Circulating markers of ageing and allostatic load: a slow train coming

Dealing with the growing burden of age-related morbidities is one of the greatest challenges facing modern society. How we age across the lifecourse and how psychosocial and lifestyle factors interplay with the biology of ageing remains to be fully elucidated. Sensitive and specific biomarkers with which to interrogate the biology of the ageing process are sparse. Recent evidence suggests that non-coding RNAs are key determinants of such processes and that these can be used as potential circulatory bio-markers of ageing. They may also provide a mechanism which mediates the spread of allostatic load across the body over time, ultimately reflecting the immunological health and physiological status of tissues and organs. The interplay between exosomal microRNAs and ageing processes is still relatively unexplored, although circulating microRNAs have been linked to the regulation of a range of physiological and pathological processes and offer insight into mechanistic determinants of healthspan

Fabry disease: a new model of premature aging?

No abstract available

Systemic and intraperitoneal interleukin‐6 system during the first year of peritoneal dialysis

Perit Dial Int. 2006 Jan-Feb;26(1):53-63. Systemic and intraperitoneal interleukin-6 system during the first year of peritoneal dialysis. Pecoits-Filho R, Carvalho MJ, Stenvinkel P, Lindholm B, Heimbürger O. Division of Renal Medicine and Baxter Novum, Karolinska Institutet, K-56, Huddinge University Hospital, 141 86 Stockholm, Sweden. [email protected] Comment in: Perit Dial Int. 2006 Jan-Feb;26(1):35-7. Abstract OBJECTIVE: To investigate if intraperitoneal and systemic interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) are related to each other and to peritoneal solute transport rate (PSTR). DESIGN: Longitudinal study in retrospectively selected patients. SETTING: Peritoneal dialysis (PD) unit of a university-based hospital. PATIENTS AND METHODS: 31 PD patients on treatment with conventional glucose-based solutions participated in a longitudinal study. IL-6 and sIL-6R were measured in plasma and overnight effluent, both at baseline and after 12 +/- 2 months on PD. C-reactive protein (CRP) and serum albumin were used as surrogate markers of inflammation. PSTR of small solutes was evaluated using the dialysate-to-plasma ratio (D/P) of creatinine after a 4-hour dwell; PSTR of large solutes was evaluated using the 24-hour D/P ratio of albumin. RESULTS: D/P creat increased over time (0.67 +/- 0.15 vs 0.80 +/- 0.11, p or = median had higher (p or = median [24.7 (16.5 - 38.5) pg/mL] compared to patients with IL-6 < median [14.1 (10 - 25.7) pg/mL]. Neither CRP nor albumin changed over time on PD, although they were closely linked to plasma IL-6 levels. A strong positive correlation was found between D/P creat and dialysate IL-6 (rho = 0.77, p < 0.0001) at baseline, but not at 1 year. In contrast, there was a significant correlation between D/P creat and dialysate sIL-6R (rho = 0.39, p < 0.05) at 1 year, but not at baseline. At 1 year, 17 patients with increasing PSTR had higher increases in dialysate IL-6 (28 +/- 26 vs -21 +/- 78 pg/mL, p < 0.05) and levels of dialysate sIL-6R (693 +/- 392 vs 394 +/- 274 pg/mL, p = 0.05) compared to patients with stable PSTR (n = 11). Patients who had peritonitis presented higher baseline serum IL-6 concentration (6.8 +/- 1.0 pg/mL) compared with patients without peritonitis (4.0 +/- 0.6 pg/mL, p < 0.05). Finally, both at baseline and after 1 year, there were significant correlations between plasma and dialysate IL-6 (rho = 0.46, p < 0.05, and rho = 0.40, p < 0.05) respectively. CONCLUSIONS: These findings indicate that, (1) intraperitoneal and systemic inflammation increase in PD patients during the first year of therapy; (2) intraperitoneal and systemic inflammation may be interrelated and the IL-6 system may be the link; (3) the IL-6 system (both intraperitoneal and systemic) is associated with PSTR, particularly in the early phase of PD treatment, in which small and large solute transport are linked. Signs of a transition between acute and chronic inflammation were observed in the follow-up evaluation. Inflammation may, at least in part, be responsible for the development of a high PSTR, and this could be one reason for the high mortality in patients with high PSTR. PMID: 16538876 [PubMed - indexed for MEDLIN

