Circulating interleukin-10 and risk of cardiovascular events: a prospective study in the elderly at risk

<p><b>Objective:</b> The goal of this study was to examine the association of the antiinflammatory interleukin-10 (IL-10) with risk of cardiovascular disease (CVD).</p> <p><b>Methods and Results:</b> In the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) cohort, we related baseline concentrations of circulating IL-10 to risk of CVD events in a nested case (n=819)-control (n=1618) study of 3.2 years of follow-up. Circulating IL-10 showed few strong associations with classical risk factors but was positively correlated with IL-6 and C-reactive protein. IL-10 was positively associated with risk of CVD events (odds ratio [OR] 1.17, 95% CI 1.05 to 1.31 per unit increase in log IL-10) after adjusting for classical risk factors and C-reactive protein. Furthermore, IL-10 was associated more strongly with CVD risk among those with no previous history of CVD (OR 1.42, 95% CI 1.18 to 1.70), compared with those with previous CVD (OR 1.04, 95% CI 0.90 to 1.19; P=0.018). Overall, IL-10 showed a modest ability to add discrimination to classical risk factors (C-statistic +0.005, P=0.002).</p> <p><b>Conclusion:</b> Baseline circulating levels of the antiinflammatory IL-10 are positively associated with risk of CVD among the elderly without prior CVD events, although the association is less evident in those with a history of CVD. Additional epidemiological and mechanistic studies investigating the role of IL-10 in CVD are warranted.</p&gt

Difficulties in recruitment for a randomized controlled trial involving hysterosalpingography

BACKGROUND: The usefulness of hysterosalpingography (HSG) as routine investigation in the fertility work-up prior to laparoscopy and dye had been assessed in a randomized controlled trial. Recruiting subjects to the study was more difficult than anticipated. The objective of this study was to explore possible reasons for non-participation in the trial. METHODS: All newly referred subfertile women admitted to the Reproductive Medicine Clinic of Leiden University Medical Centre between 1 April 1997 and 31 December 1999, were eligible for the study. The reasons for non-participation were evaluated by scrutinizing the medical records. RESULTS: Out of 759 women, a total of 127 (17%) agreed to participate in the trial. The most important reason for non-participation was because of exclusion criteria (73%). Other reasons were inattentive clinicians (3%) and patient-associated reasons (24%). Patient refusal and indecisiveness to enroll in the study were the most common patient-associated reasons. The most frequently stated reason for trial refusal was reluctance to undergo laparoscopy and dye mainly due to issues related to anesthesia and scheduling of procedure. CONCLUSION: Almost three-quarters of recruitment difficulties in this study were due to unavoidable reasons. To overcome the remaining avoidable reasons for non-participation, attention should be paid to appropriate instruction of the study protocol to the participating doctors and to provide adequate information, in layman's terms, to the patients. Reminding patients by notes or telephone calls for attending the clinic are helpful. It may be contingent upon tracing the reasons of clinicians and patients for non-participation to improve enrollment during a trial

Replication of LDL SWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses

<p><b>Background:</b> The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly.</p> <p><b>Methods:</b> The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification.</p> <p><b>Results:</b> Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results.</p> <p><b>Conclusion:</b> With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.</p&gt

Establishing a composite endpoint for measuring the effectiveness of geriatric interventions based on older persons' and informal caregivers' preference weights:a vignette study

Background: The Older Persons and Informal Caregivers Survey Minimal Dataset's (TOPICS-MDS) questionnaire which measures relevant outcomes for elderly people was successfully incorporated into over 60 research projects of the Dutch National Care for the Elderly Programme. A composite endpoint (CEP) for this instrument would be helpful to compare effectiveness of the various intervention projects. Therefore, our aim is to establish a CEP for the TOPICS-MDS questionnaire, based on the preferences of elderly persons and informal caregivers. Methods: A vignette study was conducted with 200 persons (124 elderly and 76 informal caregivers) as raters. The vignettes described eight TOPICS-MDS outcomes of older persons (morbidity, functional limitations, emotional wellbeing, pain experience, cognitive functioning, social functioning, self-perceived health and self-perceived quality of life) and the raters assessed the general well-being (GWB) of these vignette cases on a numeric rating scale (0-10). Mixed linear regression analyses were used to derive the preference weights of the TOPICS-MDS outcomes (dependent variable: GWB scores; fixed factors: the eight outcomes; unstandardized coefficients: preference weights). Results: The mixed regression model that combined the eight outcomes showed that the weights varied from 0.01 for social functioning to 0.16 for self-perceived health. A model that included "informal caregiver" showed that the interactions between this variable and each of the eight outcomes were not significant (p > 0.05). Conclusion: A preference-weighted CEP for TOPICS-MDS questionnaire was established based on the preferences of older persons and informal caregivers. With this CEP optimal comparing the effectiveness of interventions in older persons can be realized

Membrane trafficking in the yeast Saccharomyces cerevisiae model

The yeast Saccharomyces cerevisiae is one of the best characterized eukaryotic models. The secretory pathway was the first trafficking pathway clearly understood mainly thanks to the work done in the laboratory of Randy Schekman in the 1980s. They have isolated yeast sec mutants unable to secrete an extracellular enzyme and these SEC genes were identified as encoding key effectors of the secretory machinery. For this work, the 2013 Nobel Prize in Physiology and Medicine has been awarded to Randy Schekman; the prize is shared with James Rothman and Thomas Sudhof. Here, we present the different trafficking pathways of yeast S. cerevisiae. At the Golgi apparatus newly synthesized proteins are sorted between those transported to the plasma membrane (PM), or the external medium, via the exocytosis or secretory pathway (SEC), and those targeted to the vacuole either through endosomes (vacuolar protein sorting or VPS pathway) or directly (alkaline phosphatase or ALP pathway). Plasma membrane proteins can be internalized by endocytosis (END) and transported to endosomes where they are sorted between those targeted for vacuolar degradation and those redirected to the Golgi (recycling or RCY pathway). Studies in yeast S. cerevisiae allowed the identification of most of the known effectors, protein complexes, and trafficking pathways in eukaryotic cells, and most of them are conserved among eukaryotes

SUBCLINICAL THYROID DISORDERS AND COGNITIVE DECLINE IN OLD AGE: RESULTS FROM THE PROSPER STUDY

Pathophysiology, epidemiology and therapy of agein

Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

<p><b>Background:</b> Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke.</p> <p><b>Methods and Findings:</b> In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), baseline inflammatory markers in up to 5,680 men and women aged 70-82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672]), fatal CVD (n = 190), death from other CV causes (n = 38), and non-CVD mortality (n = 300), over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis) more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit increase in IL-6 1.75, 95% confidence interval [CI] 1.44-2.12) than with risk of nonfatal CVD (1.17, 95% CI 1.04-1.31), in analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction). The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001) improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20).</p> <p><b>Conclusions:</b> In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.</p&gt

Subclinical thyroid dysfunction and cognitive decline in old age

<p>Background: Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).</p> <p>Methods: Prospective longitudinal study of men and women aged 70–82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) <0.45 mU/L or >4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests.</p> <p>Results: Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up.</p> <p>Conclusion: We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.</p&gt