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Toll-like receptors (TLRs) play a key role in the response of innate and adaptive immune system to microbial and endogenous ligands. Inflammation is a common feature in end-stage renal disease (ESRD) patients; however, the mechanisms/factors triggering the inflammatory process are still poorly clarified. Our aim was to analyze the impact of the c.-1486T>C and c.896A>G polymorphisms in TLR9 and TLR4 genes, respectively, on the inflammatory response of ESRD patients. Clinical and laboratory evaluation was carried out on 184 ESRD patients. Polymerase chain reaction followed by restriction fragmens length polymorphisms (PCR-RFLP) was employed for genotyping of TLR-4 c.896A>G and TLR-9 c.-1486T>C polymorphisms. The prevalence of AA and AG of TLR4 c.896A>G polymorphism in ESRD patients was 97.8% and 2.2%, respectively. None of the individuals showed a homozygous TLR4 polymorphism. Concerning the TLR9 c.-1486T>C polymorphism, we found that ESRD patients showed a prevalence of TC and CC genotypes of 57.1% and 20.6%, respectively. We found that the heterozygous patients for the TLR4 c.896A>G polymorphism presented an increased level in lymphocyte count, a decrease in neutrophil/lymphocyte ratio and in serum levels of hepcidin. Regarding the TLR9 c.-1486T>C polymorphism, we found that it is associated with decreased white blood cell and neutrophil counts, ferritin and CRP serum levels, and with an increase in serum levels of creatinine. Our data suggest that the presence of the studied polymorphisms is associated with a decreased inflammatory response in ESRD patients under hemodialysis, and, thus its presence might have beneficial effects in ESRD patients. Moreover, our data provide new insights in the role of TLR polymorphisms in renal disease, which might have impact in the near future for the development of innovative therapies.

The article focuses on modern methods of mining activity documentation and visualization. The development of technologies that allow us to display 3D models are many in recent years, from web portals, augmented reality using smartphones or tablets to virtual reality glasses. These technologies give us a whole new way of looking at and viewing 3D models. In this study, we will use most of the available options to visualize mining activities in the UNESCO-protected Ore Mountains. Each of these technologies needs differently prepared data. Because each of these technologies have different limits, we need to find these limits and modify the 3D models. The ZEB Revo laser scanner was used for data acquisition, which uses SLAM technology and is much more suitable for such areas than conventional terrestrial scanners, with which the work is lengthy and not nearly as efficient, and not the least of which eliminates the time-consuming post-scan work of merging scans. Especially when using scanning for mining, where there is not quite enough to go around, manually splicing scans is a nightmare, and automatic post-production merging is also often problematic.

The topic of this paper is the description and analysis of technologies for generating a geometric basis for BIM. The main element is an analysis of the capabilities of mobile laser scanning and the outputs of this method compared to other methods. The selected interior space was measured by different technologies, laser scanning, classical geodetic using total station, and manual measurement. The main device tested was the ZEB-REVO. It is a handheld mobile laser scanner, carried by an operator. It has a range of 40 m, with the accuracy in measured lengths is 1–3cm per 10 m depending on the type of surface. The scanning speed is 43,000 points per second. The device is equipped with an inertial measurement unit (IMU) and uses SLAM technology for trajectory definition. The device does not have a camera in the simplest configuration and the operator cannot monitor the scanning status. Nevertheless, measurement with this scanner is very simple. The instrument is mainly used for surveying construction objects, but it can be advantageously used for documentation of underground spaces or in e.g., forestry for defining DBH or volume of stockpiles. This device is not equipped with a GNSS unit, and the typical scanning time is 20–30 min without model deformation. Accuracy and output analysis was performed for all technologies used. The results are presented in tables and show the suitability of PLS (personal laser scanner) in general.

This paper presents the development of a new three-dimensional brick finite element by the use of the strain based approach for the linear analysis of plate bending. The developed element has the three essential external degrees of freedom (U, V and W) at each of the eight corner nodes as well as at the centroidal node. The displacement field of the developed element is based on assumed functions for the various strains satisfying the compatibility equations and the static condensation technique is used for the internal node. The performance of this element is evaluated on several problems related to thick and thin plate bending in linear analysis. The obtained results show the good performances and accuracy of the present element.

Девальвационные процессы в условиях всемирного кризиса яв­ ляются неизбежным атрибутом рыночной экономики. Для Казах­ стана, как и других стран мира, в сложившихся условиях эта мера была неизбежна. Прежде всего, она позволяет повысить конкурен­ тоспособность экономики, улучшить условия работы экспортеров, что позволит сохранить или создать новые рабочие места, а также с меньшими издержками выйти из кризисной ситуации. В результате девальвации в меньшей степени тратятся золотовалютные резервы страны, создаются необходимые условия притока иностранного ка­ питала. Девальвационные процессы оказались мерами, направленными на улучшение экономических параметров страны, в первую очередь – для национальных предприятий. За счёт удешевления тенге эконо­ мические субъекты получат дополнительную прибыль, что в целом позитивно скажется на экономике республики. Әлемдік дағдарыс жағдайында құнсыздану процестері нарықтық экономиканың сөзсіз атрибуты болып табылады. Ең алдымен, дағда­ рыстан шығуға, жұмыс орындарын сақтауға немесе құруға мүмкіндік береді, ол экспорттаушылардың еңбек жағдайларын жақсарту үшін, экономиканың бәсекеге қабілеттілігін арттыру, сондай-ақ аз қымбат мүмкіндік береді. Девальвация нәтижесінде кем елдің валюталық ре­ зервтері жұмсалады, шетелдік капиталдың қажетті жағдайлар ағыны құрылады. Отандық кәсіпорындар үшін құнсыздану процестерін бірінші ке­ зекте елдің экономикалық параметрлерін жақсартуға бағытталған іс-шаралар дәлелдеді. Экономикалық субъектілердің бағасы төмен­ деуіне, қосымша пайда алуға, әдетте, республика экономикасына оң әсерін тигізеді.

