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- Nordfors, K., et al.
(author)
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Peroxiredoxins and antioxidant enzymes in pilocytic astrocytomas
- 2007
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In: Clinical Neuropathology. - 0722-5091. ; 26:5, s. 210-218
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Journal article (peer-reviewed)abstract
- Objective: Peroxiredoxins are antioxidant enzymes (AOEs), which are redox-regulated thiol proteins with potential effects on the growth, invasion and drug resistance of neoplastic cells. In this study, their biology and clinical significance were examined in pilocytic astrocytomas (PAs). Material and methods: The expression of peroxiredoxins (Prx I-VI) was investigated in 105 PAs by the means of immunohistochemistry and compared with the expression of selected other antioxidant enzymes, cell proliferation, angiogenesis, apoptosis, p53, histopathology and patient survival. Results: Peroxiredoxins were strongly expressed in general suggesting that oxidative damage and consequent defense takes place during the progression of pilocytic astrocytomas. In agreement with this hypothesis, several other AOEs correlated with the degenerative features and angiogenesis possibly associated with reactive oxygen species-derived cellular damage. Moreover, the expression of the AOEs was associated with each other indicating a concurrent activation of the enzymes. With the exception of manganese superoxide dismutase (MnSOD), a strong expression of AOEs was generally associated with higher cell proliferation. Prx VI seemed to have a positive association with a longer recurrence-free interval while other AOEs had no association with patient survival. Many AOEs, such as MnSOD, induce chemo- and radioresistance and are highly elevated in aggressive malignancies. PAs lack this confounding factor, and these tumors are treated only by surgery Conclusions: Taken together, the results of this study on pilocytic astrocytomas suggest that the levels of Prxs and other AOEs and their related thiol proteins are generally strongly expressed in these tumors. At least Prx VI can contribute to tumor behavior which can make it a potential prognostic factor.
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- Witasp, A, et al.
(author)
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Longitudinal genome-wide DNA methylation changes in response to kidney failure replacement therapy
- 2022
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1, s. 470-
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Journal article (peer-reviewed)abstract
- 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.
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- Axelsson, J, et al.
(author)
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Is fetuin-A/alpha2-Heremans-Schmid glycoprotein associated with the metabolic syndrome in patients with chronic kidney disease?
- 2008
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In: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 28:4, s. 669-676
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Journal article (peer-reviewed)abstract
- <i>Introduction:</i> Components of the metabolic syndrome are highly prevalent in chronic kidney disease (CKD) patients – some of which paradoxically appear to predict an improved outcome in this population. We hypothesized that the circulating calcification inhibitor fetuin-A/AHSG, which is also a natural inhibitor of the tyrosine kinase insulin receptor, could be one factor explaining the association between increased fat mass and a survival advantage in CKD and thus conducted an explorational study to provide preliminary data to support further research into this hypothesis. <i>Patients and Methods:</i> In a cross-sectional study, we evaluated 198 CKD stage 5 patients (GFR 6.8 ± 0.2 ml/min; 62% males, mean age 52 ± 1 years) close to the start of renal replacement therapy. We studied circulating AHSG (ELISA) and two common functional <i>AHSG</i> gene polymorphisms (at amino acids Thr248Met (C-T) and Thr256Ser (C-G) using Pyrosequencing®) and related these to multiple components of the metabolic syndrome. <i>Results:</i> Median circulating AHSG was lower (p < 0.01) in type-2 (0.22 g/l) and type-1 (0.16 g/l) diabetics as compared to non-diabetic CKD-5 patients (0.24 g/l). AHSG correlated with both total and truncal fat mass in type-2 diabetics (rho 0.37 and 0.39; p < 0.001, respectively), but not in type-1 diabetics or non-diabetics. Both SNPs significantly influenced circulating levels of AHSG, and were also associated with significant differences in serum triglycerides and HDL cholesterol. Furthermore, there were significant differences in the prevalence of metabolic syndrome criteria between the <i>AHSG</i> Thr256Ser (C-G) genotype groups, with a more atherogenic lipid profile in AHSG high producers (Thr/Thr homozygotes). In multivariate analysis, the association between circulating AHSG and fat mass remained significant also after adjustment for age, gender, inflammation (CRP >10 mg/l), and <i>AHSG</i> genotype. <i>Conclusions:</i> The present, explorational, study supports further, mechanistic, studies into a physiological link between AHSG and body fat mass in patients with CKD. As we observed an association between higher fat mass and elevated AHSG levels, these preliminary results may form the basis of further study to establish if the observed associations may be one reason why obesity has been reported to constitute a survival advantage in CKD.
