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- Bonham, LW, et al.
(författare)
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Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10854-
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Tidskriftsartikel (refereegranskat)abstract
- The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.
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- Frisoni, G. B., et al.
(författare)
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Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers
- 2017
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Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 16:8, s. 661-676
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Tidskriftsartikel (refereegranskat)abstract
- The diagnosis of Alzheimer's disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimer's disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimer's disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics.
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- Devries, K., et al.
(författare)
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Who perpetrates violence against children? A systematic analysis of age-specific and sex-specific data
- 2018
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Ingår i: BMJ Paediatr Open. - : BMJ. - 2399-9772. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The epidemiology of violence against children is likely to differ substantially by sex and age of the victim and the perpetrator. Thus far, investment in effective prevention strategies has been hindered by lack of clarity in the burden of childhood violence across these dimensions. We produced the first age-specific and sex-specific prevalence estimates by perpetrator type for physical, sexual and emotional violence against children globally. Design: We used random effects meta-regression to estimate prevalence. Estimates were adjusted for relevant quality covariates, variation in definitions of violence and weighted by region-specific, age-specific and sex-specific population data to ensure estimates reflect country population structures. Data sources: Secondary data from 600 population or school-based representative datasets and 43 publications obtained via systematic literature review, representing 13 830 estimates from 171 countries. Eligibility criteria for selecting studies: Estimates for recent violence against children aged 0-19 were included. Results: The most common perpetrators of physical and emotional violence for both boys and girls across a range of ages are household members, with prevalence often surpassing 50%, followed by student peers. Children reported experiencing more emotional than physical violence from both household members and students. The most common perpetrators of sexual violence against girls aged 15-19 years are intimate partners; however, few data on other perpetrators of sexual violence against children are systematically collected internationally. Few age-specific and sex-specific data are available on violence perpetration by schoolteachers; however, existing data indicate high prevalence of physical violence from teachers towards students. Data from other authority figures, strangers, siblings and other adults are limited, as are data on neglect of children. Conclusions: Without further investment in data generation on violence exposure from multiple perpetrators for boys and girls of all ages, progress towards Sustainable Development Goals 4, 5 and 16 may be slow. Despite data gaps, evidence shows violence from household members, peers in school and for girls, from intimate partners, should be prioritised for prevention. Trial registration number: PROSPERO 2015: CRD42015024315.
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- Bizzarri, C, et al.
(författare)
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Water Balance and 'Salt Wasting' in the First Year of Life: The Role of Aldosterone-Signaling Defects
- 2016
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Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 86:3, s. 143-153
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Tidskriftsartikel (refereegranskat)abstract
- In newborns and infants, dehydration and salt wasting represent a relatively common cause of admission to hospital and may result in life-threatening complications. Kidneys are responsible for electrolyte homoeostasis, but neonatal kidneys show low glomerular filtration rate and immaturity of the distal nephron, leading to reduced ability to concentrate urine. High extrarenal fluid losses often contribute to the increased occurrence of electrolyte disorders. Aldosterone is essential for sodium retention in the kidney, salivary glands, sweat glands and colon. A partial and transient aldosterone resistance is present in newborns and infants, thus reducing the capability of maintaining sodium balance in specific pathological conditions. The present review examines the mechanisms making infants more susceptible to salt wasting. Peculiar aspects of renal physiology in the first year of life and management of electrolyte disorders (i.e. sodium and potassium) are considered. Finally, inherited disorders associated with neonatal salt wasting are examined in detail.
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