The ability to promote an immunosuppressive microenvironment has been recognized as one of the “next generation” cancer hallmarks, being most apparent in case of HPV-induced carcinogenesis, since it is a prerequisite to the virus persistence and proliferation of keratinocytes expressing HPV-antigens. With respect to HPV-associated cervical cancer, it is commonly known that initial pre-cancerous intraepithelial lesions frequently undergo reverse development due to effective recognition and eradication by the immunocompetent cells. Both innate (e.g. NK) and adaptive (helper and cytotoxic O-cells) arms of immunity have been implicated in the regression of neoplastic cells, with NK T-cells considering as a connecting link between two branches. Progression of intraepithelial neoplasia leads to the establishment of pre-invasive cancer, which can be regarded as the result of a completed immunoediting of the tumor locus, because further, with 100% probability, it turns into invasive metastatic form. We assumed that the signs of immune activation, on the one hand, and the signs of immunosuppression, on the other hand, despite the locality of pre-invasive cervical cancer, can be found in the circulation and can be relevant to the development of tolerogenic microenvironment. The aim of the present work was to investigate the number of functionally different subpopulations of T- and NK-lymphocytes in the blood of patients with pre-invasive cervical cancer. Material and methods: Blood samples were taken from 35 HPV(+) patients diagnosed with cancer in situ. The control group consisted of 30 healthy HPV(−) women with no pathology of the cervix. Lymphocytes were immunophenotyped by MACSQuant flow cytometer. The percentage of the following populations were measured: CD3+CD95+/high, CD3+CD4+, CD3+CD4+CD95+/high, CD3+CD8+, CD3+CD8+CD95+/high, CD4+CD25+, CD4+CD25high, CD4+CD25+CD127dim/neg, CD4+CD25+FoxP3+ (CD4 Tregs), CD8+CD25+, CD8+CD25+CD127dim/neg, CD8+CD25+FoxP3+ (CD8 Tregs), CD3−CD16+, CD3−CD56+, CD3−(CD16±)CD56bright, CD3−CD16+CD56+, CD3−CD16low/negCD56+, CD3−CD16+CD56- (NK subpopulations), CD3+CD56+, CD3+CD16+CD56+ (NK T-lymphocytes). Results: Increase in the number of CD4 Tregs that are known to exert immunosuppressive effect was found in cancer patients’ group, namely the increased quantity of cells with CD4+CD25+ (especially, CD4+CD25high fraction), CD4+CD25+CD127dim/neg, or CD4+CD25+FoxP3+ phenotypes was shown. At the same time, the portion of CD4+FoxP3+ lymphocytes didn’t differ between the studied groups. A rare population of CD8+ Tregs (CD8+CD25+CD127dim/negFoxP3+) also exhibited a tendency to accumulate in the blood of cancer patients compared with the control. Analysis of the major subpopulation of NK cells performing cytotoxic reactions didn’t reveal significant difference between the examined groups. Similar result was obtained in relation to the other functional groups of NK cells, specifically CD3−CD16±CD56bright (cytokine-producing NKs with low cytotoxicity), CD3−CD16dim/−CD56+ (NKs with potential anti-tumor activity), and CD3−CD16+CD56 – (NKs associated with viral infection or NK-precursors). However, an increase of NK T-lymphocyte amounts was established, arguing both activation of anti-tumor response and its inhibition, in view of functional polymorphism of this population. Similarly, the increased number of CD3+CD95+/high cells and CD3+CD4+CD95+/high T-helpers may have dual significance, taking into account that the mid-early T-cell activation marker CD95/Fas presents the key death-receptor (earlier we have revealed the elevated activity of caspases involved in the Fas-mediated signaling in circulating lymphocytes of cervical cancer patients). The total numbers of CD3+CD4+ T-helpers and CD3+CD8+ T-killers were generally comparable between the groups analyzed, with T-killers displaying slightly decreased percentage in the patient group. Conclusion: The processes supporting establishment of immunosuppressive microenvironment extend beyond the local level during the earliest steps of cervical cancer progression. The observed changes may reflect the shift of equilibrium between immune activation and suppression, which is the essence of immunoediting. Further phenotypic analysis of cell subpopulations reported here is required for understanding the functional meaning of these changes. The study was supported by the grants NK-1404-32098, 11.G34.31.0052, the Program of strategic development of PetrSU for 2012-2016, and the State task for R&D.

Objective: Recombinant human erythropoietin (rhEPO) therapy under circumstances of moderate chronic renal failure (CRF), with yet lower kidney and heart lesion, may have a protective cardiac effect beyond the correction of anemia, whose mechanism deserves better elucidation, namely by clarifying the impact on gene expression profile of markers of apoptosis, inflammation, proliferation, angiogenesis, and lesion/stress in the heart. Materials and Methods: Four groups of rats were studied over a period of 15 weeks (n=7 each): control-without surgery and without drug treatment; rhEPO-treated with 50 IU/kg/week of rhEPO-beta; CRF-submitted to partial nephrectomy (3/4); CRF + rhEPO-CRF with rhEPO treatment after the 3rd week of surgery. The heart was collected in order to evaluate the gene expression, by real-time qPCR, of markers of apoptotic machinery, inflammation/immunology, proliferation/angiogenesis, and lesion/stress. Results: The main findings obtained were (a) CRF rats have demonstrated overexpression of EPO-R in the heart without changes on EPO expression, together with overexpression of Bax/Bcl2 ratio, PCNA, and IL-2; (b) rhEPO therapy on the heart of the rats with CRF induced by partial 3/4 nephrectomy promoted nonhematopoietic protection, demonstrated by the apoptosis prevention, viewed by the Bax/Bcl2 balance, by the promotion of proliferation, due to PCNA increment, and by the immunomodulatory action, expressed by a trend to prevent the IL-2 increment. Conclusion: In this model of moderate CRF, rhEPO treatment showed important cardiac nonhematopoietic effects, expressed mainly by the antiapoptotic and the proproliferative action, suggesting that early rhEPO therapy in moderate stages of CRF might have further therapeutic benefits.

We aimed to study the impact of polymorphisms in the genes encoding interleukin-6 (IL6) and tumor necrosis factor receptor-2 (TNFR2), reported to be mortality risk predictors, in patients with end-stage kidney disease (ESKD) undergoing dialysis. TNFRSF1B (rs3397, rs1061624, and rs1061622) and IL6 (rs1800796, rs1800797, and rs1554606) polymorphisms were studied in patients with ESKD and controls; the genotype and allele frequencies and the associations with inflammatory and erythropoiesis markers were determined; deaths were recorded throughout the following two years. The genotype and allele frequencies for the TNFRSF1B rs3397 polymorphism were different in these patients compared to those in the controls and the global and European populations, and patients with the C allele were less common. Patients with the CC genotype for TNFRSF1B rs3397 presented higher hemoglobin and erythrocyte counts and lower TNF-α levels, suggesting a more favorable inflammatory response that seems to be associated with erythropoiesis improvement. Patients with the GG genotype for TNFRSF1B rs1061622 showed lower serum ferritin levels. None of the TNFRSF1B (rs3397, rs1061624, and rs1061622) or IL6 (rs1800796, rs1800797, and rs1554606) polymorphisms had a significant impact on the all-cause mortality rate of Portuguese patients with ESKD.

Gadolinium-based contrast agents (GBCAs) have been used for more than 30 years to improve magnetic resonance imaging, a crucial tool for medical diagnosis and treatment monitoring across multiple clinical settings. Studies have shown that exposure to GBCAs is associated with gadolinium release and tissue deposition that may cause short- and long-term toxicity in several organs, including the kidney, the main excretion organ of most GBCAs. Considering the increasing prevalence of chronic kidney disease worldwide and that most of the complications following GBCA exposure are associated with renal dysfunction, the mechanisms underlying GBCA toxicity, especially renal toxicity, are particularly important. A better understanding of the gadolinium mechanisms of toxicity may contribute to clarify the safety and/or potential risks associated with the use of GBCAs. In this work, a review of the recent literature concerning gadolinium and GBCA mechanisms of toxicity was performed.

