Age-related decline in the integrity of mitochondria is an important contributor to the human ageing process. In a number of ageing stem cell populations, this decline in mitochondrial function is ...due to clonal expansion of individual mitochondrial DNA (mtDNA) point mutations within single cells. However the dynamics of this process and when these mtDNA mutations occur initially are poorly understood. Using human colorectal epithelium as an exemplar tissue with a well-defined stem cell population, we analysed samples from 207 healthy participants aged 17-78 years using a combination of techniques (Random Mutation Capture, Next Generation Sequencing and mitochondrial enzyme histochemistry), and show that: 1) non-pathogenic mtDNA mutations are present from early embryogenesis or may be transmitted through the germline, whereas pathogenic mtDNA mutations are detected in the somatic cells, providing evidence for purifying selection in humans, 2) pathogenic mtDNA mutations are present from early adulthood (<20 years of age), at both low levels and as clonal expansions, 3) low level mtDNA mutation frequency does not change significantly with age, suggesting that mtDNA mutation rate does not increase significantly with age, and 4) clonally expanded mtDNA mutations increase dramatically with age. These data confirm that clonal expansion of mtDNA mutations, some of which are generated very early in life, is the major driving force behind the mitochondrial dysfunction associated with ageing of the human colorectal epithelium.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
Anxiety, depression and fatigue are commonly reported by persons with multiple sclerosis (PwMS).
Objectives:
We estimated the prevalence of each factor in a representative sample of PwMS, ...and in subgroups defined by age, sex and disease duration, at cohort entry and over time. We further examined whether and how these factors clustered together.
Methods:
A population-based longitudinal cohort of 198 PwMS was followed 6-monthly for 2.5 years. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety (cut-point >7) and depression (>7) and the Fatigue Severity Scale (FSS) to measure fatigue (≥5).
Results:
At cohort entry, prevalence of anxiety was 44.5% (95%CI 37–51%), depression 18.5% (95%CI 12.6–23.4%), and fatigue 53.7% (95%CI 47–61%). Fatigue was more common in males than females (RR 1.29, p=0.01), with attenuation of the effect after adjustment for Expanded Disability Status Scale (adjusted RR 1.18, p=0.13). Prevalence of anxiety (but not depression or fatigue) decreased by 8.1% per year of cohort observation (RR 0.92, 95%CI 0.86–0.98, p=0.009), with the effect more pronounced in women (14.6%, RR 0.85, 95%CI 0.79–0.93, –<0.001) than men (2.6%, RR 1.03, 95%CI 0.90–1.17, p=0.77). There was no apparent seasonal variation in the prevalence of any of the three factors (p>0.05). All three factors occurred contemporaneously at cohort entry in a higher proportion of the cohort than expected by chance (p<0.001).
Conclusions:
Anxiety, depression and fatigue are common in PwMS and tend to cluster together. The findings are important for clinical management of PwMS and to the exploration of possible shared causal biological pathways.
Periodontitis is a common chronic inflammatory disease characterised by destruction of the supporting structures of the teeth (the periodontal ligament and alveolar bone). It is highly prevalent ...(severe periodontitis affects 10–15% of adults) and has multiple negative impacts on quality of life. Epidemiological data confirm that diabetes is a major risk factor for periodontitis; susceptibility to periodontitis is increased by approximately threefold in people with diabetes. There is a clear relationship between degree of hyperglycaemia and severity of periodontitis. The mechanisms that underpin the links between these two conditions are not completely understood, but involve aspects of immune functioning, neutrophil activity, and cytokine biology. There is emerging evidence to support the existence of a two-way relationship between diabetes and periodontitis, with diabetes increasing the risk for periodontitis, and periodontal inflammation negatively affecting glycaemic control. Incidences of macroalbuminuria and end-stage renal disease are increased twofold and threefold, respectively, in diabetic individuals who also have severe periodontitis compared to diabetic individuals without severe periodontitis. Furthermore, the risk of cardiorenal mortality (ischaemic heart disease and diabetic nephropathy combined) is three times higher in diabetic people with severe periodontitis than in diabetic people without severe periodontitis. Treatment of periodontitis is associated with HbA
1c
reductions of approximately 0.4%. Oral and periodontal health should be promoted as integral components of diabetes management.
Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. This increased risk cannot be fully explained by classic risk factors. One of the key features of shift workers ...is that their behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in humans. Here we show—by using two 8-d laboratory protocols—that short-term circadian misalignment (12-h inverted behavioral and environmental cycles for three days) adversely affects cardiovascular risk factors in healthy adults. Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, +5.6 mmHg; DBP, +1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, +1.6 mmHg; DBP, +1.4 mmHg). Circadian misalignment decreased wake cardiac vagal modulation by 8–15%, as determined by heart rate variability analysis, and decreased 24-h urinary epinephrine excretion rate by 7%, without a significant effect on 24-h urinary norepinephrine excretion rate. Circadian misalignment increased 24-h serum interleukin-6, C-reactive protein, resistin, and tumor necrosis factor-α levels by 3–29%. We demonstrate that circadian misalignment per se increases blood pressure and inflammatory markers. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk.
The PRISMS taxonomy of self-management support Pearce, Gemma; Parke, Hannah L; Pinnock, Hilary ...
Journal of health services research & policy,
04/2016, Letnik:
21, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Background
Supporting self-management is a core response of health care systems globally to the increasing prevalence of long-term conditions. Lack of a comprehensive taxonomy (or classification) of ...self-management support components hinders characterization and, ultimately, understanding of these frequently complex, multi-component interventions.
Objective
To develop a comprehensive, descriptive taxonomy of self-management support components.
Methods
Components were derived from the 969 unique randomized controlled trials described in the 102 systematic reviews and 61 implementation trials, examining 14 diverse long-term conditions included in the Practical Reviews in Self-Management Support (PRISMS) project followed by discussion at an expert stakeholder workshop. The utility of the taxonomy was then tested using a self-management support intervention for cancer survivors.
Results
The PRISMS taxonomy comprises 14 components that might be used to support self-management (e.g. information about condition/management, provision of equipment, social support), when delivered to someone with a long-term condition or their carer. Overarching dimensions are delivery mode; personnel delivering the support; intervention targeting; and intensity, frequency and duration of the intervention. The taxonomy does not consider the effectiveness or otherwise of the different components or the overarching dimensions.
Conclusions
The PRISMS taxonomy offers a framework to researchers describing self-management support interventions, to reviewers synthesizing evidence and to developers of health services for people with long-term conditions.
To examine whether past and recent sun exposure and vitamin D status (serum 25-hydroxyvitamin D 25(OH)D levels) are associated with risk of first demyelinating events (FDEs) and to evaluate the ...contribution of these factors to the latitudinal gradient in FDE incidence in Australia.
This was a multicenter incident case-control study. Cases (n = 216) were aged 18-59 years with a FDE and resident within one of 4 Australian centers (from latitudes 27°S to 43°S), from November 1, 2003, to December 31, 2006. Controls (n = 395) were matched to cases on age, sex, and study region, without CNS demyelination. Exposures measured included self-reported sun exposure by life stage, objective measures of skin phenotype and actinic damage, and vitamin D status.
Higher levels of past, recent, and accumulated leisure-time sun exposure were each associated with reduced risk of FDE, e.g., accumulated leisure-time sun exposure (age 6 years to current), adjusted odds ratio (AOR) = 0.70 (95% confidence interval CI 0.53-0.94) for each ultraviolet (UV) dose increment of 1,000 kJ/m(2) (range 508-6,397 kJ/m(2)). Higher actinic skin damage (AOR = 0.39 95% CI 0.17-0.92, highest grade vs the lowest) and higher serum vitamin D status (AOR = 0.93 95% CI 0.86-1.00 per 10 nmol/L increase in 25(OH)D) were independently associated with decreased FDE risk. Differences in leisure-time sun exposure, serum 25(OH)D level, and skin type additively accounted for a 32.4% increase in FDE incidence from the low to high latitude regions.
Sun exposure and vitamin D status may have independent roles in the risk of CNS demyelination. Both will need to be evaluated in clinical trials for multiple sclerosis prevention.
Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis ...with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Context.
Future astrophysical surveys such as J-PAS will produce very large datasets, the so-called “big data”, which will require the deployment of accurate and efficient machine-learning (ML) ...methods. In this work, we analyze the miniJPAS survey, which observed about ∼1 deg
2
of the AEGIS field with 56 narrow-band filters and 4
u
g
r
i
broad-band filters. The miniJPAS primary catalog contains approximately 64 000 objects in the
r
detection band (mag
A
B
≲ 24), with forced-photometry in all other filters.
Aims.
We discuss the classification of miniJPAS sources into extended (galaxies) and point-like (e.g., stars) objects, which is a step required for the subsequent scientific analyses. We aim at developing an ML classifier that is complementary to traditional tools that are based on explicit modeling. In particular, our goal is to release a value-added catalog with our best classification.
Methods.
In order to train and test our classifiers, we cross-matched the miniJPAS dataset with SDSS and HSC-SSP data, whose classification is trustworthy within the intervals 15 ≤
r
≤ 20 and 18.5 ≤
r
≤ 23.5, respectively. We trained and tested six different ML algorithms on the two cross-matched catalogs: K-nearest neighbors, decision trees, random forest (RF), artificial neural networks, extremely randomized trees (ERT), and an ensemble classifier. This last is a hybrid algorithm that combines artificial neural networks and RF with the J-PAS stellar and galactic loci classifier. As input for the ML algorithms we used the magnitudes from the 60 filters together with their errors, with and without the morphological parameters. We also used the mean point spread function in the
r
detection band for each pointing.
Results.
We find that the RF and ERT algorithms perform best in all scenarios. When the full magnitude range of 15 ≤
r
≤ 23.5 is analyzed, we find an area under the curve AUC = 0.957 with RF when photometric information alone is used, and AUC = 0.986 with ERT when photometric and morphological information is used together. When morphological parameters are used, the full width at half maximum is the most important feature. When photometric information is used alone, we observe that broad bands are not necessarily more important than narrow bands, and errors (the width of the distribution) are as important as the measurements (central value of the distribution). In other words, it is apparently important to fully characterize the measurement.
Conclusions.
ML algorithms can compete with traditional star and galaxy classifiers; they outperform the latter at fainter magnitudes (
r
≳ 21). We use our best classifiers, with and without morphology, in order to produce a value-added catalog.
Context:
Shift work is a risk factor for diabetes. The separate effects of the endogenous circadian system and circadian misalignment (ie, misalignment between the central circadian pacemaker and ...24-hour environmental/behavioral rhythms such as the light/dark and feeding/fasting cycles) on glucose tolerance in shift workers are unknown.
Objective:
The objective of the study was to test the hypothesis that the endogenous circadian system and circadian misalignment separately affect glucose tolerance in shift workers, both independently from behavioral cycle effects.
Design:
A randomized, crossover study with two 3-day laboratory visits.
Setting:
Center for Clinical Investigation at Brigham and Women's Hospital.
Patients:
Healthy chronic shift workers.
Intervention:
The intervention included simulated night work comprised of 12-hour inverted behavioral and environmental cycles (circadian misalignment) or simulated day work (circadian alignment).
Main Outcome Measures:
Postprandial glucose and insulin responses to identical meals given at 8:00 am and 8:00 pm in both protocols.
Results:
Postprandial glucose was 6.5% higher at 8:00 pm than 8:00 am (circadian phase effect), independent of behavioral effects (P = .0041). Circadian misalignment increased postprandial glucose by 5.6%, independent of behavioral and circadian effects (P = .0042). These variations in glucose tolerance appeared to be explained, at least in part, by different insulin mechanisms: during the biological evening by decreased pancreatic β-cell function (18% lower early and late phase insulin; both P ≤ .011) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 10% higher late phase insulin; P = .015) without change in early-phase insulin (P = .38).
Conclusions:
Internal circadian time affects glucose tolerance in shift workers. Separately, circadian misalignment reduces glucose tolerance in shift workers, providing a mechanism to help explain the increased diabetes risk in shift workers.
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