Inflammation and premature aging in advanced chronic kidney disease

Systemic inflammation in end-stage renal disease (ESRD) is an established risk factor for mortality and a catalyst for other complications which are related to a premature aging phenotype, including muscle wasting, vascular calcification and other forms of premature vascular disease, depression, osteoporosis and frailty. Uremic inflammation is also mechanistically related to mechanisms involved in the aging process, such as telomere shortening, mitochondrial dysfunction, and altered nutrient sensing, which can have direct effect on cellular and tissue function. In addition to uremia-specific causes such as abnormalities in the phosphate- Klotho axis, there are remarkable similarities between the pathophysiology of uremic inflammation and so-called "inflammaging" in the general population. Potentially relevant, but still somewhat unexplored in this respect are abnormal or misplaced protein structures as well as abnormalities in tissue homeostasis, which evoke danger signals through damage associated molecular patters (DAMPS) as well as the senescence associated secretory phenotype (SASP). Systemic inflammation, in combination with the loss of kidney function, can impair the resilience of the body to external and internal stressors by reduced functional and structural tissue reserve, and by impairing normal organ crosstalk, thus providing an explanation for the greatly increased risk of homeostatic breakdown in this population. In this review, the relation between uremic inflammation and a premature aging phenotype, as well as potential causes and consequences are discussed

Socio-economic status influences the relationship between obesity and antenatal depression: Data from a prospective cohort study

Background Obesity has been associated with increased risk of antenatal depression, but little is known about this relationship. This study tested whether socio-economic status (SES) influences the relationship between obesity and antenatal depression. Methods Data were taken from the Screening for Pregnancy Endpoints (SCOPE) cohort. BMI was calculated from measured height and weight at 15±1 weeks' gestation. Underweight women were excluded. SES was indicated by self-reported household income (dichotomised around the median: low SES ≤£45,000; high SES >£45,000). Antenatal depression was defined as scoring ≥13 on the Edinburgh Postnatal Depression Scale at both 15±1 and 20±1 weeks' gestation, to identify persistently elevated symptoms of depression. Results Five thousand five hundred and twenty two women were included in these analyses and 5.5% had persistently elevated antenatal depression symptoms. There was a significant interaction between SES and BMI on the risk of antenatal depression (p=0.042). Among high SES women, obese women had approximately double the odds of antenatal depression than normal weight controls (AOR 2.11, 95%CI 1.16–3.83, p=0.014, adjusted for confounders). Among low SES women there was no association between obesity and antenatal depression. The interaction effect was robust to alternative indicators of SES in sensitivity analyses. Limitations 1) Antenatal depression was assessed with a self-reported screening measure; and 2) potential mediators such as stigma and poor body-image could not be examined. Conclusions Obesity was only associated with increased risk of antenatal depression among high SES women in this sample. Healthcare professionals should be aware that antenatal depression is more common among low SES women, regardless of BMI category

Prevalence and predictors of alcohol use during pregnancy: findings from international multicentre cohort studies

Objectives To compare the prevalence and predictors of alcohol use in multiple cohorts. Design Cross-cohort comparison of retrospective and prospective studies. Setting Population-based studies in Ireland, the UK, Australia and New Zealand. Participants 17 244 women of predominantly Caucasian origin from two Irish retrospective studies (Growing up in Ireland (GUI) and Pregnancy Risk Assessment Monitoring System Ireland (PRAMS Ireland)), and one multicentre prospective international cohort, Screening for Pregnancy Endpoints (SCOPE) study. Primary and secondary outcome measures Prevalence of alcohol use pre-pregnancy and during pregnancy across cohorts. Sociodemographic factors associated with alcohol consumption in each cohort. Results Alcohol consumption during pregnancy in Ireland ranged from 20% in GUI to 80% in SCOPE, and from 40% to 80% in Australia, New Zealand and the UK. Levels of exposure also varied substantially among drinkers in each cohort ranging from 70% consuming more than 1–2 units/week in the first trimester in SCOPE Ireland, to 46% and 15% in the retrospective studies. Smoking during pregnancy was the most consistent predictor of gestational alcohol use in all three cohorts, and smokers were 17% more likely to drink during pregnancy in SCOPE, relative risk (RR)=1.17 (95% CI 1.12 to 1.22), 50% more likely to drink during pregnancy in GUI, RR=1.50 (95% CI 1.36 to 1.65), and 42% more likely to drink in PRAMS, RR=1.42 (95% CI 1.18 to 1.70). Conclusions Our data suggest that alcohol use during pregnancy is prevalent and socially pervasive in the UK, Ireland, New Zealand and Australia. New policy and interventions are required to reduce alcohol prevalence both prior to and during pregnancy. Further research on biological markers and conventions for measuring alcohol use in pregnancy is required to improve the validity and reliability of prevalence estimates