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- Carrero, J.J., et al.
(author)
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Telomere attrition is associated with inflammation, low fetuin : A levels and high mortality in prevalent haemodialysis patients
- 2008
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 263:3, s. 302-312
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Chronic kidney disease (CKD) predisposes to a 10- to 20-fold increased cardiovascular risk. Patients undergo accelerated atherogenesis and vascular ageing. We investigated whether telomere attrition, a marker of cell senescence, contributes to this increased mortality risk. METHODS: This is a cross-sectional study in prevalent haemodialysis patients [n = 175; 98 Males; median (range) age: 66 (23-86) years]. Biochemical markers of oxidative stress and inflammatory status were measured in relation to the patient's leucocyte telomere length. Overall mortality was assessed after a median of 31 (range 2-42) months. RESULTS: Telomere length was shorter in CKD men, despite women being older (average +/- SD 6.41 +/- 1.23 vs. 6.96 +/- 1.48 kb, P = 0.002). Telomere length was associated with age (rho = -0.18, P = 0.01), fetuin-A (rho = 0.26, P = 0.0004), high-sensitivity C-reactive protein (rho = -0.21, P = 0.005) and IL-6 (rho = -0.17, P = 0.02). In a multivariate logistic regression (pseudo r(2) = 0.14), telomere length was associated with age >65 years (odds ratio: 2.11; 95% CI: 1.10, 4.06), sex (2.01; 1.05, 3.86), fetuin-A (1.85; 0.97, 3.50) and white blood cell count (2.04; 1.02, 4.09). Receiver operating characteristic curves identified a telomere length < 6.28 kb as a fair predictor of mortality. Finally, reduced telomere length was associated with increased mortality, independently of age, gender and inflammation (likelihood ratio 41.6, P < 0.0001), but dependently on fetuin-A levels. CONCLUSION: Age and male gender seem to be important contributors to reduced telomere length in CKD patients, possibly via persistent inflammation. Reduced telomere length also contributes to the mortality risk of these patients through pathways that could involve circulating levels of fetuin-A.
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- Cederholm, Tommy, et al.
(author)
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Polymorphisms in cytokine genes influence long-term survival differently in elderly male and female patients
- 2007
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 262:2, s. 215-223
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Journal article (peer-reviewed)abstract
- Objectives. We asked if single nucleotide polymorphisms (SNP) in inflammatory cytokine genes related to 3-year survival in ill elderly subjects and if genotypes differed between the elderly and a younger control population. Design. Prospective observational study. Setting. Two geriatric departments at a university hospital. Subjects. Eighty three acutely admitted geriatric patients (83 ± 7 year, 70% women) and 207 young healthy subjects (40 ± 1 year, 37% women) were included. Outcome measures. Single nucleotide polymorphisms in the genes of tumour necrosis factor (TNF)-α–308 G/A, interleukin (IL)-1β–511 C/T, IL-6–174 G/C and IL-10–1082 A/G were analysed. In the geriatric patients SNP in lymphotoxin (LT)-α +252 G/A and serum levels of TNF-α, IL-6, IL-10, soluble IL-I receptor(R)II were also determined, as well as the 3-year mortality. Results. The allele distribution did not differ significantly between the elderly and the young. In the female elderly, 3-year survival was doubled (P < 0.05) in those with the high-producing genotypes of IL-6 –174 GG and TNF-α -308 GA compared with those with low-producing alleles. In contrast, men with high-producing LT-α +252 AA and IL-1β–511 CT&TT genotypes displayed halved 3-year survival (P < 0.05) compared with those with low-producing genotypes, whereas possession of the high-producing IL-10 –1082 GG genotype favoured survival. Serum IL-10 was higher in the high-producing IL-10 genotype in females. Conclusion. As high-producing IL-6 –174 genotype favoured 3-year survival in women, whereas the likewise high-producing LT-α +252 and IL-1β -511 genotypes were associated with poor survival in men, we conclude that the specific genotypes, in association with gender, may act as determinants for survival in elderly patients.
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| 34. |
- Chambers, John C., et al.
(author)
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Genetic loci influencing kidney function and chronic kidney disease
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 373-375
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Journal article (peer-reviewed)abstract
- Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.
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- Chmielewski, M, et al.