Cinacalcet-induced hypocalcemia in a cohort of European haemodialysis patients: predictors, therapeutic approaches and outcomes

BACKGROUND: Calcimimetic treatment of secondary hyperparathyroidism in chronic dialysis patients is often followed by hypocalcemia. METHODS: We investigated the frequency, predictors, consequences and therapeutic responses following cinacalcet-induced hypocalcemia in an incident European hemodialysis cohort of 1068 patients with a cinacalcet prescription. RESULTS: Of 905 normocalcemic patients initiating cinacalcet, 67% developed hypocalcemia within 12 months: 68% mild, 23% moderate, 9% severe. Compared to persistently normocalcemic patients, those with severe hypocalcemia were more often diabetic, overweight, had cardiovascular disease, shorter dialysis vintage, used a catheter dialysis access, had fewer active vitamin-D sterols, and exhibited higher CRP and iPTH and lower calcium levels. Multivariate predictors of hypocalcemia included a catheter for vascular access, low albumin and high iPTH. Generally, no therapeutic intervention to prevent hypocalcemia was taken prior to cinacalcet initiation. After the hypocalcemic event, the most common clinical response was no change of the dialysis or medical regimen. Following the hypocalcemic event, iPTH remained low even in those with severe hypocalcemia. The number of deaths and cardiovascular events did not differ between patients with and without hypocalcemia within six months following cinacalcet initiation. CONCLUSION: Two-thirds of cinacalcet initiated patients experienced hypocalcaemia with 9% being severe. Hypocalcemia was mostly asymptomatic, transient (with and without targeted intervention to correct it) and not associated with an increase in cardiovascular events or deaths

Характеристика сили нервових процесів у плавців

OBJECTIVE: Higher levels of the novel inflammatory marker pentraxin 3 (PTX3) predict cardiovascular mortality in patients with chronic kidney disease (CKD). Yet, whether PTX3 predicts worsening of kidney function has been less well studied. We therefore investigated the associations between PTX3 levels, kidney disease measures and CKD incidence. METHODS: Cross-sectional associations between serum PTX3 levels, urinary albumin/creatinine ratio (ACR) and cystatin C-estimated glomerular filtration rate (GFR) were assessed in two independent community-based cohorts of elderly subjects: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, n = 768, 51% women, mean age 75 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 651, mean age 77 years). The longitudinal association between PTX3 level at baseline and incident CKD (GFR &lt;60 mL( ) min(-1)  1.73 m(-) ²) was also analysed (number of events/number at risk: PIVUS 229/746, ULSAM 206/315). RESULTS: PTX3 levels were inversely associated with GFR [PIVUS: B-coefficient per 1 SD increase -0.16, 95% confidence interval (CI) -0.23 to -0.10, P &lt; 0.001; ULSAM: B-coefficient per 1 SD increase -0.09, 95% CI -0.16 to -0.01, P &lt; 0.05], but not ACR, after adjusting for age, gender, C-reactive protein and prevalent cardiovascular disease in cross-sectional analyses. In longitudinal analyses, PTX3 levels predicted incident CKD after 5 years in both cohorts [PIVUS: multivariable odds ratio (OR) 1.21, 95% CI 1.01-1.45, P &lt; 0.05; ULSAM: multivariable OR 1.37, 95% CI 1.07-1.77, P &lt; 0.05]. CONCLUSIONS: Higher PTX3 levels are associated with lower GFR and independently predict incident CKD in elderly men and women. Our data confirm and extend previous evidence suggesting that inflammatory processes are activated in the early stages of CKD and drive impairment of kidney function. Circulating PTX3 appears to be a promising biomarker of kidney disease

