CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease

Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a, SA-β-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-β-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence

Increased telomere attrition following renal transplantation: impact of anti-metabolite therapy

Background: The uremic milieu exposes chronic kidney disease (CKD) patients to premature ageing processes. The impact of renal replacement therapy (dialysis and renal transplantation [RTx]) or immunosuppressive treatment regimens on ageing biomarkers has scarcely been studied. Methods: In this study telomere length in whole blood cells was measured in 49 dialysis patients and 47 RTx patients close to therapy initiation and again after 12 months. Forty-three non-CKD patients were included as controls. Results: Non-CKD patients had significantly (P <= 0.01) longer telomeres than CKD patients. Telomere attrition after 12 months was significantly greater in RTx patients compared to dialysis patients (P = 0.008). RTx patients receiving mycophenolate mofetil (MMF) had a greater (P = 0.007) degree of telomere attrition compared to those treated with azathioprine. After 12 months, folate was significantly higher in RTx patients than in dialysis patients (P < 0.0001), whereas the opposite was true for homocysteine (P < 0.0001). The azathioprine group had lower levels of folate after 12 months than the MMF group (P = 0.003). Conclusions: The associations between immunosuppressive therapy, telomere attrition, and changes in folate indicate a link between methyl donor potential, immunosuppressive drugs, and biological ageing. The hypothesis that the increased telomere attrition, observed in the MMF group after RTx, is driven by the immunosuppressive treatment, deserves further attention

Biofilmdannelse i VAVs ledningsnett med nye Oset vannbehandlingsanlegg

Det ble i 2012 gjennomført kvalitative og kvantitative målinger av biofilmdannelse i råvann, filtrert vann, rentvann og nettvann i Osets forsyningsområde i Oslo. Målet med biofilmmålingene var å undersøke/dokumentere effekten av vannbehandling på biofilmdannelsen i ledningsnettet. Målingene viste at biofilmdannelsen ble redusert med 95-99 % fra råvann til rentvann og nettvann, noe som var en vesentlig større reduksjon enn det endringen i vannets begroingspotensial skulle tilsi. Sistnevnte ble omtrent halvert fra råvann til rentvann og nettvann. Biofilmdannelsen var noenlunde konstant utover på nettet. Mengden muggsopp i biofilmen varierte fra overvekst i biofilm fra råvann til minimal eller ingen vekst i biofilm fra filtrert vann, rentvann og nettvann. Mengden av bakterier i biofilmen var vesentlig høyere i råvann enn i filtrert vann og rentvann, noe som er i overensstemmelse med forskjellene i biofilmdannelsen. Mengden bakterier var spesielt lave i biofilm som vokste i rentvann fra Oset. Presumptiv Pseudomonas, presumptiv Aeromonas, koliforme bakterier og E. coli ble påvist i biofilm fra råvann, men ikke i biofilm fra filtrert vann, rentvann eller nettvann. Presumptiv Legionella ble påvist i biofilm fra alle prøvepunktene med unntak av i rentvann fra Oset.publishedVersio

Visualization of causation in social-ecological systems

In social-ecological systems (SES), where social and ecological processes are intertwined, phenomena are usually complex and involve multiple interdependent causes. Figuring out causal relationships is thus challenging but needed to better understand and then affect or manage such systems. One important and widely used tool to identify and communicate causal relationships is visualization. Here, we present several common visualization types: diagrams of objects and arrows, X-Y plots, and X-Y-Z plots, and discuss them in view of the particular challenges of visualizing causation in complex systems such as SES. We use a simple demonstration model to create and compare exemplary visualizations and add more elaborate examples from the literature. This highlights implicit strengths and limitations of widely used visualization types and facilitates adequate choices when visualizing causation in SES. Thereupon, we recommend further suitable ways to account for complex causation, such as figures with multiple panels, or merging different visualization types in one figure. This provides caveats against oversimplifications. Yet, any single figure can rarely capture all relevant causal relationships in an SES. We therefore need to focus on specific questions, phenomena, or subsystems, and often also on specific causes and effects that shall be visualized. Our recommendations allow for selecting and combining visualizations such that they complement each other, support comprehensive understanding, and do justice to the existing complexity in SES. This lets visualizations realize their potential and play an important role in identifying and communicating causation.Peer reviewe

Scandiatransplant acceptable mismatch program-10 years with an effective strategy for transplanting highly sensitized patients

In March 2009, the Scandiatransplant acceptable mismatch program (STAMP) was introduced as a strategy toward improving kidney allocation to highly sensitized patients. Patients with a transplantability scorePeer reviewe

CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease

Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a, SA-β-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-β-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence

Change in lifestyle behaviors and diabetes risk: evidence from a population-based cohort study with 10 year follow-up