Economic evaluation of day hospital versus intensive outpatient mentalization-based treatment alongside a randomized controlled trial with 36-month follow-up

Mentalization-based treatment (MBT) has demonstrated robust effectiveness in the treatment of borderline personality disorder (BPD) in both day hospital (MBT-DH) and intensive outpatient MBT (MBT-IOP) programs. Given the large differences in intensity and associated treatment costs, there is a need for studies comparing their cost-effectiveness. A health economic evaluation of MBT-DH versus MBT-IOP was performed alongside a multicenter randomized controlled trial with a 36-month follow-up. In three mental health-care institutions in the Netherlands, 114 patients were randomly allocated to MBT-DH (n = 70) or MBT-IOP (n = 44) and assessed every 6 months. Societal costs were compared with quality-adjusted life years (QALYs) gained and the number of months in remission over 36 months. The QALY gains over 36 months were 1.96 (SD = 0.58) for MBT-DH and 1.83 (SD = 0.56) for MBT-IOP; the respective number of months in remission were 16.0 (SD = 11.5) and 11.1 (SD = 10.7). Societal costs were €106,038 for MBT-DH and €91,368 for MBT-IOP. The incremental cost for one additional QALY with MBT-DH compared with MBT-IOP was €107,000. The incremental cost for 1 month in remission was almost €3000. Assuming a willingness-to-pay threshold of €50,000 for a QALY, there was a 33% likelihood that MBT-DH is more cost-effective than MBT-IOP in terms of costs per QALY. Although MBT-DH leads to slightly more QALYs and remission months, it is probably not cost-effective when compared with MBT-IOP for BPD patients, as the small additional health benefits in MBT-DH did not outweigh the substantially higher societal costs

Possible Beneficial Effect of Exercise, by Reducing Oxidative Stress, on the Incidence of Preeclampsia

We hypothesize that regular exercise enhances antioxidative enzymes in pregnant women, which reduce oxidative stress and, thus, the incidence of preeclampsia. Oxidative stress with enhanced lipid peroxide formation could lead to endothelial dysfunction in preeclampsia. Other conditions, such as increased transferrin saturation and decreased iron-binding capacity, directly and indirectly promote the process of oxidative stress and subsequent endothelial dysfunction. Exercise increases oxidative metabolism and produces a prooxidant environment. This acidic environment during exercise (at or beyond anaerobic threshold) promotes oxygen release from hemoglobin and increases in PO2 in tissues, as well as releases iron from transferrin. When exercise is repeated regularly, the body promptly adjusts so that oxidative stress is eliminated or reduced. The body's adaptations to a regular exercise habit seem to have an antioxidant effect. In humans, training effects have been identified with an enhanced activity of antioxidative enzymes. Another concerted adaptation that regular exercise brings to women's bodies is resistance against production of prooxidants by increasing the number of mitochondria. Equally important is a training effect that decreases susceptibility to lipid peroxidation. Evidence suggests that physically active women are less likely to develop preeclampsia. In theory, intracellular and extracellular conditions resulting from regular exercise should counteract the enhancement of oxidative stress, thus interfering with the process leading to endothelial dysfunction. This position paper describes a hypothesis and includes a brief review of exercise physiology and biochemical research in preeclampsia. Unlike other preventive treatments, such as aspirin or calcium supplements, a regular exercise habit leads to a positive and healthy lifestyle without concern of side effects.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63167/1/152460901317193558.pd

