| 1. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 2. |
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| 3. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 4. |
- Begley, Cecily, 1954, et al.
(författare)
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Evaluation of an intervention to increase vaginal birth after caesarean section through enhanced women-centred care: The OptiBIRTH randomised trial (ISRCTN10612254)
- 2017
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Ingår i: 31th ICM Triennial Congress.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Vaginal birth after a previous caesarean (VBAC) is a safe alternative to repeat caesarean section (CS), is the preferred option of most women and may reduce overall CS rates.1 However, VBAC rates vary; e.g., rates in Germany, Ireland and Italy are considerably lower (29-36%) than those in the Netherlands, Sweden and Finland (45-55%). Purpose/Objective: To evaluate the effectiveness of an intervention to maximise VBAC rates. The OptiBIRTH Project was funded by a European Union Grant: FP7-HEALTH-2012-INNOVATION-1-HEALTH.2012.3.2-1. Agreement No:305208 Method: A cluster randomised trial was used. A sample size of 12 maternity units was required, each recruiting 120 consenting women, to detect an absolute 15% difference in successful VBACs (increase from 25% in control to 40% in intervention groups), using an ICC of 0.05, with power of >80% and an alpha of 0.05. To allow for loss to follow-up, 15 trial units were randomised across three countries with low VBAC rates (Germany, Ireland and Italy) and the trial commenced April 2014. An evidence-based intervention was introduced in all intervention sites. Control sites had usual care. Interim analysis by an independent Data Monitoring Committee at mid-point permitted continuation. Data were analysed using intention to treat. Key Findings: Recruitment closed October 2015, with the last babies born in December 2015, and data analysis will be completed in April 2016. The primary outcome, comparison of annual VBAC rates for each hospital before and after introduction of the intervention will be presented, and selected secondary outcomes for the recruited women including: mode of birth, perineal trauma, breastfeeding, uterine rupture, wound breakdown, perinatal mortality, Apgar scores, and admission to neonatal intensive care unit. Discussion: If the OptiBIRTH intervention increases VBAC rates safely, its introduction across Europe could prevent 160,000 unnecessary CSs every year, saving maternity services >€150 million annually and contributing to the normalisation of birth for thousands of women. References: 1 Cunningham et al (2010). National Institute of Health Consensus Development Conference Statement: Vaginal birth after caesarean. Obstet & Gynecol 115(6): 1279-1295. 2 EURO-PERISTAT 2008: CD006066.EURO-PERISTAT Project (2008). European Perinatal Health Report. (www.europeristat.com).
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| 5. |
- Clarke, Gerard Janez Brett, et al.
(författare)
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Chronic immunosuppression across 12 months and high ability of acute and subacute CNS-injury biomarker concentrations to identify individuals with complicated mTBI on acute CT and MRI.
- 2024
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Ingår i: Journal of Neuroinflammation. - 1742-2094. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Identifying individuals with intracranial injuries following mild traumatic brain injury (mTBI), i.e. complicated mTBI cases, is important for follow-up and prognostication. The main aims of our study were (1) to assess the temporal evolution of blood biomarkers of CNS injury and inflammation in individuals with complicated mTBI determined on computer tomography (CT) and magnetic resonance imaging (MRI); (2) to assess the corresponding discriminability of both single- and multi-biomarker panels, from acute to chronic phases after injury.Patients with mTBI (n=207), defined as Glasgow Coma Scale score between 13 and 15, loss of consciousness<30min and post-traumatic amnesia<24h, were included. Complicated mTBI - i.e., presence of any traumatic intracranial injury on neuroimaging - was present in 8% (n=16) on CT (CT+) and 12% (n=25) on MRI (MRI+). Blood biomarkers were sampled at four timepoints following injury: admission (within 72h), 2 weeks (±3 days), 3 months (±2 weeks) and 12 months (±1 month). CNS biomarkers included were glial fibrillary acidic protein (GFAP), neurofilament light (NFL) and tau, along with 12 inflammation markers.The most discriminative single biomarkers of traumatic intracranial injury were GFAP at admission (CT+:AUC=0.78; MRI+:AUC=0.82), and NFL at 2 weeks (CT+:AUC=0.81; MRI+:AUC=0.89) and 3 months (MRI+:AUC=0.86). MIP-1β and IP-10 concentrations were significantly lower across follow-up period in individuals who were CT+and MRI+. Eotaxin and IL-9 were significantly lower in individuals who were MRI+only. FGF-basic concentrations increased over time in MRI- individuals and were significantly higher than MRI+individuals at 3 and 12 months. Multi-biomarker panels improved discriminability over single biomarkers at all timepoints (AUCs>0.85 for admission and 2-week models classifying CT+and AUC≈0.90 for admission, 2-week and 3-month models classifying MRI+).The CNS biomarkers GFAP and NFL were useful single diagnostic biomarkers of complicated mTBI, especially in acute and subacute phases after mTBI. Several inflammation markers were suppressed in patients with complicated versus uncomplicated mTBI and remained so even after 12 months. Multi-biomarker panels improved diagnostic accuracy at all timepoints, though at acute and 2-week timepoints, the single biomarkers GFAP and NFL, respectively, displayed similar accuracy compared to multi-biomarker panels.
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| 6. |
- Clarke, Gerard, et al.
