Circulating cell-free DNA is associated with mortality and inflammatory markers in nonagenarians: the Vitality 90+ Study

Aging is characteristically accompanied by a low-grade inflammatory state and increased cellular death. In this study, we analyzed the associations between the plasma cell-free DNA (cf-DNA) level and immunoinflammatory factors and 4-year mortality. The distribution of qualitative cf-DNA patterns in relation to the total cf-DNA concentration and the antinuclear antibody (ANA) serostatus was also evaluated. The study population consisted of n=258 nonagenarians who were participants in the Vitality 90+ Study. Cf-DNA levels were positively correlated with the C-reactive protein (CRP) level, the interleukin-1 receptor antagonist (IL-1ra) level, the serum amyloid A (SAA) level and the indoleamine 2,3-dioxygenase enzyme activity (IDO), weight and chair-stand test time and inversely correlated with the HDL cholesterol level. The total cf-DNA concentration also remained as an independent predictor of 4-year all-cause mortality. A predominance of low-molecular-weight cf-DNA was observed in ANA-seropositive subjects but this cf-DNA pattern was not associated with mortality. The cf-DNA concentration could thus represent a novel biomarker for systemic inflammation and mortality in the elderly.     

Factors associated with objectively measured physical activity and sedentary time of 5–6-year-old children in the STEPS Study

Background: The factors associated with preschool-aged children’s physical activity (PA) remains unclear. The aim of this cross-sectional study was to examine how different factors were associated with preschool-aged children’s objectively measured PA and sedentary time. Methods: The study population was 5–6-year-old children (n?=?140) and their parents (n?=?138) from the STEPS Study in Turku in Southwest Finland in 2013–2014. PA and sedentary time were measured objectively by accelerometers from children and parents and body mass index with Tanita scale. Other factors (siblings, day care, organized PA and parents’ education) were collected with questionnaires. Linear models were conducted. Results: Child’s PA was positively associated with mother’s PA and day care attendance. Child’s sedentary time was positively associated with mother’s sedentary time. Father’s PA and sedentary time were associated with respective variables in children, but only among fathers with high education. Conclusion: Parental role modelling is essential in developing child’s physically active and less sedentary lifestyle.     

The trajectory of the blood DNA methylome ageing rate is largely set before adulthood: evidence from two longitudinal studies

The epigenetic clock, defined as the DNA methylome age (DNAmAge), is a candidate biomarker of ageing. In this study, we aimed to characterize the behaviour of this marker during the human lifespan in more detail using two follow-up cohorts (the Young Finns study, calendar age i.e. cAge range at baseline 15–24 years, 25-year-follow-up, N = 183; The Vitality 90+ study, cAge range at baseline 19–90 years, 4-year-follow-up, N = 48). We also aimed to assess the relationship between DNAmAge estimate and the blood cell distributions, as both of these measures are known to change as a function of age. The subjects’ DNAmAges were determined using Horvath’s calculator of epigenetic cAge. The estimate of the DNA methylome age acceleration (Δ-cAge-DNAmAge) demonstrated remarkable stability in both cohorts: the individual rank orders of the DNAmAges remained largely unchanged during the follow-ups. The blood cell distributions also demonstrated significant intra-individual correlation between the baseline and follow-up time points. Interestingly, the immunosenescence-associated features (CD8+CD28? and CD4+CD28? cell proportions and the CD4/CD8 cell ratio) were tightly associated with the estimate of the DNA methylome age. In summary, our data demonstrate that the general level of Δ-cAge-DNAmAge is fixed before adulthood and appears to be quite stationary thereafter, even in the oldest-old ages. Moreover, the blood DNAmAge estimate seems to be tightly associated with ageing-associated shifts in blood cell composition, especially with those that are the hallmarks of immunosenescence. Overall, these observations contribute to the understanding of the longitudinal aspects of the DNAmAge estimate.     

CRP gene is involved in the regulation of human longevity: a follow-up study in Finnish nonagenarians

Chronic low-grade inflammation is involved in the pathogenesis of many disease conditions in humans and it is frequently quantified by measuring the blood concentration of C-reactive protein (CRP). Here we show that the CRP concentration in old people (nonagenarians) is, at least partially, genetically determined, and that the high producer genotype is associated with a shorter life expectancy during follow-up. Thus, the data imply that the CRP gene may be a longevity gene in humans.     

Indoleamine 2,3-dioxygenase activity is increased in patients with systemic lupus erythematosus and predicts disease activation in the sunny season

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme which suppresses T lymphocyte activity. IDO activity can be determined by relating kynurenine, the main metabolite of tryptophan, to tryptophan (kyn/trp). We have demonstrated recently that systemic lupus erythematosus (SLE) is activated during the sunny season as measured by the European Consensus Lupus Activity Measurement Index (ECLAM) activity score. Our aim here was to establish whether IDO-dependent mechanisms are involved in the activation process of SLE. Kyn/trp was measured by reverse-phase high-performance liquid chromatography (HPLC) in 33 (30 female, three male) SLE patients in winter, spring and summer and in 309 healthy control subjects. At the same time-points the SLE patients were examined by a rheumatologist and a dermatologist and the activity of SLE assessed by the ECLAM score. IDO activity was higher in SLE patients than in healthy subjects. There was no seasonal variation in IDO activity in SLE patients and it did not correlate with the ECLAM activity score in winter. However, there was a significant correlation between IDO activity and the ECLAM score both in spring and in summer. High IDO activity in winter predicted subsequent activation of SLE in spring and summer. Our results indicate that IDO-dependent immunosuppressive mechanisms are activated in SLE patients. Exposure to sunlight or another factor causing seasonal variation in SLE activity leads to insufficiency of this suppression in a subgroup of patients, causing activation of SLE. High IDO activity in winter predicts activation of SLE in the sunny season.     

