175 research outputs found
The role of change- and stability-oriented place attachment in rural community resilience: a case study in south-west Scotland
Electroconvulsive seizures (ECS) do not prevent LPS-induced behavioral alterations and microglial activation
Background: Long-term neuroimmune activation is a common finding in major depressive disorder (MDD). Literature suggests a dual effect of electroconvulsive therapy (ECT), a highly effective treatment strategy for MDD, on neuroimmune parameters: while ECT acutely increases inflammatory parameters, such as serum levels of pro-inflammatory cytokines, there is evidence to suggest that repeated ECT sessions eventually result in downregulation of the inflammatory response. We hypothesized that this might be due to ECT-induced attenuation of microglial activity upon inflammatory stimuli in the brain. Methods: Adult male C57Bl/6J mice received a series of ten electroconvulsive seizures (ECS) or sham shocks, followed by an intracerebroventricular (i.c.v.) lipopolysaccharide (LPS) or phosphate-buffered saline (PBS) injection. Brains were extracted and immunohistochemically stained for the microglial marker ionized calcium-binding adaptor molecule 1 (Iba1). In addition, a sucrose preference test and an open-field test were performed to quantify behavioral alterations. Results: LPS induced a short-term reduction in sucrose preference, which normalized within 3 days. In addition, LPS reduced the distance walked in the open field and induced alterations in grooming and rearing behavior. ECS did not affect any of these parameters. Phenotypical analysis of microglia demonstrated an LPS-induced increase in microglial activity ranging from 84 to 213 % in different hippocampal regions (CA3 213 %; CA1 84 %; dentate gyrus 131 %; and hilus 123 %). ECS-induced alterations in microglial activity were insignificant, ranging from -2.6 to 14.3 % in PBS-injected mice and from -20.2 to 6.6 % in LPS-injected mice. Conclusions: We were unable to demonstrate an effect of ECS on LPS-induced microglial activity or behavioral alterations
Achieving Near-Optimal Traffic Engineering Solutions for Current OSPF/IS-IS Networks
Traffic engineering is aimed at distributing traffic so as to optimize a given performance criterion. The ability to carry out such an optimal distribution depends on the routing protocol and the forwarding mechanisms in use in the network. In IP networks running the OSPF or IS-IS protocols, routing is along shortest paths, and forwarding mechanisms are constrained to distributing traffic uniformly over equal cost shortest paths. These constraints often make achieving an optimal distribution of traffic impossible. In this paper, we propose and evaluate an approach that is capable of realizing near optimal traffic distribution without any change to existing routing protocols and forwarding mechanisms. In addition, we explore the trade-off that exists between performance and the overhead associated with the additional configuration steps that our solution requires. The paper\u27s contributions are in formulating and evaluating an approach to traffic engineering for existing IP networks that achieves performance levels comparable to that offered when deploying other forwarding technologies such as MPLS
Cognitive and neurological outcome of patients in the Dutch pyridoxine-dependent epilepsy (PDE-ALDH7A1) cohort, a cross- sectional study
Item does not contain fulltextBACKGROUND: Pyridoxine monotherapy in PDE-ALDH7A1 often results in adequate seizure control, but neurodevelopmental outcome varies. Detailed long-term neurological outcome is unknown. Here we present the cognitive and neurological features of the Dutch PDE-ALDH7A1 cohort. METHODS: Neurological outcome was assessed in 24 patients (age 1-26 years); classified as normal, complex minor neurological dysfunction (complex MND) or abnormal. Intelligence quotient (IQ) was derived from standardized IQ tests with five severity levels of intellectual disability (ID). MRI's and treatments were assessed. RESULTS: Ten patients (42%) showed unremarkable neurological examination, 11 (46%) complex MND, and 3 (12%) cerebral palsy (CP). Minor coordination problems were identified in 17 (71%), fine motor disability in 11 (46%), posture/muscle tone deviancies in 11 (46%) and abnormal reflexes in 8 (33%). Six patients (25%) had an IQÂ >Â 85, 7 (29%) borderline, 7 (29%) mild, 3 (13%) moderate, and 1 severe ID. Cerebral ventriculomegaly on MRI was progressive in 11. Three patients showed normal neurologic exam, IQ, and MRI. Eleven patients were treated with pyridoxine only and 13 by additional lysine reduction therapy (LRT). LRT started at age <3 years demonstrated beneficial effect on IQ results in 3 patients. DISCUSSION: Complex MND and CP occurred more frequently in PDE-ALDH7A1 (46% and 12%) than in general population (7% and 0.2%, Peters et al., 2011, Schaefer et al., 2008). Twenty-five percent had a normal IQ. Although LRT shows potential to improve outcomes, data are heterogeneous in small patient numbers. More research with longer follow-up via the International PDE Registry (www.pdeonline.org) is needed
Thematic Working Group 5: Formative assessment supported by technology.