Worldwide, the number of elderly individuals receiving chronic hemodialysis is rising. The aim of our study was to evaluate several clinical and analytical biomarkers in chronically dialyzed patients and analyze how they change with age. A cross-sectional study was performed by evaluating 289 end-stage renal disease patients undergoing dialysis. We evaluated the hemogram, adipokines, the lipid profile, and several markers related to inflammation, endothelial function/fibrinolysis, nutrition, iron metabolism, and cardiac and renal fibrosis. Clinical data and dialysis efficacy parameters were obtained from all patients. The relationships between studied biomarkers and age were assessed by a statistical comparison between younger (adults with age < 65 years) and older (age ≥ 65 years) patients and by performing regression analysis. Participants presented a mean age of 68.7 years (±13.6), with 66.8% ( n = 193) being classified as older. Compared to younger patients, older patients presented the following: (a) significantly lower values of diastolic blood pressure (DBP) and ultrafiltration volume; (b) lower levels of phosphorus, uric acid, creatinine, and albumin; and (c) higher circulating concentrations of tissue-type plasminogen activator (tPA), D-dimer, interleukin-6, leptin, N -terminal pro B-type natriuretic peptide, and tissue inhibitor of metalloproteinase-1. In the multiple linear regression analysis, DBP values, tPA, phosphorus, and D-dimer levels were independently associated with the age of patients (standardized betas: -0.407, 0.272, -0.230, and 0.197, respectively; p < 0.001 for all), demonstrating relevant changes in biomarkers with increasing age at cardiovascular and nutritional levels. These findings seem to result from crosstalk mechanisms between aging and chronic kidney disease.

One of the industrialized cities in the Philippines is Meycauayan, Bulacan. This study reports the elemental distribution and source apportionment in eight varying land cover-land use type sampling points located along the Marilao-Meycauayan- Obando Rivers System. Elemental analysis was conducted using a scanning electron microscope coupled with energy dispersive x-ray. Cu, Pb, Zn, Cr, Mn, As, Cd, Co, Fe, Ni, Ti, and V concentrations were determined using Inductively Coupled Plasma Mass Spectrometry, and Hg concentrations by Mercury analyzer. Principal component analysis (PCA), hierarchical cluster analysis (HCA), and Pearson's r correlation were used to analyze different sources of heavy metals and its corresponding land use-land cover type. The aerosol samples showed the presence of heavy metals Pb and Hg, elements that were also detected in trace amounts in the water measurements. Concentrations of heavy metals such as Cu, Fe, Pb, Zn, V, Ni, and As found in the atmospheric aerosols and urban dusts were attributed to anthropogenic sources such as residential, commercial and industrial wastes. Other source of aerosols in the area were traffic and crustal emissions in Meycauayan. Using HCA, there are 3 clusters observed based on the similar sets of heavy metals: (1) AQS1 (Caingin), AQS2 (Banga), and AQS8 (Malhacan); (2) AQS3(Calvario), AQS4 (Camalig), and AQS5(Langka); (3) AQS1(Sto Nino-Perez), and (AQS7) (Sterling). These groups are related based on different land use setting such as residential/commercial, agricultural, and commercial/industrial areas. Our study recommends the need to address heavy metal pollution in Meycauayan in support to the ongoing implementation of laws and regulations by the local and private sectors., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Left ventricular hypertrophy (LVH) is a common cardiovascular complication in end-stage kidney disease (ESKD) patients. We aimed at studying the association of LVH with adiponectin and leptin levels, cardiovascular stress/injury biomarkers and nutritional status in these patients. We evaluated the LV mass (LVM) and calculated the LVM index (LVMI) in 196 ESKD patients on dialysis; the levels of hemoglobin, calcium, phosphorus, parathyroid hormone, albumin, adiponectin, leptin, N-terminal pro B-type natriuretic peptide (NT-proBNP) and growth differentiation factor (GDF)-15 were analyzed. ESKD patients with LVH ( n = 131) presented higher NT-proBNP and GDF-15, lower hemoglobin and, after adjustment for gender, lower leptin levels compared with non-LVH patients. LVH females also showed lower leptin than the non-LVH female group. In the LVH group, LVMI presented a negative correlation with leptin and a positive correlation with NT-proBNP. Leptin emerged as an independent determinant of LVMI in both groups, and NT-proBNP in the LVH group. Low hemoglobin and leptin and increased calcium, NT-proBNP and dialysis vintage are associated with an increased risk of developing LVH. In ESKD patients on dialysis, LVH is associated with lower leptin values (especially in women), which are negatively correlated with LVMI, and with higher levels of biomarkers of myocardial stress/injury. Leptin and NT-proBNP appear as independent determinants of LVMI; dialysis vintage, hemoglobin, calcium, NT-proBNP and leptin emerged as predicting markers for LVH development. Further studies are needed to better understand the role of leptin in LVH in ESKD patients.

The inflammatory pathway driven by TNF-α, through its receptors TNFR1 and TNFR2, is a common feature in the pathogenesis of chronic kidney disease (CKD), regardless of the initial disease cause. Evidence correlates the chronic inflammatory status with decreased renal function. Our aim was to evaluate the potential of TNF receptors as biomarkers for CKD diagnosis and staging, as well as their association with the progression of renal lesions, in rat models of early and moderate CKD. We analyzed the circulating levels of inflammatory molecules-tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1) and 2 (TNFR2) and tissue inhibitor of metalloproteinase-1 (TIMP-1)-and studied their associations with TNFR1 and TNFR2 renal expression, glomerular and tubulointerstitial lesions, and with biomarkers of renal (dys)function. An increase in all inflammatory markers was observed in moderate CKD, as compared to controls, but only circulating levels of both TNFR1 and TNFR2 were significantly increased in the early disease; TNFR2 serum levels were negatively correlated with eGFR. However, only TNFR2 renal expression increased with CKD severity and showed correlations with the score of mild and advanced tubular lesions. Our findings suggest that renal TNFR2 plays a role in CKD development, and has potential to be used as a biomarker for the early detection and progression of the disease. Still, the potential value of this biomarker in disease progression warrants further investigation.

Chronic kidney disease (CKD) is commonly associated with a high burden of comorbidities and poor clinical outcomes. Malnutrition-inflammation-atherosclerosis syndrome is common in the more severe stages of CKD, suggesting a close interplay for these three comorbid conditions. Both malnutrition and obesity are associated with a disturbed adipokine profile and inflammation, contributing to a higher risk of cardiovascular disease (CVD) events. Adiponectin and leptin have important roles in carbohydrate and lipid metabolism, and in the inflammatory process. The effects of adiponectin and leptin alterations in CKD, which are usually increased, and their association with the different comorbidities found in CKD, will be focused on to understand their crosstalk with the risk of CVD events. Nonetheless, although adiponectin and leptin contribute to a higher risk of CVD events, further studies are warranted to fully clarify their roles, especially when different comorbidities exist.