Autoimmunity and atherosclerosis: functional polymorphism of PTPN22 is associated with phenotypes related to the risk of atherosclerosis. The Cardiovascular Risk in Young Finns Study

There is a growing body of evidence attesting the significance of inflammation in the pathogenesis of atherosclerosis. Protein tyrosine phosphate PTPN22 C/T single nucleotide polymorphism (SNP) at + 1858 has been identified recently as a susceptibility factor for various inflammatory autoimmune diseases. We hypothesized that data on the genetic polymorphism of the PTPN22 enzyme associated with an increased risk of autoimmunity could also provide insight into the possible role of autoimmunity in the pathogenesis of atherosclerosis. Therefore we analysed the PTPN22 + 1858 C/T polymorphism in a population of young Finnish adults (n = 2268) for whom data on carotid artery intima-media thickness (IMT), a presymptomatic predictor of atherosclerosis, and risk factors for atherosclerosis were available. In males carriage of the T allele of PTPN22 + 1858 was associated significantly with IMT in univariate and multivariate analyses, while in females it was associated with several risk factors for atherosclerosis (BMI, waist circumference, waist-to-hip ratio, serum concentrations of C-reactive protein and triglycerides) but not with IMT. Our results indicate that the genetic polymorphism of PTPN22 + 1858 known to predispose to autoimmunity also enhances the development of atherosclerosis and thereby links the genetics of autoimmunity and atherosclerosis.     

Altered expression of p120catenin predicts poor outcome in invasive breast cancer

Purpose  

The study focuses on p120catenin, a regulator of cell adhesion, which has previously been described in many malignancies and suggested with a role in invasion and metastatic behaviour. In this study, we investigate the role of altered immunoexpression of p120catenin isoforms in the prognosis of invasive breast cancer (n = 351).     

Electronic medical records for appropriate timing of arthroplasty

Objective The objective of this study was to analyse whether electronic medical records (EMRs) of total hip and knee arthroplasty can be used to manage the optimal time of surgery. Design Retrospective registry study. Setting Data on waiting time for operation, age, gender, body mass index (BMI), operable condition pre‐operatively and the functional scores at 3 and 12 months after arthroplasty were obtained from EMRs and from an electronic implant database. Participants The participants of the study were 162 arthroplasty patients. Results An increase in waiting time of hip patients decreased significantly the change in functional scores at 3 months (P = 0.006, n = 56). The score reductions of older patients were more marked than of younger patients and of patients of normal weight compared with overweight patients. In patients undergoing knee arthroplasty, the association between a longer waiting time and profound change in functional score was statistically significant after 1 year (P = 0.03, n = 75). After adjustment of the results for pre‐operative scores, age group, BMI class, American Society of Anesthesiologists class and gender, the waiting time turned out to affect only the scores of patients undergoing hip arthroplasty at 3 months post‐operatively. Conclusions Data from electronic patient entries complemented with data of the operable condition can be used for defining the optimal operation time with regard to the pre‐operative condition of the patients. The implication of prolonged waiting times was not very profound, but elderly patients benefit from a short waiting time.     

Increase in plasma proinflammatory cytokines after electroconvulsive therapy in patients with depressive disorder

OBJECTIVES: Electroconvulsive therapy (ECT) is regarded as an effective treatment of drug-resistant depression, but its mechanism of action is mostly unknown. We have previously reported that epileptic seizures result in cerebral production of cytokines, which are also reflected in the plasma. In this study, we tested whether ECT is associated with similar acute release of cytokines. METHODS: The plasma levels of cytokines interleukin (IL) 1beta, IL-1 receptor antagonist, and IL-6 were measured using enzyme-linked immunosorbent assay at several time points after ECT. The study included 9 patients who met the diagnostic criteria of major depression (mean age, 55 years; mean Montgomery-Asberg Depression Rating Scale score, 30). RESULTS: Our results demonstrate that cytokines IL-1beta and IL-6 are increased at 3- and 6-hour time points after ECT. IL-6 release also correlated to the stimulus dose used, suggesting neuronal depolarization as a mechanism of cytokine release. CONCLUSIONS: These results indicate that ECT is associated with rapid induction of inflammatory cytokines most likely in the central nervous system, which are also measurable in the peripheral blood.     

Indoleamine 2,3-dioxygenase activity associates with cardiovascular risk factors: the Health 2000 study

Indoleamine 2,3-dioxygenase (IDO) is an important immunomodulator suppressing the activation of T lymphocytes, and its level in blood is increased in several autoimmune and inflammatory diseases. We have previously shown that this activity associates with several signs and risk factors of atherosclerosis in 24 to 39-year-old females. Now we repeat this analysis in an older population (n = 921, age range 46-76 years), i.e. in a population with more advanced atherosclerosis. IDO activity had a significant positive correlation in both sexes with carotid artery intima/media thickness (IMT), an early marker of atherosclerosis. In females, a significant negative correlation with HDL cholesterol and a positive correlation with triglycerides levels was observed. The association with IMT did not remain significant after adjustment with classical risk factors of atherosclerosis. It is thus concluded that IDO is a sensitive marker of atherosclerosis--or the inflammatory response associated with it--but does not have an independent role in the pathogenesis of this disease.