Principles of meiotic chromosome assembly revealed in S. cerevisiae

During meiotic prophase, chromosomes organise into a series of chromatin loops emanating from a proteinaceous axis, but the mechanisms of assembly remain unclear. Here we use Saccharomyces cerevisiae to explore how this elaborate three-dimensional chromosome organisation is linked to genomic sequence. As cells enter meiosis, we observe that strong cohesin-dependent grid-like Hi-C interaction patterns emerge, reminiscent of mammalian interphase organisation, but with distinct regulation. Meiotic patterns agree with simulations of loop extrusion with growth limited by barriers, in which a heterogeneous population of expanding loops develop along the chromosome. Importantly, CTCF, the factor that imposes similar features in mammalian interphase, is absent in S. cerevisiae, suggesting alternative mechanisms of barrier formation. While grid-like interactions emerge independently of meiotic chromosome synapsis, synapsis itself generates additional compaction that matures differentially according to telomere proximity and chromosome size. Collectively, our results elucidate fundamental principles of chromosome assembly and demonstrate the essential role of cohesin within this evolutionarily conserved process

Clinical risk factors of colorectal cancer in patients with serrated polyposis syndrome: a multicentre cohort analysis

OBJECTIVE: Serrated polyposis syndrome (SPS) is accompanied by an increased risk of colorectal cancer (CRC). Patients fulfilling the clinical criteria, as defined by the WHO, have a wide variation in CRC risk. We aimed to assess risk factors for CRC in a large cohort of patients with SPS and to evaluate the risk of CRC during surveillance. DESIGN: In this retrospective cohort analysis, all patients with SPS from seven centres in the Netherlands and two in the UK were enrolled. WHO criteria were used to diagnose SPS. Patients who only fulfilled WHO criterion-2, with IBD and/or a known hereditary CRC syndrome were excluded. RESULTS: In total, 434 patients with SPS were included for analysis; 127 (29.3%) were diagnosed with CRC. In a per-patient analysis ≥1 serrated polyp (SP) with dysplasia (OR 2.07; 95% CI 1.28 to 3.33), ≥1 advanced adenoma (OR 2.30; 95% CI 1.47 to 3.67) and the fulfilment of both WHO criteria 1 and 3 (OR 1.60; 95% CI 1.04 to 2.51) were associated with CRC, while a history of smoking was inversely associated with CRC (OR 0.36; 95% CI 0.23 to 0.56). Overall, 260 patients underwent surveillance after clearing of all relevant lesions, during which two patients were diagnosed with CRC, corresponding to 1.9 events/1000 person-years surveillance (95% CI 0.3 to 6.4). CONCLUSION: The presence of SPs containing dysplasia, advanced adenomas and/or combined WHO criteria 1 and 3 phenotype is associated with CRC in patients with SPS. Patients with a history of smoking show a lower risk of CRC, possibly due to a different pathogenesis of disease. The risk of developing CRC during surveillance is lower than previously reported in literature, which may reflect a more mature multicentre cohort with less selection bias

Metabolic syndrome in pregnancy and risk for adverse pregnancy outcomes: A prospective cohort of nulliparous women

Background: Obesity increases the risk for developing gestational diabetes mellitus (GDM) and preeclampsia (PE), which both associate with increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) in women in later life. In the general population, metabolic syndrome (MetS) associates with T2DM and CVD. The impact of maternal MetS on pregnancy outcomes, in nulliparous pregnant women, has not been investigated. Methods and findings: Low-risk, nulliparous women were recruited to the multi-centre, international prospective Screening for Pregnancy Endpoints (SCOPE) cohort between 11 November 2004 and 28 February 2011. Women were assessed for a range of demographic, lifestyle, and metabolic health variables at 15 ± 1 weeks’ gestation. MetS was defined according to International Diabetes Federation (IDF) criteria for adults: waist circumference ≥80 cm, along with any 2 of the following: raised trigycerides (≥1.70 mmol/l [≥150 mg/dl]), reduced high-density lipoprotein cholesterol (<1.29 mmol/l [<50 mg/dl]), raised blood pressure (BP) (i.e., systolic BP ≥130 mm Hg or diastolic BP ≥85 mm Hg), or raised plasma glucose (≥5.6 mmol/l). Log-binomial regression analyses were used to examine the risk for each pregnancy outcome (GDM, PE, large for gestational age [LGA], small for gestational age [SGA], and spontaneous preterm birth [sPTB]) with each of the 5 individual components for MetS and as a composite measure (i.e., MetS, as defined by the IDF). The relative risks, adjusted for maternal BMI, age, study centre, ethnicity, socioeconomic index, physical activity, smoking status, depression status, and fetal sex, are reported. A total of 5,530 women were included, and 12.3% (n = 684) had MetS. Women with MetS were at an increased risk for PE by a factor of 1.63 (95% CI 1.23 to 2.15) and for GDM by 3.71 (95% CI 2.42 to 5.67). In absolute terms, for PE, women with MetS had an adjusted excess risk of 2.52% (95% CI 1.51% to 4.11%) and, for GDM, had an adjusted excess risk of 8.66% (95% CI 5.38% to 13.94%). Diagnosis of MetS was not associated with increased risk for LGA, SGA, or sPTB. Increasing BMI in combination with MetS increased the estimated probability for GDM and decreased the probability of an uncomplicated pregnancy. Limitations of this study are that there are several different definitions for MetS in the adult population, and as there are none for pregnancy, we cannot be sure that the IDF criteria are the most appropriate definition for pregnancy. Furthermore, MetS was assessed in the first trimester and may not reflect pre-pregnancy metabolic health status. Conclusions: We did not compare the impact of individual metabolic components with that of MetS as a composite, and therefore cannot conclude that MetS is better at identifying women at risk. However, more than half of the women who had MetS in early pregnancy developed a pregnancy complication compared with just over a third of women who did not have MetS. Furthermore, while increasing BMI increases the probability of GDM, the addition of MetS exacerbates this probability. Further studies are required to determine if individual MetS components act synergistically or independently