Background: Inflammation is a common feature in the pathogenesis of chronic kidney disease (CKD), regardless of the disease cause. Our aim was to evaluate the potential of several inflammatory biomarkers in CKD diagnosis and staging., Methods: A total of 24 healthy controls and 92 pre-dialysis CKD patients with diverse etiologies, were enrolled in this study and grouped according to their CKD stage. We analysed the circulating levels of inflammatory molecules, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 2 (TNFR2), pentraxin 3 (PTX3) and leptin, as well as the hemogram. We studied their association with parameters of kidney function and kidney injury, to evaluate their potential as early markers of the disease and/or of its worsening, as well as their interplay., Results: Compared to controls, patients in CKD stages 1-2 presented significantly higher IL-6 and TNFR2 levels, and higher neutrophil-to-lymphocyte ratio. All inflammatory cytokines and acute-phase proteins showed a trend to increase up to stage 3, stabilizing or declining thereafter, save for TNFR2, which steadily increased from stage to stage. All inflammatory molecules, apart from PTX3, were negatively and significantly correlated with eGFR, with a remarkable value for TNFR2 (r = - 0.732, p < 0.001)., Conclusion: TNFR2 might be useful for an early detection of CKD, as well as for disease staging/worsening. Still, the potential value of this biomarker in disease progression warrants further investigation., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Chronic kidney disease (CKD) has been recognized as a global public health problem. Despite the current advances in medicine, CKD-associated morbidity and mortality remain unacceptably high. Several studies have highlighted the contribution of inflammation and inflammatory mediators to the development and/or progression of CKD, such as tumor necrosis factor (TNF)-related biomarkers. The inflammation pathway driven by TNF-α, through TNF receptors 1 (TNFR1) and 2 (TNFR2), involves important mediators in the pathogenesis of CKD. Circulating levels of TNFRs were associated with changes in other biomarkers of kidney function and injury, and were described as predictors of disease progression, cardiovascular morbidity, and mortality in several cohorts of patients. Experimental studies describe the possible downstream signaling pathways induced upon TNFR activation and the resulting biological responses. This review will focus on the available data on TNFR1 and TNFR2, and illustrates their contributions to the pathophysiology of kidney diseases, their cellular and molecular roles, as well as their potential as CKD biomarkers. The emerging evidence shows that TNF receptors could act as biomarkers of renal damage and as mediators of the disease. Furthermore, it has been suggested that these biomarkers could significantly improve the discrimination of clinical CKD prognostic models.

Chronic inflammation plays an important role in the progression and outcome of chronic kidney disease (CKD). The circulating levels of the inflammatory biomarkers interleukin 6 (IL6) and pentraxin 3 (PTX3) are enhanced in CKD patients, and are associated with the progression of the disease and with higher risk for cardiovascular events, the major cause of death in CKD patients. Our aim was to study how specific polymorphisms of IL6 and PTX3 encoding genes affect the inflammatory response and outcome of end-stage renal disease (ESRD) patients on dialysis. Methodology included the analysis of two single nucleotide polymorphisms (SNP), namely the IL6 (rs1800795) polymorphism in the promoter region (-174G > C), and the PTX3 (rs2305619) polymorphism in the intron 1 (+ 281A > G), which were analyzed in ESRD patients on dialysis and in a group of heathy individuals. The allelic frequencies, genotype distribution and their association with circulating levels of the inflammatory markers C-reactive protein (CRP), IL6, growth differentiation factor 15 (GDF15) and PTX3, were determined in ESRD patients. Events of death were recorded along one year, to assess the association of the studied SNPs with all-cause mortality and the inflammatory biomarkers, in ESRD patients. Results showed that the allelic frequencies and genotype distribution for IL6 and PTX3 SNPs in the control group and ESRD patients were similar and in agreement with other European reports. For the IL6 polymorphism, we found a trend towards higher levels of high-sensitivity (hs) CRP, IL6 and PTX3 in the homozygous genotypes; the CC genotype also showed the highest levels of GDF15. The mortality rate after the 1-year follow-up was 10.4%. The CC genotype (IL6 SNP) was associated to a higher risk of mortality and deceased patients carrying this genotype also showed the highest levels of hsCRP. Regarding the studied PTX3 SNP, the AA genotype was linked to an enhanced inflammatory response, showing the highest values of hsCRP and IL6. Nevertheless, this genotype had no significant impact on the mortality rate. In conclusion, both studied SNPs seem to modulate the inflammatory response in ESRD and may, therefore, be determinant on disease progression and patients' outcome. Our data also highlights the importance of research on genetic variants that, although less frequent, may have significant biological value., (© 2021. The Author(s).)

Dyslipidemia is a major traditional risk factor for cardiovascular disease (CVD) in chronic kidney disease (CKD) patients, although the altered lipid profile does not explain the number and severity of CVD events. High-density lipoprotein (HDL) is a heterogeneous (size, composition, and functionality) population of particles with different atherogenic or atheroprotective properties. HDL-cholesterol concentrations per se may not entirely reflect a beneficial or a risk profile for CVD. Large HDL in CKD patients may have a unique proteome and lipid composition, impairing their cholesterol efflux capacity. This lack of HDL functionality may contribute to the paradoxical coexistence of increased large HDL and enhanced risk for CVD events. Moreover, CKD is associated with inflammation, oxidative stress, diabetes, and/or hypertension that are able to interfere with the anti-inflammatory, antioxidative, and antithrombotic properties of HDL subpopulations. How these changes interfere with HDL functions in CKD is still poorly understood. Further studies are warranted to fully clarify if different HDL subpopulations present different functionalities and/or atheroprotective effects. To achieve this goal, the standardization of techniques would be valuable.

The prevalence of chronic kidney disease (CKD) is increasing worldwide, and the mortality rate continues to be unacceptably high. The biomarkers currently used in clinical practice are considered relevant when there is already significant renal impairment compromising the early use of potentially successful therapeutic interventions. More sensitive and specific biomarkers to detect CKD earlier on and improve patients' prognoses are an important unmet medical need. The aim of this review is to summarize the recent literature on new promising early CKD biomarkers of renal function, tubular lesions, endothelial dysfunction and inflammation, and on the auspicious findings from metabolomic studies in this field. Most of the studied biomarkers require further validation in large studies and in a broad range of populations in order to be implemented into routine CKD management. A panel of biomarkers, including earlier biomarkers of renal damage, seems to be a reasonable approach to be applied in clinical practice to allow earlier diagnosis and better disease characterization based on the underlying etiologic process.

