Genetic Risk Factors in Lupus Nephritis and IgA Nephropathy - No Support of an Overlap

Background: IgA nephropathy (IgAN) and nephritis in Systemic Lupus Erythematosus (SLE) are two common forms of glomerulonephritis in which genetic findings are of importance for disease development. We have recently reported an association of IgAN with variants of TGFB1. In several autoimmune diseases, particularly in SLE, IRF5, STAT4 genes and TRAF1-C5 locus have been shown to be important candidate genes. The aim of this study was to compare genetic variants from the TGFB1, IRF5, STAT4 genes and TRAF1-C5 locus with susceptibility to IgAN and lupus nephritis in two Swedish cohorts. Patients and Methods: We genotyped 13 single nucleotide polymorphisms (SNPs) in four genetic loci in 1252 DNA samples from patients with biopsy proven IgAN or with SLE (with and without nephritis) and healthy age-and sex-matched controls from the same population in Sweden. Results: Genotype and allelic frequencies for SNPs from selected genes did not differ significantly between lupus nephritis patients and SLE patients without nephritis. In addition, haplotype analysis for seven selected SNPs did not reveal a difference for the SLE patient groups with and without nephritis. Moreover, none of these SPNs showed a significant difference between IgAN patients and healthy controls. IRF5 and STAT4 variants remained significantly different between SLE cases and healthy controls. In addition, the data did not show an association of TRAF1-C5 polymorphism with susceptibility to SLE in this Swedish population. Conclusion: Our data do not support an overlap in genetic susceptibility between patients with IgAN or SLE and reveal no specific importance of SLE associated SNPs for the presence of lupus nephritis.Original Publication: Mai Tuyet Vuong, Iva Gunnarsson, Sigrid Lundberg, Elisabet Svenungsson, Lars Wramner, Anders Fernström, Ann-Christine Syvanen, Lieu Thi Do, Stefan H. Jacobson and Leonid Padyukov, Genetic Risk Factors in Lupus Nephritis and IgA Nephropathy - No Support of an Overlap, 2010, PLOS ONE, (5), 5. http://dx.doi.org/10.1371/journal.pone.0010559 Licensee: Public Library of Science (PLoS) http://www.plos.org/</p

Association between serum ferritin and mortality : findings from the USA, Japan and European Dialysis Outcomes and Practice Patterns Study

Background: The Kidney Disease: Improving Global Outcomes guidelines have cautioned against administering intravenous (IV) iron to hemodialysis patients with high serum ferritin levels due to safety concerns, but prior research has shown that the association between high ferritin and mortality could be attributed to confounding by malnutrition and inflammation. Our goal was to better understand the ferritin-mortality association and relative influence of IV iron and inflammation in the USA, where ferritin levels have recently increased dramatically, and in Europe and Japan, where ferritin levels are lower and anemia management practices differ. Methods: Data from 18 261 patients in Phases 4 and 5 (2009-15) of the international Dialysis Outcomes and Practice Patterns Study, a prospective cohort study, were analyzed. Using Cox regression, we modeled the association between baseline ferritin and 1-year mortality with restricted cubic splines and assessed the impact of potential confounders. Results: Median ferritin levels were 718 ng/mL in the USA, 405 in Europe and 83 in Japan. High ferritin levels were associated with elevated mortality (relative to region-specific medians) in all three regions. The strength of this association was attenuated more by adjustment for malnutrition and inflammation than by IV iron and erythropoiesis-stimulating agent dose in each region. Conclusion: The utility of high ferritin as a biomarker for clinical risk due to excess iron stores may be limited, although caution regarding IV iron dosing to higher upper ferritin targets remains warranted. Research to resolve biomarker criteria for iron dosing, and whether optimal anemia management strategies differ internationally, is still needed

Genetic variation in the transforming growth factor-β1 gene is associated with susceptibility to IgA nephropathy

Background. There is growing evidence of genetic risk for susceptibility to IgA nephropathy. Among several candidate genes related to immunological regulation in renal tissue, TGFB1 is known to be a contributor to proliferation and the development of fibrosis

Low hemoglobin at hemodialysis initiation : an international study of anemia management and mortality in the early dialysis period

Background. Anemia at hemodialysis (HD) initiation is common. Correcting low hemoglobin (Hgb) before HD initiation may improve survival by avoiding potential harms of chronic anemia, high doses of erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron in the early HD period, and/or rapid Hgb rise. Methods. We included 4604 incident HD patients from 21 countries in the Dialysis Outcomes and Practice Patterns Study Phases 4-5 (2009-15). Because low Hgb at HD start may reflect comorbidity or ESA hyporesponse, we restricted our analysis to the 80% of patients who achieved Hgb >= 10 g/dL 91-120 days after HD start (Month 4). Results. About 53% of these patients had Hgb = 10 g/dL). Month 1 Hgb was associated with first-year HD mortality (adjusted hazard ratio for 1 g/dL higher Hgb was 0.89; 95% confidence interval: 0.81-0.97), despite minimal differences in Month 4 Hgb. Patients with lower Hgb in Month 1 received higher doses of ESA, but not IV iron, over the first 3 months of HD. Results were consistent when excluding catheter users or adjusting for IV iron and ESA dose over the first 3 months. Conclusions. Even among patients with Hgb >= 10 g/dL 3 months later, anemia at HD initiation was common and associated with elevated mortality. A more proactive approach to anemia management in advanced chronic kidney disease (CKD) may thus improve survival on HD, though long-term prospective studies of non-dialysis CKD patients are needed

Mortality risk in patients on hemodiafiltration versus hemodialysis : a 'real-world' comparison from the DOPPS