(author)
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Lipoprotein lipase 1595 c/g and hepatic lipase -480 c/t polymorphisms--impact on lipid profile in incident dialysis patients
- 2008
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In: Blood purification. - : S. Karger AG. - 1421-9735 .- 0253-5068. ; 26:6, s. 555-560
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Journal article (peer-reviewed)abstract
- <i>Background:</i> Dyslipidemia is a common complication of chronic kidney disease. Lipoprotein lipase (LPL) 1595 C/G and hepatic lipase (HL) –480 C/T single nucleotide polymorphisms (SNPs) influence lipid profile and predisposition for cardiovascular disease in the general population. The present study was undertaken to clarify the impact of the two polymorphisms on lipid parameters and cardiovascular risk in incident dialysis patients. <i>Methods:</i> LPL 1595 C/G and HL –480 C/T SNPs were evaluated in 293 chronic kidney disease patients close to dialysis initiation. Associations with lipid parameters, presence of cardiovascular disease, and survival were assessed. <i>Results:</i> LPL 1595 C/G SNP was associated with significantly lower triglyceride levels [1.55 (1.00–2.20) vs. 1.90 (1.40–2.48) m<i>M</i>; p < 0.01], while HL –480 C/T polymorphism was associated with increased high density lipoprotein cholesterol concentration [1.30 (1.00–1.60) vs. 1.10 (0.90–1.40) m<i>M</i>; p < 0.05]. Neither of the polymorphisms showed any relationship with patient survival. <i>Conclusions:</i> LPL 1595 C/G and HL –480 C/T polymorphisms affect lipid profile in incident dialysis patients.
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- Grahl, DA, et al.
(author)
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Associations between the CYBA 242C/T and the MPO -463G/A polymorphisms, oxidative stress and cardiovascular disease in chronic kidney disease patients
- 2007
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In: Blood purification. - : S. Karger AG. - 1421-9735 .- 0253-5068. ; 25:2, s. 210-218
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Journal article (peer-reviewed)abstract
- Genetic variations in the NADPH/MPO system in chronic kidney disease (CKD) patients might lead to altered activity of these enzymes, and thus to altered risk for oxidative stress (OS) and cardiovascular disease (CVD). We evaluated the impact of 242C/T <i>CYBA</i> and –463G/A <i>MPO</i> polymorphisms on OS and CVD mortality in stage 5 CKD patients starting dialysis. Two hundred and fifty-seven patients were genotyped using Pyrosequencing. Plasmalogen [dimethylacetal (DMA) 16/C16:0] was used as OS marker. CVD was assessed from patient history and clinical symptoms. Prevalence of CVD was higher (35%) in GG patients (<i>MPO</i>) compared to AG (26%) and AA (0%) patients (p < 0.01). Patients with CC genotype (<i>CYBA</i>) had lower levels of DMA 16/C16:0 (ratio 0.071 ± 0.003) compared to TT patients (0.089 ± 0.006; p < 0.05). These patients also had increased CVD mortality compared to CT and TT patients (χ<sup>2</sup> 2.19; p < 0.05). We conclude that genetic variations in the NADPH/MPO system are associated with OS, presence of CVD and CVD-related mortality in CKD patients.
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- Kato, S, et al.
(author)
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Telomere Attrition and Elongation after Chronic Dialysis Initiation in Patients with End-Stage Renal Disease
- 2016
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In: Blood purification. - : S. Karger AG. - 1421-9735 .- 0253-5068. ; 41:1-3, s. 25-33
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Journal article (peer-reviewed)abstract
- <b><i>Aims:</i></b> To analyze changes in telomere length (TL) after dialysis initiation. <b><i>Methods:</i></b> In 59 Japanese incident dialysis patients, associations between TL in peripheral blood leukocytes, inflammatory biomarkers and nutritional status at baseline and changes in TL during 1 year of dialysis, were investigated. <b><i>Results:</i></b> Whereas relative TL decreased by 8.6% (median 14.4%), TL elongation occurred in 16 patients (27%). Change in TL (ΔTL), defined as TL at 1 year minus TL at baseline, was associated with baseline TL (ρ = -0.70, p < 0.0001) and leukocyte count (ρ = 0.26, p = 0.044). In a logistic regression model, baseline TL (p < 0.0001) and leukocyte count (p = 0.047) were associated with ΔTL. <b><i>Conclusions:</i></b> TL shortening was observed in most incident dialysis patients. In 16 of the 59 patients, TL elongation occurred, possibly reflecting a more robust biological aging in patients whose naïve leukocytes may have undergone less proliferation to replace lost leukocytes.
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