We examined the effects of a 6-month school-based soccer programme on cardiovascular (CV) and metabolic risk factors in overweight children. Methods: 40 boys [8-12 years; body mass index (BMI) >2 standard deviations of WHO reference values] participated in complementary school-based physical education classes (two sessions per week, 45-90 min each). The participants were divided into a soccer group (SG; n = 20) and a control group (CG; n = 20). The SG intervention involved 3 extra-curricular school-based soccer sessions per week, 60-90 min each. The intervention lasted for 6-months. All measurements were taken at baseline and after 6-months. From baseline to 6-months, the SG significantly improved (p < .05) BMI z-score, waist circumference, waist-to-height ratio, percentage of fat mass, percentage of fat-free mass, diastolic blood pressure, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol, but no such improvements were observed for the CG. After the intervention, the prevalence of soccer participants with normal waist-to-height ratio (30 vs. 5%; p = .037), systolic blood pressure (90 vs. 55%; p = .039), total cholesterol (80 vs. 65%; p = .035) and LDL-C (90 vs. 75%; p = .012) were significantly higher than at baseline. The findings suggest that a 6-month school-based soccer intervention program represents an effective strategy to reduce CV and metabolic risk factors in overweight children prepared to take part in a soccer program., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: DNA damage and inflammation are common in end-stage renal disease (ESRD). Our aim was to evaluate the levels of circulating cell-free DNA (cfDNA) and the relationship with inflammation, anaemia, oxidative stress and haemostatic disturbances in ESRD patients on dialysis. By performing a 1-year follow-up study, we also aimed to evaluate the predictive value of cfDNA for the outcome of ESRD patients., Methods: A total of 289 ESRD patients on dialysis were enrolled in the study: we evaluated cfDNA, haemogram, serum iron, hepcidin, inflammatory and oxidative stress markers, and haemostasis. Events and causes of deaths were recorded throughout the follow-up period., Results: ESRD patients, as compared with controls, presented significantly higher levels of cfDNA, hepcidin, and inflammatory and oxidative stress markers, and significantly lower values of iron and anaemia-related haemogram parameters. The all-cause mortality rate was 9.7%; compared with alive patients, deceased patients ( n  =   28) were older and presented significantly higher values of inflammatory markers and of cfDNA, which was almost 2-fold higher. Furthermore, cfDNA was the best predictor of all-cause mortality and cardiovascular mortality in ESRD patients, in both unadjusted and adjusted models for basic confounding factors in dialysis., Conclusions: Our data show cfDNA to be a valuable predictive marker of prognosis in ESRD patients on dialysis treatment; high levels of cfDNA were associated with a poor outcome., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Hereditary Spherocytosis (HS) is a non-immune hemolytic anemia associated to oxidative stress (OS), namely to the linkage of cytosolic antioxidant enzymes to the erythrocyte membrane. Our aims were to evaluate erythrocyte OS changes and the membrane linkage of peroxiredoxin 2 (Prx2), glutathione peroxidase (GPx) and catalase (CAT) in unsplenectomized (unspl) and splenectomized (spl) HS patients and to search for associations with clinical severity (in unspl HS patients). We studied 114 HS patients (74 unspl and 40 spl) and 30 healthy individuals and we evaluated membrane bound hemoglobin (MBH), membrane lipid-peroxidation (LPO), enzymatic activities of GPx and CAT and the amounts of membrane bound Prx2, GPx and CAT, as well as, clinical and analytical parameters for characterization of HS. We found that unspl HS patients showed clear signs of anemia and in spl HS, a correction to this anemia was observed; the latter patients presented higher levels of OS biomarkers, namely, MBH and LPO. CAT was detected in the membrane of all individuals (control and HS groups), while GPx and Prx2 were only present in HS patients; moreover, their linkage to the membrane (in HS) appears to be cumulative since membrane bound peroxidases amount was higher as the number of peroxidases detected increased. MBH increased with the number/amount of membrane bound peroxidases, however LPO levels remained similar. In conclusion, our data suggest that the binding of these typically cytosolic peroxidases to erythrocyte membrane may be part of a mechanism of membrane protection to maintain its integrity by possibly regulating LPO., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Soluble transferrin receptor (sTfR) is a biomarker of erythropoiesis, which is often impaired in dialysis patients. The aim of our study was to evaluate sTfR levels in chronically dialyzed patients and assess potential determinants of its levels. Methods: We performed a cross-sectional study by evaluating 246 end-stage renal disease patients undergoing dialysis and 32 healthy controls. Circulating levels of interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, hepcidin, sTfR, growth differentiation factor 15 (GDF15), and traditional iron metabolism markers were measured, as well as hemogram parameters. Clinical data was obtained from all patients. Results: Compared to controls, patients presented similar values of sTfR, reticulocytes and reticulocyte production index (RPI), and significantly higher levels of IL-6, CRP, ferritin, hepcidin, TNF-α, and GDF15. Iron, transferrin, hemoglobin levels, erythrocyte count, mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC) values were significantly lower in dialysis group. Within patients, sTfR values were higher in diabetic patients and were positively and significantly correlated with reticulocytes and erythrocytes, RPI, and therapeutic doses of erythropoiesis stimulating agents (ESA) and intravenous iron; and inversely and significantly correlated with circulating iron, ferritin, transferrin saturation, hepcidin, MCH, and MCHC. In multiple linear regression analysis, ESA dose, RPI, serum iron, diabetes, and hepcidin levels were independently associated with sTfR levels in dialysis patients and, thus, with erythropoiesis. Conclusion: Our data suggest that, besides RPI and ESA dose, diabetes and hepcidin are closely related to erythropoiesis in dialysis patients. The influence of diabetes on sTfR levels deserves further investigation.

The phytoremediation potential of three bamboo species, i.e. Bambusa merilliana , Bambusa blumeana , and Dendrocalamus asper , were evaluated for their total Cu uptake ability in hydroponics. Dendrocalamus asper proved to be the most efficient in terms of Cu phytoremediating potential with a constant positive uptake of 80 μM in a contaminated substrate and a bioconcentration factor of 50.57. Copper accumulation was found to concentrate the most in the roots compared to the amount translocated in the shoots. Analysis of the Cu uptake of D. asper roots at varying concentrations of Cu contamination (40, 80 and 120 μM) allowed for the fitting of the kinetics of Cu uptake and removal with existing kinetic models. The rate of copper removal per mass of plant was the best for the 0 th order model in the 80 μM solution with an R 2 of 0.954 and rate constant of 3.136 mg-kg -1 d -1 . The accumulation of Cu within the roots on day 7 (7d) followed the Michaelis-Menten model with an R 2 of 0.970. The Michaelis-Menten constant (K M ) was 4.87 mg/L and maximum accumulation velocity (Vmax) was 66.26 mg Cu-kg -1 -day -1 . Results suggest that D. asper is a potential hyperaccumulator plant that can be used in clean-up of domestic and industrial wastes present along river systems in the Philippines., (© 2019 The Author(s).)