Abstract Background Promoting positive changes in lifestyle behavior in the whole population may be a feasible and effective approach to reducing type 2 diabetes burden, but the impact of population shifts of modifiable risk factors remains unclear. Currently most of the evidence on modifiable lifestyle behavior and type 2 diabetes risk on a population level comes from studies of between-individual differences. The objective of the study was to investigate the association and potential impact on disease burden for within-individual change in lifestyle behavior and diabetes risk. Methods Population-based prospective cohort study of 35,680 participants aged 30–50 at baseline in 1990–2003 in Västerbotten County, Sweden (follow-up until 2013). Five self-reported modifiable lifestyle behaviors (tobacco use, physical activity, alcohol intake, dietary fiber intake and dietary fat intake) were measured at baseline and 10 year follow-up. Lifestyle behaviors were studied separately, and combined in a score. Incident diabetes was detected by oral glucose tolerance tests. Multivariate logistic regression models and population attributable fractions (PAF) were used to analyze the association between change in lifestyle behavior between baseline and 10 year follow-up, and risk of incident diabetes. Results Incident diabetes was detected in 1,184 (3.3%) participants at 10 year follow-up. There was a reduced diabetes risk associated with increase in dietary fiber intake, odds ratio (OR) 0.79 (95% confidence interval (CI) 0.66, 0.96) for increase of at least one unit standard deviation (3.0 g/1,000 kcal) of the baseline distribution, PAF 16.0% (95% CI 4.2, 26.4%). Increase in the lifestyle behavior score was associated with reduced diabetes risk, OR 0.92 (95% CI 0.85, 0.99) per unit increase of the score. Conclusions These results support a causal link between lifestyle behavior and type 2 diabetes incidence. A small shift in lifestyle behaviors, in particular intake of dietary fiber, has the potential to reduce diabetes burden in the population and might be a suitable target for public health intervention

Longitudinal genome-wide DNA methylation changes in response to kidney failure replacement therapy

Chronic kidney disease (CKD) is an emerging public health priority associated with high mortality rates and demanding treatment regimens, including life-style changes, medications or even dialysis or renal transplantation. Unavoidably, the uremic milieu disturbs homeostatic processes such as DNA methylation and other vital gene regulatory mechanisms. Here, we aimed to investigate how dialysis or kidney transplantation modifies the epigenome-wide methylation signature over 12 months of treatment. We used the Infinium HumanMethylation450 BeadChip on whole blood samples from CKD-patients undergoing either dialysis (n = 11) or kidney transplantation (n = 12) and 24 age- and sex-matched population-based controls. At baseline, comparison between patients and controls identified several significant (PFDR < 0.01) CpG methylation differences in genes with functions relevant to inflammation, cellular ageing and vascular calcification. Following 12 months, the global DNA methylation pattern of patients approached that seen in the control group. Notably, 413 CpG sites remained differentially methylated at follow-up in both treatment groups compared to controls. Together, these data indicate that the uremic milieu drives genome-wide methylation changes that are partially reversed with kidney failure replacement therapy. Differentially methylated CpG sites unaffected by treatment may be of particular interest as they could highlight candidate genes for kidney disease per se

The on-orbit performance of the Orbiting Carbon Observatory-2 (OCO-2) instrument and its radiometrically calibrated products

The Orbiting Carbon Observatory-2 (OCO-2) carries and points a three-channel imaging grating spectrometer designed to collect high-resolution, co-boresighted spectra of reflected sunlight within the molecular oxygen (O_2) A-band at 0.765 microns and the carbon dioxide (CO_2) bands at 1.61 and 2.06 microns. These measurements are calibrated and then combined into soundings that are analyzed to retrieve spatially resolved estimates of the column-averaged CO_2 dry-air mole fraction, XCO_2. Variations of XCO_2 in space and time are then analyzed in the context of the atmospheric transport to quantify surface sources and sinks of CO_2. This is a particularly challenging remote-sensing observation because all but the largest emission sources and natural absorbers produce only small (< 0.25 %) changes in the background XCO_2 field. High measurement precision is therefore essential to resolve these small variations, and high accuracy is needed because small biases in the retrieved XCO_2 distribution could be misinterpreted as evidence for CO_2 fluxes. To meet its demanding measurement requirements, each OCO-2 spectrometer channel collects 24 spectra s^(−1) across a narrow ( 17 000), dynamic range (∼ 10^4), and sensitivity (continuum signal-to-noise ratio > 400). The OCO-2 instrument performance was extensively characterized and calibrated prior to launch. In general, the instrument has performed as expected during its first 18 months in orbit. However, ongoing calibration and science analysis activities have revealed a number of subtle radiometric and spectroscopic challenges that affect the yield and quality of the OCO-2 data products. These issues include increased numbers of bad pixels, transient artifacts introduced by cosmic rays, radiance discontinuities for spatially non-uniform scenes, a misunderstanding of the instrument polarization orientation, and time-dependent changes in the throughput of the oxygen A-band channel. Here, we describe the OCO-2 instrument, its data products, and its on-orbit performance. We then summarize calibration challenges encountered during its first 18 months in orbit and the methods used to mitigate their impact on the calibrated radiance spectra distributed to the science community