237 research outputs found
Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses
The neuronal ceroid lipofuscinoses (NCL) are a group of disorders defined by shared clinical and pathological features, including seizures and progressive decline in vision, neurocognition, and motor functioning, as well as accumulation of autofluorescent lysosomal storage material, or 'ceroid lipofuscin'. Research has revealed thirteen distinct genetic subtypes. Precisely how the gene mutations lead to the clinical phenotype is still incompletely understood, but recent research progress is starting to shed light on disease mechanisms, in both gene-specific and shared pathways. As the application of new sequencing technologies to genetic disease diagnosis has grown, so too has the spectrum of clinical phenotypes caused by mutations in the NCL genes. Most genes causing NCL have probably been identified, underscoring the need for a shift towards applying genomics approaches to achieve a deeper understanding of the molecular basis of the NCLs and related disorders. Here, we summarize the current understanding of the thirteen identified NCL genes and the proteins they encode, touching upon the spectrum of clinical manifestations linked to each of the genes, and we highlight recent progress leading to a broader understanding of key pathways involved in NCL disease pathogenesis and commonalities with other neurodegenerative diseases
Prediction of texture-induced plastic anisotropy in AA6014-T4 aluminium sheets utilising two different crystal plasticity-based constitutive models
Prescription of respiratory medication without an asthma diagnosis in children: a population based study
Background. In pre-school children a diagnosis of asthma is not easily made and only a minority of wheezing children will develop persistent atopic asthma. According to the general consensus a diagnosis of asthma becomes more certain with increasing age. Therefore the congruence between asthma medication use and doctor-diagnosed asthma is expected to increase with age. The aim of this study is to evaluate the relationship between prescribing of asthma medication and doctor-diagnosed asthma in children age 0-17. Methods. We studied all 74,580 children below 18 years of age, belonging to 95 GP practices within the second Dutch national survey of general practice (DNSGP-2), in which GPs registered all physician-patient contacts during the year 2001. Status on prescribing of asthma medication (at least one prescription for beta2-agonists, inhaled corticosteroids, cromones or montelukast) and doctor-diagnosed asthma (coded according to the International Classification of Primary Care) was determined. Results. In total 7.5% of children received asthma medication and 4.1% had a diagnosis of asthma. Only 49% of all children receiving asthma medication was diagnosed as an asthmatic. Subgroup analyses on age, gender and therapy groups showed that the Positive Predictive Value (PPV) differs significantly between therapy groups only. The likelihood of having doctor-diagnosed asthma increased when a child received combination therapy of short acting beta2-agonists and inhaled corticosteroids (PPV = 0.64) and with the number of prescriptions (3 prescriptions or more, PPV = 0.66). Both prescribing of asthma medication and doctor-diagnosed asthma declined with age but the congruence between the two measures did not increase with age. Conclusion. In this study, less than half of all children receiving asthma medication had a registered diagnosis of asthma. Detailed subgroup analyses show that a diagnosis of asthma was present in at most 66%, even in groups of children treated intensively with asthma medication. Although age strongly influences the chance of being treated, remarkably, the congruence between prescribing of asthma medication and doctor-diagnosed asthma does not increase with age
Spatially distributed dendritic resonance selectively filters synaptic input
© 2014 Laudanski et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.An important task performed by a neuron is the selection of relevant inputs from among thousands of synapses impinging on the dendritic tree. Synaptic plasticity enables this by strenghtening a subset of synapses that are, presumably, functionally relevant to the neuron. A different selection mechanism exploits the resonance of the dendritic membranes to preferentially filter synaptic inputs based on their temporal rates. A widely held view is that a neuron has one resonant frequency and thus can pass through one rate. Here we demonstrate through mathematical analyses and numerical simulations that dendritic resonance is inevitably a spatially distributed property; and therefore the resonance frequency varies along the dendrites, and thus endows neurons with a powerful spatiotemporal selection mechanism that is sensitive both to the dendritic location and the temporal structure of the incoming synaptic inputs.Peer reviewe
Cardiovascular imaging 2011 in the International Journal of Cardiovascular Imaging
Cardiovascular Aspects of Radiolog
Genetic alterations on chromosome 17p associated with response to radiotherapy in bulky cervical cancer