The future of assessment faces major challenges including the use of IT to facilitate
formative assessment that is important for improving learnersâ development, motivation
and engagement in learning. In many countries, in recent years, a renewed focus on
assessments to support learning has been pushing against the burgeoning of testing for
accountability, which in some countries, renders effective formative assessment
practices almost impossible. Moreover, a systematic review by Harlen and Deakin Crick
(2002) revealed that a strong focus on summative assessment for accountability can
reduce motivation and disengage many learners. At the same time use of ITâenabled
assessments has been increasing rapidly, as they offer promise of cheaper ways of
delivering and marking assessments as well as access to vast amounts of assessment
data from which a wide range of judgements might be made about students, teachers,
schools and education systems (Gibson & Webb, 2015). These opportunities also extend
to assessment of complex collaborative work (Webb & Gibson, 2015). Current
opportunities for using IT, including for harnessing the data that is being collected
automatically, for formative assessment are underexplored and less well understood
than those for summative assessments. Opportunities for learning with IT and perhaps
with less teacher input are increasing but this depends on students developing as
autonomous or independent learners. Research in formative assessment including
effective feedback has emphasised the value of peer assessment practices for
developing selfâassessment capabilities and hence independent learners (Black,
Harrison, Lee, Marshall, & William, 2003). At previous EDUsummITs the possibilities and
challenges for ITâenabled assessments to support simultaneously both formative and
summative purposes were analysed (Webb, Gibson, & ForkoshâBaruch, 2013). While these challenges remain, at EDUsummIT 2017 we focused on the opportunities and
challenges of IT supporting formative assessment because effective formative
assessment is known to be extremely important for learning.RETHINKING LEARNING IN A DIGITAL AGE, EDUsummIT 2017 Summary Reports 18-20 september, Bulgari
Establishing and Coordinating a Nationwide Multidisciplinary Study Group: Lessons Learned by the Dutch Pancreatic Cancer Group
Surgical oncolog
Serious child and adolescent behaviour disorders; a valuation study by professionals, youth and parents
Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy
Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. As novel and improved immunotherapies may fill this need, we dissected the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 25 tumors (10 pre- and 15 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas were infiltrated by NK, T and B cells, and immunosuppressive myeloid populations. NK cells showed reduced cytotoxicity and T cells had a dysfunctional profile. Interaction analysis revealed a vast immunoregulatory network and identified NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduced neuroblastoma growth, with complete responses in vivo. Moreover, addition of TIGIT blockade to standard relapse treatment in a chemotherapy-resistant Th-ALKF1174L/MYCN 129/SvJ syngeneic model significantly improved survival. Concluding, our integrative analysis of neuroblastomaâs vast immunoregulatory network provides novel targets and a rationale for immunotherapeutic combination strategies
Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative
Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. Material and methods: All patients aged â„18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting
Treatment and survival of resected and unresected distal cholangiocarcinoma: a nationwide study
Background: Population-based data on distal cholangiocarcinoma (DCC) from the Western world are
not available, albeit essential to identify areas for improvement. This study investigated the incidence,
treatment and outcomes, including time trends and predictors for survival, in a nationwide cohort
of DCC.
Methods: This is a retrospective cohort study of patients diagnosed with DCC (2009â2016)
derived from the Netherlands Cancer Registry. Overall survival (OS) and its predictors were analyzed
using KaplanâMeier and Cox regres
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