Persistent inflammation in end-stage renal disease (ESRD) patients is known to underlie the progression of chronic kidney disease and to be associated with multiple risk factors including malnutrition, atherosclerosis, and cardiovascular disease (CVD). The acute-phase protein pentraxin 3 (PTX3) has a proven potential as a local inflammatory biomarker, but its clinical utility in ESRD remains unclear. Circulating levels of PTX3 and classical inflammatory mediators, including the clinical prototypical C-reactive protein (CRP), were assessed in 246 ESRD patients on dialysis and analysed in relation to the lipid profile, adipokine levels, and nutritional, cardiac, and renal fibrosis markers. Occurrence of deaths was recorded for the following year. Contrarily to the classical inflammatory markers, PTX3 levels were negatively correlated with nutritional markers and associated with a less atherogenic lipid profile. Levels of the cardiac and renal fibrosis markers and of the oxidized LDL/LDL-C ratio were found to be independent determinants of PTX3 concentration. When comparing inflammatory mediators, the increase in the PTX3 levels was the only predictor of all-cause mortality in dialysis patients in a survival model adjusted to all markers under study, other than the inflammatory ones, besides common confounding factors in dialysis. Data support the clinical applicability of PTX3 as a broader inflammatory biomarker than the classical ones, presenting a close association with inflammation, malnutrition, CVD, and renal fibrosis and a great potential to predict all-cause mortality in dialysis patients. The pleiotropic character of PTX3 may be of clinical relevance, and it could be targeted to ameliorate the high morbidity and mortality associated with ESRD.

Cardiovascular disease (CVD) events are the main causes of death in end-stage renal disease (ESRD) patients on dialysis. The number and severity of CVD events remain inappropriate and difficult to explain by considering only the classic CVD risk factors. Our aim was to clarify the changes and the relationship of lipoprotein subfractions with other CVD risk factors, namely, body mass index (BMI) and adipokines, inflammation and low-density lipoprotein (LDL) oxidation, and the burden of the most prevalent comorbidities, diabetes mellitus (DM) and hypertension (HT). We studied 194 ESRD patients on dialysis and 22 controls; lipid profile, including lipoprotein subpopulations and oxidized LDL (oxLDL), C-reactive protein (CRP), adiponectin, leptin, and paraoxonase 1 activity were evaluated. Compared to controls, patients presented significantly lower levels of cholesterol, high-density lipoprotein cholesterol (HDLc), LDLc, oxLDL, and intermediate and small HDL and higher triglycerides, CRP, adiponectin, large HDL, very-low-density lipoprotein (VLDL), and intermediate-density lipoprotein- (IDL) B. Adiponectin levels correlated positively with large HDL and negatively with intermediate and small HDL, oxLDL/LDLc, and BMI; patients with DM ( n = 17) and with DM+HT ( n = 70), as compared to patients without DM or HT ( n = 69) or only with HT ( n = 38), presented significantly higher oxLDL, oxLDL/LDLc, and leptin and lower adiponectin. Obese patients ( n = 45), as compared to normoponderal patients ( n = 81), showed lower HDLc, adiponectin, and large HDL and significantly higher leptin, VLDL, and intermediate and small HDL. In ESRD, the higher adiponectin seems to favor atheroprotective HDL modifications and protect LDL particles from oxidative atherogenic changes. However, in diabetic and obese patients, adiponectin presents the lowest values, oxLDL/LDLc present the highest ones, and the HDL profile is the more atherogenic. Our data suggest that the coexistence of DM and adiposity in ESRD patients on dialysis contributes to a higher CVD risk, as showed by their lipid and adipokine profiles.

Objectives: Weight loss achieved by laparoscopic adjustable gastric banding (LAGB) induces an increase in high-density lipoprotein cholesterol (HDLc) but a small effect on low-density lipoprotein (LDL), although changes in their quality (size and composition) are uncertain. Our aim was to study the impact of weight loss, achieved 13-months after LAGB, on inflammation and dyslipidemia, focusing on HDL and LDL subfractions, and oxidized LDL (oxLDL)., Design & Methods: We evaluated standard lipid profile, HDL and LDL subfractions, oxLDL, interleukin (IL)-6 and C-reactive protein (CRP), in twenty obese patients, before (T0) and 13-months after LAGB (T1), and in seventeen healthy controls., Results: At T1, patients showed lower body weight (12% median weight loss) and anthropometric indices; reduction in TG, atherogenic indices, oxLDL, oxLDL/LDL ratio, CRP and IL-6, and enhancement in HDLc; an increase in large HDL and intermediate HDL subfractions, and a decrease in small HDL subfraction; LDL subfractions were not modified. Percentual change (%Δ) of oxLDL, from T0 to T1, correlated significantly and positively with %Δ of small HDL subfraction and with %Δ of body mass index., Conclusions: Weight loss induced atheroprotective changes on inflammation, and lipid profile, enhancing larger HDL, the more atheroprotective subfraction, reducing the less protective subclass, small HDL, and reducing oxLDL and oxLDL/LDL ratio. Quality of lipoproteins appears useful cardiovascular risk biomarkers, deserving further studies., (Copyright © 2018 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Chronic kidney disease (CKD) is associated with several complications that worsen with progression of disease; anemia, disturbances in iron metabolism and inflammation are common features. Inflammatory response starts early, releasing pro-inflammatory cytokines, acute phase reactants and hepcidin. Hepcidin production is modulated by several factors, as hypoxia/anemia, erythropoietin and erythropoiesis products, transferrin saturation (TSAT) and liver iron levels, which are altered in CKD. Treatment of CKD anemia is based on pharmaceutical intervention, with erythropoietic stimulating agents and/or iron supplementation; however, in spite of the erythropoietic benefits, this therapy, on a regular basis, involves risks, namely iron overload. To overcome these risks, some therapeutic approaches are under study to target CKD anemia. Considering the actual alerts about risk of iron overload in dialysis patients, inhibition of hepcidin, the central key player in iron homeostasis, could be a pivotal strategy in the management of CKD anemia., (© 2019 Elsevier Inc. All rights reserved.)

BackgroundWe intended to evaluate the effects of physical activity (PA) programs on renal function in obese boys.MethodsThirty-nine boys participated in one of the following three groups: soccer (SG, n=13), traditional PA (AG, n=13), and sedentary control (CG, n=13). SG and AG were involved in 6-month PA programs, involving three sessions/week for 60-90 min. Anthropometric measurements, body composition, creatinine and cystatin C plasmatic levels, and estimated glomerular filtration rate (eGFR) were evaluated.ResultsAt baseline (n=39), age and lean mass index (LMI) were positively correlated with creatinine levels. After 6 months, both intervention groups decreased the BMI z-score and waist circumference, while the CG increased the body fat percentage (BFP). LMI increased in all the groups. SG presented a small increment in plasma creatinine and a decrease in the eGFR values, using the Schwartz formula. Concerning the cystatin C levels and eGFR values using Filler (cystatin C-based) or Combined Zappitelli (creatinine/cystatin C-based) formulas, no significant changes were observed in any group.ConclusionThe combined Zappitelli formula showed no significant impact of PA on eGFR in obese boys. Although plasma creatinine is significantly influenced by lean body mass, cystatin C is likely to be a more accurate marker of renal function in this population.

