| 1. |
- Clarke, R., et al.
(författare)
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Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals
- 2014
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165. ; 100:2, s. 657-666
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Tidskriftsartikel (refereegranskat)abstract
- Background: Elevated plasma homocysteine is a risk factor for Alzheimer disease, but the relevance of homocysteine lowering to slow the rate of cognitive aging is uncertain. Objective: The aim was to assess the effects of treatment with B vitamins compared with placebo, when administered for several years, on composite domains of cognitive function, global cognitive function, and cognitive aging. Design: A meta-analysis was conducted by using data combined from 11 large trials in 22,000 participants. Domain-based z scores (for memory, speed, and executive function and a domain-composite score for global cognitive function) were available before and after treatment (mean duration: 2.3 y) in the 4 cognitive-domain trials (1340 individuals); Mini-Mental State Examination (MMSE) type tests were available at the end of treatment (mean duration: 5 y) in the 7 global cognition trials (20,431 individuals). Results: The domain-composite and MMSE-type global cognitive function z scores both decreased with age (mean SE: 0.054 0.004 and 0.036 0.001/y, respectively). Allocation to B vitamins lowered homocysteine concentrations by 28% in the cognitive-domain trials but had no significant effects on the z score differences from baseline for individual domains or for global cognitive function (z score difference: 0.00; 95% CI: 0.05, 0.06). Likewise, allocation to B vitamins lowered homocysteine by 26% in the global cognition trials but also had no significant effect on end-treatment MMSE-type global cognitive function (z score difference: 0.01; 95% CI: 0.03, 0.02). Overall, the effect of a 25% reduction in homocysteine equated to 0.02 y (95% CI: 0.10, 0.13 y) of cognitive aging per year and excluded reductions of >1 mo per year of treatment. Conclusion: Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging.
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| 2. |
- Peden, John F., et al.
(författare)
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A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:4, s. 339-344
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified 11 common variants convincingly associated with coronary artery disease (CAD)(1-7), a modest number considering the apparent heritability of CAD(8). All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with similar to 575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5 x 10(-8) in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis expression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility.
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| 3. |
- Alfirevic, A., et al.
(författare)
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Phenotype Standardization for Statin-Induced Myotoxicity
- 2014
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 96:4, s. 470-476
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Forskningsöversikt (refereegranskat)abstract
- Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.
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| 4. |
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| 5. |
- Armitage, Emily G, et al.
(författare)
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Time-of-flight SIMS as a novel approach to unlocking the hypoxic properties of cancer
- 2013
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Ingår i: Surface and Interface Analysis. - 1096-9918 .- 0142-2421. ; 45:1, s. 282-285
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Tidskriftsartikel (refereegranskat)abstract
- It is known that hypoxia-inducible factor 1 (HIF-1) activity results in the coordinated up-regulation of a large number of proteins that facilitate cell survival in tumours; however, the effect of HIF-1 on cancer metabolism is less well characterised. With knowledge of the specific effect of HIF-1 on cancer metabolism, biomarkers could be identified for which new drugs could be targeted. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) offers the potential to analyse intact cells in situ and has a mass spectral coverage that is applicable to metabolic profiling. It has been used to analyse the effects of HIF-1 on multicellular tumour models. Multicellular tumour spheroids (MTSs) have been cultured from human colon carcinoma cells with and without the expression of HIF-1, and the surface of the cross sections of each MTS has been analysed. Because metabolic profiling is an emerging field in ToF-SIMS, there is a requirement to determine which metabolites can be detected using this technique and which of those can be identified in complex mixtures within biological samples. For this, a selection of metabolites have been analysed, and the ToF-SIMS standard spectra acquired have been used to localise metabolites in MTS sections. The comparison of metabolic profiles of MTSs with and without the expression of HIF-1 has elucidated potential biomarkers for tumour survival in hypoxia, some of which may be HIF-1 regulated.
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| 6. |
- Baigent, Colin, et al.
(författare)
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The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection) : a randomised placebo-controlled trial
- 2011
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 377:9784, s. 2181-2192
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Tidskriftsartikel (refereegranskat)abstract
- Background Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. Methods This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and I SRCTN54137607. Findings 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0.85 mmol/L (SE 0.02; with about two-thirds compliance) during a median follow-up of 4.9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11.3%] simvastatin plus ezetimibe vs 619 [13.4%] placebo; rate ratio [RR] 0.83, 95% CI 0.74-0.94; log-rank p=0.0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4.6%] vs 230 [5.0%]; RR 0.92,95% CI 0.76-1.11; p=0.37) and there were significant reductions in non-haemorrhagic stroke (131 [2.8%] vs 174 [3.8%]; RR 0.75,95% CI 0.60-0.94; p=0.01) and arterial revascularisation procedures (284 [6.1%] vs 352 [7.6%]; RR 0.79, 95% CI 0.68-0.93; p=0.0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0.2%] vs 5 [0.1%]). There was no evidence of excess risks of hepatitis (21 [0.5%] vs 18 [0.4%]), gallstones (106 [2.3%] vs 106 [2.3%]), or cancer (438 [9.4%] vs 439 [9.5%], p=0.89) and there was no significant excess of death from any non-vascular cause (668 [14.4%] vs 612 [13.2%], p=0.13). Interpretation Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.
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| 7. |
- Kotze, Helen L., et al.
(författare)
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ToF-SIMS as a tool for metabolic profiling small biomolecules in cancer systems
- 2013
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Ingår i: Surface and Interface Analysis. - 1096-9918 .- 0142-2421. ; 45:1, s. 277-281
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Tidskriftsartikel (refereegranskat)abstract
- Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is emerging as a tool for studying the metabolism of disease. ToF-SIMS enables chemical specificity in addition to high spatial resolution imaging of biological samples from cells to tissue. Here, ToF-SIMS has been used to investigate the metabolic regulation of hypoxia-induced chemoresistance to doxorubicin treatment using multicellular tumour spheroids. Imaging principal component analysis (PCA) was used as a tool to identify the regions of chemistry present within the image that differ as a result of drug treatment. A series of metabolite ToF-SIMS spectra were acquired, which were used to identify quasi-molecular ions and fragments correlated to the PCA loading plots. Metabolite patterns have been identified as potential biomarkers of hypoxia-induced chemoresistance.
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| 8. |
- MacLeod, Matthew, et al.
(författare)
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BETR global - A geographically-explicit global-scale multimedia contaminant fate model
- 2011
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Ingår i: Environmental Pollution. - : Elsevier BV. - 0269-7491 .- 1873-6424. ; 159:5, s. 1442-1445
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Tidskriftsartikel (refereegranskat)abstract
- We present two new software implementations of the BETR Global multimedia contaminant fate model. The model uses steady-state or non-steady-state mass-balance calculations to describe the fate and transport of persistent organic pollutants using a desktop computer. The global environment is described using a database of long-term average monthly conditions on a 15 degrees x 15 degrees grid. We demonstrate BETR Global by modeling the global sources, transport, and removal of decamethylcyclopentasiloxane (D5).
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