Enrichment analysis of Alu elements with different spatial chromatin proximity in the human genome

Transposable elements (TEs) have no longer been totally considered as “junk DNA” for quite a time since the continual discoveries of their multifunctional roles in eukaryote genomes. As one of the most important and abundant TEs that still active in human genome, Alu, a SINE family, has demonstrated its indispensable regulatory functions at sequence level, but its spatial roles are still unclear. Technologies based on 3C(chromosomeconformation capture) have revealed the mysterious three-dimensional structure of chromatin, and make it possible to study the distal chromatin interaction in the genome. To find the role TE playing in distal regulation in human genome, we compiled the new released Hi-C data, TE annotation, histone marker annotations, and the genome-wide methylation data to operate correlation analysis, and found that the density of Alu elements showed a strong positive correlation with the level of chromatin interactions (hESC: r=0.9, P<2.2×1016; IMR90 fibroblasts: r = 0.94, P < 2.2 × 1016) and also have a significant positive correlation withsomeremote functional DNA elements like enhancers and promoters (Enhancer: hESC: r=0.997, P=2.3×10−4; IMR90: r=0.934, P=2×10−2; Promoter: hESC: r = 0.995, P = 3.8 × 10−4; IMR90: r = 0.996, P = 3.2 × 10−4). Further investigation involving GC content and methylation status showed the GC content of Alu covered sequences shared a similar pattern with that of the overall sequence, suggesting that Alu elements also function as the GC nucleotide and CpG site provider. In all, our results suggest that the Alu elements may act as an alternative parameter to evaluate the Hi-C data, which is confirmed by the correlation analysis of Alu elements and histone markers. Moreover, the GC-rich Alu sequence can bring high GC content and methylation flexibility to the regions with more distal chromatin contact, regulating the transcription of tissue-specific genes

Vitality and the course of limitations in activities in osteoarthritis of the hip or knee

<p>Abstract</p> <p>Background</p> <p>The objective of the study was to determine whether psychological and social factors predict the course of limitations in activities in elderly patients with osteoarthritis of the hip or knee, in addition to established somatic and cognitive risk factors.</p> <p>Methods</p> <p>A longitudinal cohort study with a follow-up period of three years was conducted. Patients (N = 237) with hip or knee osteoarthritis were recruited from rehabilitation centers and hospitals. Body functions, comorbidity, cognitive functioning, limitations in activities and psychological and social factors (mental health, vitality, pain coping and perceived social support) were assessed. Statistical analyses included univariate and multivariate regression analyses. Psychological and social factors were added to a previously developed model with body functions, comorbidity and cognitive functioning.</p> <p>Results</p> <p>In knee OA, low vitality has a negative impact on the course of self-reported and performance-based limitations in activities, after controlling for somatic and cognitive factors. In hip OA, psychological and social factors had no additional contribution to the model.</p> <p>Conclusion</p> <p>Low vitality predicts deterioration of limitations in activities in elderly patients with osteoarthritis of the knee, in addition to established somatic and cognitive risk factors. However, the contribution of vitality is relatively small. Results of this study are relevant for the group of patients with knee or hip OA, attending hospitals and rehabilitation centers.</p