Highlights • Progress in genetics and proteomics has provided new insights on renal aging. • Renal aging is a multifactorial process involving several key factors. • None of the macroscopic and ...microscopic features of the aging kidney is pathognomonic of aging. • The assessment of renal function in the elderly is problematic and it is still debated whether renal aging should be considered as a physiological or pathological process. • Proper lifestyle modifications currently represent the most plausible approach to maintain kidney health.
Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of ...atherosclerosis remains unknown.
We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries.
The primary outcome, the mean (+/-SE) change in the carotid-artery intima-media thickness, was 0.0058+/-0.0037 mm in the simvastatin-only group and 0.0111+/-0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol level was 192.7+/-60.3 mg per deciliter (4.98+/-1.56 mmol per liter) in the simvastatin group and 141.3+/-52.6 mg per deciliter (3.65+/-1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups.
In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097 ClinicalTrials.gov.).
Homozygous autosomal dominant hypercholesterolaemia (hoADH), an orphan disease caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase ...subtilisin-kexin type 9 (PCSK9), is characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels and high risk for premature cardiovascular disease (CVD). The exact prevalence of molecularly defined hoADH is unknown. Therefore, we investigated the prevalence and phenotypical characteristics of this disease in an open society, i.e. the Netherlands.
The database of the nationwide ADH molecular diagnostic center was queried to identify all molecularly defined hoADH patients. Carriers of non-pathogenic mutations were excluded. Medical records were analysed for data regarding lipid levels and CVD events. Of 104,682 individuals screened for molecular defects, 49 were classified as hoADH (0.05%); 20 were true homozygotes, 25 were compound heterozygotes for LDLR mutations, and 4 were homozygous for APOB mutations. No bi-allelic PCSK9 mutation carriers were identified. Consequently, the prevalence of hoADH was estimated to be ∼1 : 300,000. Mean LDL-C levels prior to lipid-lowering treatment were 12.9 ± 5.1 mmol/L (range 4.4-21.5 mmol/L). Surprisingly, only 50% of the patients met the clinical criteria for hoADH (LDL-C >13.0 mmol/L); 29% of patients suffered from a CVD event.
The prevalence of molecularly defined hoADH is much higher and the clinical phenotype is more variable than previously assumed. In light of the fact that novel therapies are, or will be registered for the treatment of hoADH patients, an uniform definition of hoADH either as a phenotypic or molecular entity is warranted in order to identify patients who are considered to be eligible for these novel agents.
OBJECTIVE:--To investigate the association between serum uric acid level and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS--The population for analysis consisted of 4,536 subjects free from ...diabetes at baseline. During a mean of 10.1 years of follow-up, 462 subjects developed diabetes. RESULTS:--The age- and sex-adjusted hazard ratios (HRs) (95% CIs) for diabetes were 1.30 (0.96-1.76) for the second, 1.63 (1.21-2.19) for the third, and 2.83 (2.13-3.76) for the fourth quartile of serum uric acid, in comparison with the first quartile. After adjustment for BMI, waist circumference, systolic and diastolic blood pressure, and HDL cholesterol, the HRs decreased to 1.08 (0.78-1.49), 1.12 (0.81-1.53), and 1.68 (1.22-2.30), respectively. CONCLUSIONS:--The results of this population-based study suggest that serum uric acid is a strong and independent risk factor for diabetes.
