDL versus native-LDL (N-LDL; 200 mg protein/L) for 6 or 24 hours, with/ without pretreatment with berberine (5 lM, 1 hour) and/or the adenosine monophosphate (AMP)-activated protein kinase (AMPK) inhibitor, Compound C (5 lM, 1 hour). Using techniques including Western blots, reactive oxygen species (ROS) detection assay, and quantitative real-time PCR, the following outcomes were assessed: cell viability (CCK-8 assay), autophagy (LC3, Beclin-1, ATG-5), apoptosis (cleaved caspase 3, cleaved poly-ADP ribose polymerase), oxidative stress (ROS, nuclear factor erythroid 2-related factor 2, glutathione peroxidase 1, NADPH oxidase 4), angiogenesis (VEGF, pigment epithelium-derived factor), inflammation (inducible nitric oxide synthase, intercellular adhesion molecule 1, IL-6, IL-8, TNF-a), and glial cell activation (glial fibrillary acidic protein). RESULTS. Native-LDL had no effect on cultured human M¨uller cells, but HOG-LDL exhibited marked toxicity, significantly decreasing viability and inducing autophagy, apoptosis, oxidative stress, expression of angiogenic factors, inflammation, and glial cell activation. Berberine attenuated all the effects of HOG-LDL (all P < 0.05), and its effects were mitigated by AMPK inhibition (P < 0.05). CONCLUSIONS. Berberine inhibits modified LDL-induced M¨uller cell injury by activating the AMPK pathway, and merits further study as an agent for preventing and/or treating DR.

Pharmacist-led feedback workshops increase appropriate prescribing of antimicrobials

Objectives To investigate whether and how structured feedback sessions can increase rates of appropriate antimicrobial prescribing by junior doctors.

Methods This was a mixed-methods study, with a conceptual orientation towards complexity and systems thinking. Fourteen junior doctors, in their first year of training, were randomized to intervention (feedback) and 21 to control (routine practice) groups in a single UK teaching hospital. Feedback on their antimicrobial prescribing was given, in writing and via group sessions. Pharmacists assessed the appropriateness of all new antimicrobial prescriptions 2 days per week for 6 months (46 days). The mean normalized prescribing rates of suboptimal to all prescribing were compared between groups using the t-test. Thematic analysis of qualitative interviews with 10 participants investigated whether and how the intervention had impact.

Results Data were collected on 204 prescriptions for 166 patients. For the intervention group, the mean normalized rate of suboptimal to all prescribing was 0.32 ± 0.36; for the control group, it was 0.68 ± 0.36. The normalized rates of suboptimal prescribing were significantly different between the groups (P = 0.0005). The qualitative data showed that individuals' prescribing behaviour was influenced by a complex series of dynamic interactions between individual and social variables, such as interplay between personal knowledge and the expectations of others.

Conclusions The feedback intervention increased appropriate prescribing by acting as a positive stimulus within a complex network of behavioural influences. Prescribing behaviour is adaptive and can be positively influenced by structured feedback. Changing doctors' perceptions of acceptable, typical and best practice could reduce suboptimal antimicrobial prescribing.

Schizophrenia risk from complex variation of complement component 4

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.