Background: Most of surgical site infections (SSI) are caused by commensal and pathogenic agents from the patient's microbiota, which may include antibiotic resistant strains. Pre-surgical asepsis of the skin is one of the preventive measures performed to reduce SSI incidence and also antibiotic resistance dissemination. However, in veterinary medicine there is no agreement on which biocide is the most effective. The aim of this study was to evaluate the effectiveness of two pre-surgical skin asepsis protocols in dogs. A total of 46 animals were randomly assigned for an asepsis protocol with an aqueous solution of 7.5% povidone-iodine or with an alcoholic solution of 2% chlorhexidine. For each dog, two skin swab samples were collected at pre-asepsis and post-asepsis, for bacterial quantification by conventional techniques and isolation of methicillin-resistant species., Results: Most samples collected at the post-asepsis did not present bacterial growth, both for the animals subjected to the povidone-iodine (74%) or to the chlorhexidine (70%) protocols. In only 9% of the cases a significant bacterial logarithmic reduction was not observed, indicating possible resistance to these agents. Also, the logarithmic reduction of the bacterial quantification from pre- and post-asepsis time, was not statistically different for povidone-iodine (6.51 ± 1.94 log10) and chlorhexidine (6.46 ± 2.62 log10) protocol. From the 39% pre-asepsis swabs which showed bacterial growth in MRSA modified chromogenic agar medium, only one isolate was identified as Staphylococcus aureus and one as S. epidermidis. False positives were mainly other staphylococci species, as well as Enterobacteriaceae., Conclusions: Pre-surgical skin asepsis protocols with povidone-iodine or chlorhexidine showed similar efficacy in the elimination of methicillin resistant bacteria and preventing surgical site infections in dogs undergoing surgery.

Adipose tissue produces several adipokines that are enrolled in different metabolic and inflammatory pathways that may disturb iron metabolism and erythropoiesis. Considering that laparoscopic adjustable gastric banding (LAGB) has not been associated with a long-term risk of malabsorption, we performed a 13-month follow-up study in severe obese patients submitted to LAGB in order to clarify its impact on inflammation, iron metabolism and on red blood cell (RBC) biomarkers. Twenty obese patients were enrolled in the study, being clinical and analytically assessed before (T0) and 13 months after LAGB intervention (T1). Inflammation, iron bioavailability and RBC biomarkers were evaluated at T0 and T1. At T1, weight and anthropometric indices decreased significantly; patients showed a significant increase in mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration (MCHC), and a reduction in red cell distribution width, ferritin, hepcidin, tumor necrosis factor-α, interleukin-6 (IL-6) and C-reactive protein. Before LAGB, IL-6 correlated negatively with iron, hemoglobin concentration and MCHC; hepcidin correlated inversely with transferrin. Our data show that 13 months after LAGB, the weight loss is associated with an improvement in inflammation, namely a reduction in IL-6 that may reduce hepcidin production, improving iron availability for erythropoiesis, as shown by more adequate erythrocyte hemoglobinization., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

BackgroundObesity is often associated with iron deficiency in children and adolescents. We aimed to study the effect of an 8-month physical exercise (PE) intervention on hepcidin and other markers of inflammation and on iron status in overweight/obese children and adolescents.MethodsSeventy-three overweight/obese children and adolescents participated in the 8-month-long longitudinal study. They were divided into two groups according to their participation in an after-school PE program: the PE group (n=44) and the control group (n=29). Hepcidin, interleukin (IL)-6, C-reactive protein (CRP), iron, ferritin, transferrin, and soluble transferrin receptor (sTfR) were evaluated.ResultsAt baseline, IL-6 correlated positively with hepcidin and negatively with iron and transferrin saturation, suggesting that increasing adiposity associates with increasing IL-6 and hepcidin synthesis, reducing iron availability. After 8 months, the PE group showed a decrease in BMI z-score (P=0.003), body fat mass (P=0.012), CRP (P=0.002), IL-6 (P=0.048), ferritin (P=0.013), hepcidin (P=0.040), and sTfR (P=0.010), and an increase in iron concentration (P=0.002). Moreover, the PE group, when compared with the control group, showed lower weight (P=0.026), BMI (P=0.040), waist circumference (P=0.010), and waist-to-height ratio (P=0.046).ConclusionWe showed that an 8-month-long intervention at school allowed a reduction in BMI z-score and an improvement in inflammation, reducing hepcidin levels and the disturbances in iron status.

Metabolomics, an emerging field of "omics" sciences, has caught wide scientific attention in the area of biomarker research for cancers in which early diagnostic biomarkers have the potential to greatly improve patient outcome, such as renal cell carcinoma (RCC). Metabolomic approaches have been successfully applied to various human RCC model systems, mostly ex vivo neoplastic renal tissues and biofluids (urine and serum) from patients with RCC. Importantly, in contrast to other cancers, only a few studies have addressed the RCC metabolome using cancer cell culture-based in vitro models. Herein, we first carried out a comprehensive review of current metabolomic data in RCC, with emphasis on metabolite disturbances and dysregulated metabolic pathways identified in each of these experimental models. We then critically analyzed the consistency of evidence in this field and whether metabolites found altered in tumor cell and tissue microenvironment are reflected in biofluids, which constitute the rationale underlying the translation of discovered metabolic biomarkers into noninvasive diagnostic tools. Finally, dominant metabolic pathways and promising metabolites as biomarkers for diagnosis and prognosis of RCC are outlined., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Physical activity is important in obesity prevention, but the effectiveness of different physical activity modalities remains to be determined among children. The main purpose of this study was to compare the effects of a 6-month soccer programme and a traditional physical activity programme on changes in body composition, cardiometabolic risk factors, inflammatory and oxidative markers, cardiorespiratory fitness and perceived psychological status in obese boys. Eighty-eight boys (8-12 years; BMI > +2 standard deviations of WHO reference values) participated in one of three groups: soccer, traditional activity and control. Soccer and traditional activity programmes involved 3 sessions per week for 60-90 min at an average intensity of 70-80% of maximal heart rate. Control group participated in activities of normal daily living. All boys participated in school physical education, two sessions per week of 45-90-min. Measurements were taken at baseline and after 6 months, and included body size and composition, cardiometabolic risk factors, inflammatory and oxidative markers, cardiorespiratory fitness and perceived psychological status. Physical activity and dietary intake were assessed before and immediately following the intervention. The three groups had similar characteristics at baseline. After 6 months, both intervention groups had significantly lower relative fatness (% fat), waist circumference and total cholesterol, and higher cardiorespiratory fitness, self-esteem, perceived physical competence and attraction to physical activity compared with control group. In conclusion, physical activity interventions over 6 months positively influenced several indicators of health status among obese boys. The results also suggested that soccer has the potential as an effective tool for the prevention and reduction of childhood obesity and associated consequences.