Modern biomarker and translational research as well as personalized health care studies rely heavily on powerful omics’ technologies, including metabolomics and lipidomics. However, to translate ...metabolomics and lipidomics discoveries into a high-throughput clinical setting, standardization is of utmost importance. Here, we compared and benchmarked a quantitative lipidomics platform. The employed Lipidyzer platform is based on lipid class separation by means of differential mobility spectrometry with subsequent multiple reaction monitoring. Quantitation is achieved by the use of 54 deuterated internal standards and an automated informatics approach. We investigated the platform performance across nine laboratories using NIST SRM 1950–Metabolites in Frozen Human Plasma, and three NIST Candidate Reference Materials 8231–Frozen Human Plasma Suite for Metabolomics (high triglyceride, diabetic, and African-American plasma). In addition, we comparatively analyzed 59 plasma samples from individuals with familial hypercholesterolemia from a clinical cohort study. We provide evidence that the more practical methyl-tert-butyl ether extraction outperforms the classic Bligh and Dyer approach and compare our results with two previously published ring trials. In summary, we present standardized lipidomics protocols, allowing for the highly reproducible analysis of several hundred human plasma lipids, and present detailed molecular information for potentially disease relevant and ethnicity-related materials.
Abstract Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature ...coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remain undetected and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors, and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgement and be adjusted for country-specific and local health care needs and resources.
Data are scarce for the lifetime risk of developing impaired glucose metabolism, including prediabetes, as are data for the risk of eventual progression from prediabetes to diabetes and for ...initiation of insulin treatment in previously untreated patients with diabetes. We aimed to calculate the lifetime risk of the full range of glucose impairments, from normoglycaemia to prediabetes, type 2 diabetes, and eventual insulin use.
In this prospective population-based cohort analysis, we used data from the population-based Rotterdam Study. We identified diagnostic events by use of general practitioners' records, hospital discharge letters, pharmacy dispensing data, and serum fasting glucose measurements taken at the study centre (Rotterdam, Netherlands) visits. Normoglycaemia, prediabetes, and diabetes were defined on the basis of WHO criteria for fasting glucose (normoglycaemia: ≤6·0 mmol/L; prediabetes: >6·0 mmol/L and <7·0 mmol/L; and diabetes ≥7·0 mmol/L or use of glucose-lowering drug). We calculated lifetime risk using a modified version of survival analysis adjusted for the competing risk of death. We also estimated the lifetime risk of progression from prediabetes to overt diabetes and from diabetes free of insulin treatment to insulin use. Additionally, we calculated years lived with healthy glucose metabolism.
We used data from 10 050 participants from the Rotterdam Study. During a follow-up of up to 14·7 years (between April 1, 1997, and Jan 1, 2012), 1148 participants developed prediabetes, 828 developed diabetes, and 237 started insulin treatment. At age 45 years, the remaining lifetime risk was 48·7% (95% CI 46·2-51·3) for prediabetes, 31·3% (29·3-33·3) for diabetes, and 9·1% (7·8-10·3) for insulin use. In individuals aged 45 years, the lifetime risk to progress from prediabetes to diabetes was 74·0% (95% CI 67·6-80·5), and 49·1% (38·2-60·0) of the individuals with overt diabetes at this age started insulin treatment. The lifetime risks attenuated with advancing age, but increased with increasing BMI and waist circumference. On average, individuals with severe obesity lived 10 fewer years without glucose impairment compared with normal-weight individuals.
Impaired glucose metabolism is a substantial burden on population health, and our findings emphasise the need for more effective prevention strategies, which should be implemented as soon in a person's life as possible. The substantial lifetime risk of prediabetes and diabetes in lean individuals also supports risk factor control in non-obese individuals.
Erasmus MC and Erasmus University Rotterdam; Netherlands Organisation for Scientific Research; Netherlands Organisation for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Netherlands Ministry of Education, Culture and Science; Netherlands Ministry of Health, Welfare and Sports; European Commission; and Municipality of Rotterdam.
Critical care medicine is a natural environment for machine learning approaches to improve outcomes for critically ill patients as admissions to ICUs generate vast amounts of data. However, ...technical, legal, ethical, and privacy concerns have so far limited the critical care medicine community from making these data readily available. The Society of Critical Care Medicine and the European Society of Intensive Care Medicine have identified ICU patient data sharing as one of the priorities under their Joint Data Science Collaboration. To encourage ICUs worldwide to share their patient data responsibly, we now describe the development and release of Amsterdam University Medical Centers Database (AmsterdamUMCdb), the first freely available critical care database in full compliance with privacy laws from both the United States and Europe, as an example of the feasibility of sharing complex critical care data.