ISCR and their association with antibiotic resistance genes

A prevalência de bactérias resistentes a antibióticos em ambiente hospitalar tem vindo a tornar-se dramática e preocupante a nível mundial. Contudo, com a utilização inadequada de antibióticos em áreas tão diversas como a veterinária, a aquacultura e a agricultura, esta deixou de estar confinada ao ambiente hospitalar, sendo o ambiente um reservatório natural de microganismos resistentes a estes compostos. O conhecimento detalhado dos determinantes de resistência a antibióticos presentes nestes ambientes, sejam estes genes de resistência ou estruturas envolvidas na sua mobilização, é fundamental, não só do ponto de vista do conhecimento como para a eventual implementação de medidas de contenção da sua disseminação. Neste contexto, são necessários estudos que permitam conhecer o panorama mais realista da distribuição destes determinantes de resistência a antibióticos, quer no meio ambiente quer no ambiente clínico. Assim, constituiu objectivo principal deste trabalho contribuir para o conhecimento do panorama actual da prevalência e distribuição dos elementos ISCR, bem como de outros determinantes de resistência a antibióticos em espécies de Gram-negativo clinicamente relevantes (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii e Citrobacter freundii) recolhidas a partir de amostras de pacientes do Hospital Infante D. Pedro, EPE, Aveiro, Portugal, entre 2006 e 2008. Adicionalmente, foram também recolhidas bactérias de Gram-negativo do meio ambiente, a partir de amostras de águas e de vísceras de peixes, nas quais foram igualmente pesquisados os elementos acima referidos. À excepção dos isolados de E. coli e de Gramnegativo ambientais, todas as estirpes estudadas foram seleccionadas com base no seu perfil de multirresistência a antibióticos. Os resultados mostraram que em todas as espécies recolhidas no ambiente hospitalar foi detectada a presença de elementos ISCR, do tipo ISCR1 ou ISCR2. O elemento ISCR1, foi encontrado em isolados de E. coli, K. pneumoniae e C. freundii e o elemento ISCR2 em isolados de A. baumannii. Não foi detectada a presença de ISCRs nos isolados de Gram-negativo ambientais, o que sugere que a ocorrência dos mesmos é fortemente influenciada pela pressão selectiva exercida pelo ambiente em que os microrganismos se encontram. Genes qnr e integrões de classe 1 foram os determinantes de resistência mais frequentemente encontrados associados aos elementos ISCR1. Os vários determinantes de resistência foram encontrados em diferentes contextos genéticos e localizados em estruturas móveis, nomeadamente em plasmídeos. O elemento ISCR2 presente em isolados de A. baumannii encontra-se associado ao gene sul2 em todos os isolados, dentro de um mesmo contexto genético e com uma localização cromossomal. Contudo, o contexto genético encontrado nestes isolados é novo não tendo sido descrito até à data em outros microrganismos. O presente estudo constitui a primeira descrição de elementos ISCR intrinsecamente ligados a genes de resistência a antibióticos, em Portugal. Uma vez que estes elementos parecem ser responsáveis pela mobilização de um grande número de genes de resistência a antibióticos, a sua elevada incidência entre estirpes resistentes e multirresistentes, bem como a sua associação com genes de resistência é preocupante e requer vigilância.

Role of Automated Open Source Systems in the Intelligence Analysis of a High-Level Domain Expert

Design and Qualitative/Quantitative Analysis of Multi-Agent Spatial Simulation Library

Thesis (Master's)--University of Washington, 2012

'Incorrigibly Plural’: New Histories of Ulster and Northern Ireland’

Review article of Carson’s Army: The Ulster Volunteer Force, 1910–22. By Timothy Bowman. Manchester University Press, Manchester, 2007. 256 pp. ISBN 0719073715, £55. A History of the Northern Ireland Labour Party: Democratic Socialism and Sectarianism. By Aaron Edwards. Manchester University Press, Manchester, 2009. xiii + 240 pp. ISBN 0719078741, £60. Catholic Belfast and Nationalist Ireland in the Era of Joe Devlin 1871–1934. By A.C. Hepburn. Oxford University Press, Oxford, 2008. xix +307 pp. ISBN 019929884X, £55. The Big House in the North of Ireland: Land, Power and Social Elites, 1878–1960. By Olwen Purdue. University College Dublin Press, Dublin, 2009. xv + 297 pp. ISBN 978-1-906359-25-6, £24.

"24" Wind Ensemble, Campus Band, Concert Band, Symphonic Band, March 11, 2008

Concert program for '24' Wind Ensemble, Campus Band, Concert Band, Symphonic Band, March 11, 2008

The Wind Ensemble, December 4, 1991

Concert Program for The Wind Ensemble, December 4, 1991

From T cell “exhaustion” to anti-cancer immunity

The immune system has the potential to protect from malignant diseases for extended periods of time. Unfortunately, spontaneous immune responses are often inefficient. Significant effort is required to develop reliable, broadly applicable immunotherapies for cancer patients. A major innovation was transplantation with hematopoietic stem cells from genetically distinct donors for patients with hematologic malignancies. In this setting, donor T cells induce long-term remission by keeping cancer cells in check through powerful allogeneic graft-versus-leukemia effects. More recently, a long awaited breakthrough for patients with solid tissue cancers was achieved, by means of therapeutic blockade of T cell inhibitory receptors. In untreated cancer patients, T cells are dysfunctional and remain in a state of T cell "exhaustion". Nonetheless, they often retain a high potential for successful defense against cancer, indicating that many T cells are not entirely and irreversibly exhausted but can be mobilized to become highly functional. Novel antibody therapies that block inhibitory receptors can lead to strong activation of anti-tumor T cells, mediating clinically significant anti-cancer immunity for many years. Here we review these new treatments and the current knowledge on tumor antigen-specific T cells.

Réception de M. Herrick à l'Hôtel de Ville, 26/7/20, M. Herrick [signe le livre d'or] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 60228