Chromosome 17 alterations are found in more cancers than those of any other chromosome, and frequently involve the p53 gene on 17p13. The aim of this study was to identify the correlations between the presence of loss of heterozygosity (LOH) and microsatellite instability (MI) on chromosome 17p13 in patients with cervical cancer and the patients’ response to radiotherapy. A total of 50 patients were treated with definitive radiotherapy. We performed biopsies and took specimens from the tumour and venous blood of all patients. Tumour and normal DNAs were analysed by polymerase chain reaction for genetic losses and instability at three polymorphic microsatellite loci mapped to 17p13. Nineteen of the 50 tumours (38%) displayed a genetic alteration (GA) on 17p13, 16 (32%) were found to have LOH, and three (6%) showed MI. The sizes of the tumours of the GA-positive patients were significantly greater than those of the GA-negative patients (P = 0.009). The mean tumour diameter of all patients was 6 ± 2.4 cm. We divided the patients into those with tumours smaller than 6 cm in diameter (n = 26) and those with tumours equal to or greater than 6 cm in diameter (n = 24). The former group survived significantly longer compared to the latter group (P = 0.0002). Among the patients with < 6 cm tumours, all six GA-positive patients are alive with no evidence of disease (NED), whereas of the 20 GA-negative patients, 18 have NED and two are alive with disease (AWD) or suffered cancer-caused death (CD). Thus, there was no correlation between GA and radiotherapy response in the tumours smaller than 6 cm. However, among the patients with ≥ 6 cm tumours, two of the GA-positive patients have NED and 11 are AWD/CD, whereas seven of the GA-negative patients have NED and four are AWD/CD. Among the patients with ≥ 6 cm tumours, the response to radiotherapy of the GA-positive patients were significantly poorer than those of the GA-negative patients (P = 0.02). In addition, the GA-negative patients survived significantly longer compared to the GA-positive patients (P = 0.026). The results of this study suggest that GA increases with tumour growth. Improved success in the management of bulky cervical cancer requires a better understanding of its biological behaviour. © 1999 Cancer Research Campaig
Self-care support for children and adolescents with long-term conditions : the REfOCUS evidence synthesis
Background: Self-care support (e.g. education, training, peer/professional support) is intended to enhance the self-care capacities of children and young people, while simultaneously reducing the financial burden facing health-care systems. Objectives: To determine which models of self-care support for long-term conditions (LTCs) are associated with significant reductions in health utilisation and costs without compromising outcomes for children and young people. Design: Systematic review with meta-analysis. Population: Children and young people aged 0–18 years with a long-term physical or mental health condition (e.g. asthma, depression). Intervention: Self-care support in health, social care, educational or community settings. Comparator: Usual care. Outcomes: Generic/health-related quality of life (QoL)/subjective health symptoms and health service utilisation/costs. Design: Randomised/non-randomised trials, controlled before-and-after studies, and interrupted time series designs. Data sources: MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, ISI Web of Science, NHS Economic Evaluation Database, The Cochrane Library, Health Technology Assessment database, Paediatric Economic Database Evaluation, IDEAS, reference scanning, targeted author searches and forward citation searching. All databases were searched from inception to March 2015. Methods: We conducted meta-analyses, simultaneously plotting QoL and health utilisation effects. We conducted subgroup analyses for evidence quality, age, LTC and intervention (setting, target, delivery format, intensity). Results: Ninety-seven studies reporting 114 interventions were included. Thirty-seven studies reported adequate allocation concealment. Fourteen were UK studies. The vast majority of included studies recruited children and young people with asthma (n = 66, 68%). Four per cent of studies evaluated ‘pure’ self-care support (delivered through health technology without additional contact), 23% evaluated facilitated self-care support (≤ 2 hours’/four sessions’ contact), 65% were intensively facilitated (≥ 2 hours’/four sessions’ contact) and 8% were case management (≥ 2 hours’ support with multidisciplinary input). Self-care support was associated with statistically significant, minimal benefits for QoL [effect size (ES) –0.17, 95% confidence interval (CI) –0.23 to –0.11], but lacked clear benefit for hospital admissions (ES –0.05, 95% CI –0.12 to 0.03). This finding endured across intervention intensities and LTCs. Statistically significant, minimal reductions in emergency use were observed (ES –0.11, 95% CI –0.17 to –0.04). The total cost analysis was limited by the small number of data. Subgroup analyses revealed statistically significant, minimal reductions in emergency use for children aged ≤ 13 years (ES –0.10, 95% CI –0.17 to –0.04), children and young people with asthma (ES –0.12, 95% CI –0.18 to –0.06) and children and young people receiving ≥ 2 hours per four sessions of support (ES –0.10, 95% CI –0.17 to –0.03). Preliminary evidence suggested that interventions that include the child or young person, and deliver some content individually, may optimise QoL effects. Face-to-face delivery may help to maximise emergency department effects. Caution is required in interpreting these findings. Limitations: Identification of optimal models of self-care support is challenged by the size and nature of evidence available. The emphasis on meta-analysis meant that a minority of studies with incomplete but potentially relevant data were excluded. Conclusions: Self-care support is associated with positive but minimal effects on children and young people’s QoL, and minimal, but potentially important, reductions in emergency use. On current evidence, we cannot reliably conclude that self-care support significantly reduces health-care costs. Future work: Research is needed to explore the short- and longer-term effects of self-care support across a wider range of LTCs. Study registration: This study is registered as PROSPERO CRD42014015452. Funding: The National Institute for Health Research Health Services and Delivery Research programme
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Search for neutral MSSM Higgs bosons decaying to a pair of tau leptons in pp collisions
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Measurement of top quark–antiquark pair production in association with a W or Z boson in pp collisions at √s=8 TeV
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