Background. With its convective component, hemodiafiltration (HDF) provides better middle molecule clearance compared with hemodialysis (HD) and is postulated to improve survival. A previous analysis of Dialysis Outcomes and Practice Patterns Study (DOPPS) data in 1998-2001 found lower mortality rates for high replacement fluid volume HDF versus HD. Randomized controlled trials have not shown uniform survival advantage for HDF; in secondary (non-randomized) analyses, better outcomes were observed in patients receiving the highest convection volumes. Methods. In a 'real-world' setting, we analyzed patients on dialysis >90 days from seven European countries in DOPPS Phases 4 and 5 (2009-15). Adjusted Cox regression was used to study HDF (versus HD) and mortality, overall and by replacement fluid volume. Results. Among 8567 eligible patients, 2012 (23%) were on HDF, ranging from 42% in Sweden to 12% in Germany. Median follow-up was 1.5 years during which 1988 patients died. The adjusted mortality hazard ratio (95% confidence interval) was 1.14 (1.00-1.29) for any HDF versus HD and 1.08 (0.92-1.28) for HDF > 20 L replacement fluid volume versus HD. Similar results were found for cardiovascular and infection-related mortality. In an additional analysis aiming to avoid treatment-by-indication bias, we did not observe lower mortality rates in facilities usingmore HDF (versus HD). Conclusions. Our results do not support the notion that HDF provides superior patient survival. Further trials designed to test the effect of high-volume HDF (versus lower volume HDF versus HD) on clinical outcomes are needed to adequately inform clinical practices

Depths and Thermal Habitat Used by Large versus Small Northern Pike in Three Minnesota Lakes

We monitored depths and temperatures used by large (>71‐cm) versus small Northern Pike Esox lucius in three north‐central Minnesota lakes with either acoustic telemetry or archival tags. Individual Northern Pike demonstrated flexibility in depths used within a season and between years. The fish had some tolerance for low levels of dissolved oxygen (<3 mg/L), but depth selection was generally constrained by low dissolved oxygen in summer and winter. The fish more fully exploited all available depths during winter and thermal turnover periods. During July and August, large Northern Pike tended to follow the thermocline into cooler water as upper water layers warmed. Selection ratios indicated that large Northern Pike preferred water temperatures of 16–21°C during August when temperatures up to 28°C were available. In two lakes providing dense overhead cover from water lilies in shallow water, small Northern Pike used warmer, shallower water compared with large fish during summer. In a third lake providing no such cover, small fish were more often in deeper, cooler water. For small Northern Pike, temperature seemed to be a secondary habitat consideration behind the presence of shallow vegetated cover. This study provided detailed temperature selection information that will be useful when considering temperature as an ecological resource for different sizes of Northern Pike.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141595/1/tafs1629.pd

Identifying a Safe and Just Corridor for People and the Planet

Keeping the Earth system in a stable and resilient state, to safeguard Earth's life support systems while ensuring that Earth's benefits, risks, and related responsibilities are equitably shared, constitutes the grand challenge for human development in the Anthropocene. Here, we describe a framework that the recently formed Earth Commission will use to define and quantify target ranges for a “safe and just corridor” that meets these goals. Although “safe” and “just” Earth system targets are interrelated, we see safe as primarily referring to a stable Earth system and just targets as being associated with meeting human needs and reducing exposure to risks. To align safe and just dimensions, we propose to address the equity dimensions of each safe target for Earth system regulating systems and processes. The more stringent of the safe or just target ranges then defines the corridor. Identifying levers of social transformation aimed at meeting the safe and just targets and challenges associated with translating the corridor to actors at multiple scales present scope for future work

Identifying a Safe and Just Corridor for People and the Planet

Keeping the Earth system in a stable and resilient state, to safeguard Earth's life support systems while ensuring that Earth's benefits, risks, and related responsibilities are equitably shared, constitutes the grand challenge for human development in the Anthropocene. Here, we describe a framework that the recently formed Earth Commission will use to define and quantify target ranges for a “safe and just corridor” that meets these goals. Although “safe” and “just” Earth system targets are interrelated, we see safe as primarily referring to a stable Earth system and just targets as being associated with meeting human needs and reducing exposure to risks. To align safe and just dimensions, we propose to address the equity dimensions of each safe target for Earth system regulating systems and processes. The more stringent of the safe or just target ranges then defines the corridor. Identifying levers of social transformation aimed at meeting the safe and just targets and challenges associated with translating the corridor to actors at multiple scales present scope for future work

Malnutrition and Infection: Complex Mechanisms and Global Impacts

The authors discuss current concepts and controversies surrounding the complex influences of malnutrition on infection and immunity, and point to practical consequences of countermeasures in acute malnutrition

3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands

Histone-lysine acetylation is a vital chromatin post-translational modification involved in the epigenetic regulation of gene transcription. Bromodomains bind acetylated lysines, acting as readers of the histone-acetylation code. Competitive inhibitors of this interaction have antiproliferative and anti-inflammatory properties. With 57 distinct bromodomains known, the discovery of subtype-selective inhibitors of the histone-bromodomain interaction is of great importance. We have identified the 3,5 dimethylisoxazole moiety as a novel acetyl-lysine bioisostere, which displaces acetylated histone-mimicking peptides from bromodomains. Using X-ray crystallographic analysis, we have determined the interactions responsible for the activity and selectivity of 4-substituted 3,5-dimethylisoxazoles against a selection of phylogenetically diverse bromodomains. By exploiting these interactions, we have developed compound 4d, which has IC50 values of &lt;5 μM for the bromodomain-containing proteins BRD2(1) and BRD4(1). These compounds are promising leads for the further development of selective probes for the bromodomain and extra C-terminal domain (BET) family and CREBBP bromodomains