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

Klotho, ageing and the failing kidney

Klotho has been recognised as a gene involved in the ageing process in mammals for over thirty years, where it regulates phosphate homeostasis and the activity of members of the fibroblast growth factor (FGF) family. The α -Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23), regulating phosphate homeostasis and vitamin D metabolism. Phosphate toxicity is a hallmark of mammalian ageing and correlates with diminution of Klotho levels with increasing age. As such, modulation of Klotho activity is an attractive target for therapeutic intervention in the diseasome of ageing; in particular for chronic kidney disease (CKD), where Klotho has been implicated directly in the pathophysiology. A range of senotherapeutic strategies have been developed to directly or indirectly influence Klotho expression, with varying degrees of success. These include administration of exogenous Klotho, synthetic and natural Klotho agonists and indirect approaches, via modulation of the foodome and the gut microbiota. All these approaches have significant potential to mitigate loss of physiological function and resilience accompanying old age and to improve outcomes within the diseasome of ageing

Технологические решения для строительства разведочной вертикальной скважины глубиной 2750 метров на нефтяном месторождении (ХМАО)

Технологические решения для строительства разведочной вертикальной скважины глубиной 2750 метров на нефтяном месторождении (ХМАО).Technological solutions for the construction of an exploration vertical well with a depth of 2,750 meters at the oil field (KhMAO)

Circulating proteins as predictors of cardiovascular mortality in endstage renal disease

Introduction: Proteomic profiling of end-stage renal disease (ESRD) patients could lead to improved risk prediction and novel insights into cardiovascular disease mechanisms. Plasma levels of 92 cardiovascular disease-associated proteins were assessed by proximity extension assay (Proseek Multiplex CVD-1, Olink Bioscience, Uppsala, Sweden) in a discovery cohort of dialysis patients, the Mapping of Inflammatory Markers in Chronic Kidney disease cohort [MIMICK; n = 183, 55% women, mean age 63 years, 46 cardiovascular deaths during follow-up (mean 43 months)]. Significant results were replicated in the incident and prevalent hemodialysis arm of the Salford Kidney Study [SKS dialysis study, n = 186, 73% women, mean age 62 years, 45 cardiovascular deaths during follow-up (mean 12 months)], and in the CKD5-LD-RTxcohort with assessments of coronary artery calcium (CAC)-score by cardiac computed tomography (n = 89, 37% women, mean age 46 years). Results: In age and sex-adjusted Cox regression in MIMICK, 11 plasma proteins were nominally associated with cardiovascular mortality (in order of significance: Kidney injury molecule-1 (KIM-1), Matrix metalloproteinase-7, Tumour necrosis factor receptor 2, Interleukin-6, Matrix metalloproteinase-1, Brain-natriuretic peptide, ST2 protein, Hepatocyte growth factor, TNF-related apoptosis inducing ligand receptor-2, Spondin-1, and Fibroblast growth factor 25). Only plasma KIM-1 was associated with cardiovascular mortality after correction for multiple testing, but also after adjustment for dialysis vintage, cardiovascular risk factors and inflammation (hazard ratio) per standard deviation (SD) increase 1.84, 95% CI 1.26–2.69, p = 0.002. Addition of KIM-1, or nine of the most informative proteins to an established risk-score (modified AROii CVM-score) improved discrimination of cardiovascular mortality risk from C = 0.777 to C = 0.799 and C = 0.823, respectively. In the SKS dialysis study, KIM-1 predicted cardiovascular mortality in age and sex adjusted models (hazard ratio per SD increase 1.45, 95% CI 1.03–2.05, p = 0.034) and higher KIM-1 was associated with higher CACscores in the CKD5-LD-RTx-cohort. Conclusions Our proteomics approach identified plasma KIM-1 as a risk marker for cardiovascular mortality and coronary artery calcification in three independent ESRD-cohorts. The improved risk prediction for cardiovascular mortality by plasma proteomics merit further studies.Swedish Research CouncilSwedish Heart–Lung foundationEuropean Union Horizon 2020 (Grant number 634869)Dalarna UniversityUppsala UniversitySwedish Medical Research CouncilNjurfondenEuropean Union’s Horizon 2020 research and innovation programme, Marie Sklodowska-Curie Grant Agreement no. 722609Publishe