University hospital ICU.
Data from ICU patients admitted between 2003 and 2016.
We used a risk-based deidentification strategy to maintain data utility while preserving privacy. In addition, we implemented contractual and governance processes, and a communication strategy. Patient organizations, supporting hospitals, and experts on ethics and privacy audited these processes and the database.
AmsterdamUMCdb contains approximately 1 billion clinical data points from 23,106 admissions of 20,109 patients. The privacy audit concluded that reidentification is not reasonably likely, and AmsterdamUMCdb can therefore be considered as anonymous information, both in the context of the U.S. Health Insurance Portability and Accountability Act and the European General Data Protection Regulation. The ethics audit concluded that responsible data sharing imposes minimal burden, whereas the potential benefit is tremendous.
Technical, legal, ethical, and privacy challenges related to responsible data sharing can be addressed using a multidisciplinary approach. A risk-based deidentification strategy, that complies with both U.S. and European privacy regulations, should be the preferred approach to releasing ICU patient data. This supports the shared Society of Critical Care Medicine and European Society of Intensive Care Medicine vision to improve critical care outcomes through scientific inquiry of vast and combined ICU datasets.
The risk of premature cardiovascular disease in patients with familial hypercholesterolemia (FH) can be profoundly reduced by cholesterol-lowering therapy, and current guidelines for FH advocate ...ambitious low-density lipoprotein cholesterol (LDL-C) goals. In the present study, we determined whether these goals are reflected in current clinical practice once FH has been diagnosed.
In 2008, we sent questionnaires to all subjects (aged 18-65 years) who were molecularly diagnosed with FH in the year 2006 through the screening program in The Netherlands. Of these 1062 subjects, 781 completed the questionnaire (46% males; mean age: 42+/-12 years; mean LDL-C at molecular diagnosis (baseline): 4.1+/-1.3 mmol/L). The number of persons that used cholesterol-lowering therapy increased from 397 (51%) at baseline to 636 (81%) after diagnosis. Mean treated LDL-C levels decreased significantly to 3.2+/-1.1 mmol/L two years after diagnosis. Only 22% achieved the LDL-C target level of < or = 2.5 mmol/L.
The proportion of patients using cholesterol-lowering medication was significantly increased after FH diagnosis through genetic cascade screening. The attained LDL-C levels were lower than those reported in previous surveys on medication use in FH, which could reflect the effect of more stringent lipid target levels. However, only a minority of the medication users reached the LDL-C target.
Abstract Alterations in cerebral cholesterol metabolism are thought to play a role in the progression of Alzheimer's disease (AD). Liver X receptors (LXRs) are key regulators of cholesterol ...metabolism. The synthetic LXR activator, T0901317 has been reported to improve memory functions in animal models for AD and to reduce amyloid-β (Aβ) deposition in the brain. Here we provide evidence that long-term administration of T0901317 to aged, 21-month-old APPSLxPS1mut mice restores impaired memory. Cerebral cholesterol turnover was enhanced as indicated by the increased levels of brain cholesterol precursors and the upregulation of LXR-target genes Abca1, Abcg1, and Apoe. Unexpectedly, the improved memory functions in the APPSLxPS1mut mice after T0901317 treatment were not accompanied by a decrease in Aβ plaque load in the cortex or hippocampus DG, CA1 or CA3. T0901317 administration also enhanced cerebral cholesterol turnover in aged C57BL/6NCrl mice, but did not further improve their memory functions. In conclusion, long-term activation of the LXR-pathway restored memory functions in aged APPSLxPS1mut mice with advanced Aβ deposition. However the beneficial effects of T0901317 on memory in the APPSLxPS1mut mice were independent of the Aβ plaque load in the hippocampus, but were associated with enhanced brain cholesterol turnover.
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