(författare)
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Longitudinal Associations Between Persistent Post-Concussion Symptoms and Blood Biomarkers of Inflammation and CNS-Injury Following Mild Traumatic Brain Injury
- 2024
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Ingår i: Journal of neurotrauma. - 1557-9042. ; 41:7-8, s. 862-878
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Tidskriftsartikel (refereegranskat)abstract
- The aim of our study was to investigate the biological underpinnings of persistent post-concussion symptoms (PPCS) at 3 months following mild traumatic brain injury (mTBI). Patients (n = 192, 16-60 years) with mTBI, defined as Glasgow Coma Scale (GCS) score between 13 and 15, loss of consciousness (LOC)<30 min and post-traumatic amnesia (PTA)<24 hours were included. Blood samples were collected at admission (within 72 hours), 2 weeks and 3 months. From the blood, concentrations of blood biomarkers associated with CNS damage (GFAP, NFL and tau) and inflammation (IFN, IL-8, eotaxin, MIP-1, MCP-1, IP-10, IL-17A, IL-9, TNF, FGF-basic PDGF and IL-1ra) were obtained. Demographic and injury-related factors investigated were age, sex, GCS score, LOC, PTA duration, traumatic intracranial finding on MRI (within 72 hours), and extracranial injuries. Delta values, i.e., timepoint differences in biomarker concentrations between 2 weeks minus admission and 3 months minus admission, were also calculated. PPCS was assessed with the British Columbia Post-Concussion Symptom Inventory (BC-PSI). In single variable analyses, longer PTA duration and a higher proportion of intracranial findings on MRI were found in the PPCS group, but no single biomarker differentiated those with PPCS from those without. In multivariable models, female sex, longer PTA duration, MRI findings and lower GCS scores were associated with increased risk of PPCS. Inflammation markers, but not GFAP, NFL or tau, were associated with PPCS. At admission, higher concentrations of IL-8 and IL-9 and lower concentrations of TNF, IL-17a, and MCP-1 were associated with greater likelihood of PPCS; at 2 weeks, higher IL-8 and lower IFN were associated with PPCS; at 3 months, higher PDGF was associated with PPCS. Higher delta values of PDGF, IL-17A and FGF-basic at 2 weeks compared to admission, MCP-1 at 3 months compared to admission and TNF at 2 weeks and 3 months compared to admission were associated with greater likelihood of PPCS. Higher IL-9 delta values at both timepoint comparisons were negatively associated with PPCS. Discriminability of individual CNS-injury and inflammation biomarkers for PPCS was around chance level, while the optimal combination of biomarkers yielded AUCs between 0.62 and 0.73. We demonstrate a role of biological factors on PPCS, including both positive and negative effects of inflammation biomarkers that differed based on sampling timepoint after mTBI. PPCS was associated more with acute inflammatory processes, rather than ongoing inflammation or CNS-injury biomarkers. However, the modest discriminative ability of the models suggests other factors are more important in the development of PPCS.
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| 7. |
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| 8. |
- Clarke, Mike, et al.
(författare)
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OptiBIRTH: a cluster randomised trial of acomplex intervention to increase vaginalbirth after caesarean section
- 2020
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Ingår i: BMC Pregnancy and Childbirth. - : Springer Science and Business Media LLC. - 1471-2393 .- 1471-2393.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite evidence supporting the safety of vaginal birth after caesarean section (VBAC), rates are lowin many countries.Methods: OptiBIRTH investigated the effects of a woman-centred intervention designed to increase VBAC ratesthrough an unblinded cluster randomised trial in 15 maternity units with VBAC rates < 35% in Germany, Ireland andItaly. Sites were matched in pairs or triplets based on annual birth numbers and VBAC rate, and randomised, 1:1 or 2:1, intervention versus control, following trial registration. The intervention involved evidence-based education ofclinicians and women with one previous caesarean section (CS), appointment of opinion leaders, audit/peer review,and joint discussions by women and clinicians. Control sites provided usual care. Primary outcome was annualhospital-level VBAC rates before the trial (2012) versus final year of the trial (2016). Between April 2014 and October2015, 2002 women were recruited (intervention 1195, control 807), with mode-of-birth data available for 1940women.Results: The OptiBIRTH intervention was feasible and safe across hospital settings in three countries. There was nostatistically significant difference in the change in the proportion of women having a VBAC between interventionsites (25.6% in 2012 to 25.1% in 2016) and control sites (18.3 to 22.3%) (odds ratio adjusted for differences betweenintervention and control groups (2012) and for homogeneity in VBAC rates at sites in the countries: 0.87, 95% CI:0.67, 1.14, p = 0.32 based on 5674 women (2012) and 5284 (2016) with outcome data. Among recruited womenwith birth data, 4/1147 perinatal deaths > 24 weeks gestation occurred in the intervention group (0.34%) and 4/782in the control group (0.51%), and two uterine ruptures (one per group), a rate of 1:1000.Conclusions: Changing clinical practice takes time. As elective repeat CS is the most common reason for CS inmultiparous women, interventions that are feasible and safe and that have been shown to lead to decreasingrepeat CS, should be promoted. Continued research to refine the best way of promoting VBAC is essential. Thismay best be done using an implementation science approach that can modify evidence-based interventions inresponse to changing clinical circumstances.Trial registration: The OptiBIRTH trial was registered on 3/4/2013. Trial registration number ISRCTN10612254.
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| 9. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 10. |
- Freitag, Daniel F., et al.
(författare)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Tidskriftsartikel (refereegranskat)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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