Purpose: There are few reliable studies assessing the effect of physical exercise (PE) on adipokines levels at young ages. Our objective was to study the effects of regular PE on plasma adipokines in pediatric overweight and obesity., Method: 117 overweight and obese children and adolescents (47% females; 10.2 years) participated in an 8-month longitudinal study divided in two groups: PE group (n = 80), engaged in an after-school PE program; control group (n = 37), with no PE program. Plasma lipids, C-reactive protein (CRP), adiponectin, resistin, leptin, IL-6, IL-1beta, TNF-alpha, insulin and glucose levels were determined., Results: contrarily to the control group, the PE group presented reductions in body mass index z-score (BMIzsc) and body fat percentage that were accompanied by an improvement in lipid profile and insulin resistance, a reduction in CRP and TNF-alpha and an increase in adiponectin levels. The reductions in BMIzsc were inversely correlated with changes in adiponectin (r=-0.329, p = .003) and positively correlated with changes in percentage body fat (r = .262, p = .032), triglycerides (r = .228, p = .042) and leptin (r = .285, p = .010)., Conclusions: Moderate reductions in adiposity improve proinflammatory status in obese children and adolescents. A more substantial reduction in BMIzsc was associated with a greater increment in adiponectin and reduction in leptin.

Background: The genetic contribution to obesity and to circulating adipokine levels has not been completely clarified. We aimed to evaluate adipokine genes' single-nucleotide polymorphism (SNP) prevalence and its association with circulating adipokine levels and risk factors for cardiovascular disease in an obese Portuguese pediatric population., Methods: Two hundred forty-eight obese adolescents (mean age 13.4 years old; 47.2% females) participated in a cohort study. We screened 12 SNPs by direct sequencing in five adipokine genes: adiponectin (ADIPOQ: rs16861194, rs17300539, rs266729, rs2241766, rs1501299), interleukin-1β (IL-1β; rs1143627), IL-6 (IL-6; rs1800795), tumor necrosis factor-α (TNF-α; rs1800629), and resistin (RETN; rs1862513, rs3219177, rs3745367, rs3745368). Biochemical analysis included determination of circulating adipokines, C-reactive protein (CRP) levels, lipid profile, and markers of insulin resistance., Results: Compared to males, females presented higher circulating levels of insulin, adiponectin, IL-6, resistin, and leptin concentrations, but lower TNF-α levels. No statistically significant differences were found for genotype or allelic distributions between genders. In the whole sample population, adiponectin levels were influenced by ADIPOQ rs17300539 (c.-1138G>A; lower in subjects with GG genotype). When only males were considered, IL-1β, IL-6, and TNF-α levels were associated with ADIPOQ rs1501299 (c.214 + 62G>T; higher in GG subjects). TNF-α concentrations were modulated by TNF-α rs1800629 (c.-488G>A; lower in GG males), RETN rs1862513 (c.-216C>G; higher in CC subjects), and RETN rs3219177 (c.118 + 39C>T; higher in CC subjects). Leptin levels were influenced by IL-1β rs1143627 (c.-118C>T) presenting TT individuals' lower levels., Conclusions: Our data demonstrate that in pediatric obese patients, some adipokine gene SNPs have an association with circulating adipokine levels and lipid profile.

Metabolomics has recently proved to be useful in the area of biomarker discovery for cancers in which early diagnostic and prognostic biomarkers are urgently needed, as is the case of bladder cancer (BC). This article presents a comprehensive review of the literature on the metabolomic studies on BC, highlighting metabolic pathways perturbed in this disease and the altered metabolites as potential biomarkers for BC detection. Current disease model systems used in the study of BC metabolome include in vitro-cultured cancer cells, ex vivo neoplastic bladder tissues and biological fluids, mainly urine but also blood serum/plasma, from BC patients. The major advantages and drawbacks of each model system are discussed. Based on available data, it seems that BC metabolic signature is mainly characterized by alterations in metabolites related to energy metabolic pathways, particularly glycolysis, amino acid and fatty acid metabolism, known to be crucial for cell proliferation, as well as glutathione metabolism, known to be determinant in maintaining cellular redox balance. In addition, purine and pyrimidine metabolism as well as carnitine species were found to be altered in BC. Finally, it is emphasized that, despite the progress made in respect to novel biomarkers for BC diagnosis, there are still some challenges and limitations that should be addressed in future metabolomic studies to ensure their translatability to clinical practice., (© 2016 UICC.)

The crosstalk between several factors controlling hepcidin synthesis is poorly clarified for different physiological and pathological conditions. Our aim was to study the impact of increasing recombinant human erythropoietin (rHuEPO) doses on erythropoiesis, iron metabolism and hepcidin, using a rat model. Male Wistar rats were divided in 5 groups: control (vehicle) and rHuEPO-treated groups (100, 200, 400 and 600IU/kgbody weight/week), 3 times per week, during 3weeks. Hematological and iron data were evaluated. The expression of several genes involved in iron metabolism was analyzed by qPCR. Liver hepcidin protein was evaluated by Western Blot. The rHuEPO treatment induced erythropoiesis and increased transferrin saturation (TSAT) in a dose dependent manner. Tf receptor 2 (TfR2), hemojuvelin (HJV) and bone morphogenetic protein 6 (BMP6) were up-regulated in rHuEPO200 group. Matriptase-2 was down-regulated in rHuEPO200 group, and up-regulated in the other rHuEPO-treated groups. Hepcidin synthesis was increased in rHuEPO200 group, and repressed in the rHuEPO400 and rHuEPO600 groups. Our study showed that when a high erythropoietic stimulus occurs, hepcidin synthesis is mainly regulated by TSAT; however, when the erythropoiesis rate reaches a specific threshold, extramedullary hematopoiesis is triggered, and the control of hepcidin synthesis is switched to matriptase-2, thus inhibiting hepcidin synthesis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Anemia of chronic kidney disease (CKD) can be corrected by treatment with recombinant human erythropoietin (rHuEPO); however, some patients become hyporesponsive. The molecular mechanisms underlying this resistance remain to be elucidated. Our aim was to study hyporesponsiveness to rHuEPO therapy using the remnant kidney rat model of anemia associated with CKD induced by 5/6 nephrectomy. At starting, male Wistar rats were divided in 3 groups, for a 3-week protocol: Sham, CRF (vehicle) and two rHuEPO (200 k/kg body weight [BW]/week) treated groups; at the end of protocol, the rHuEPO treated rats were subdivided in responders (CRF200) and non-responders (CRF200NR), according to their hematologic response; blood, cellular and tissue studies were performed. The CRF200 group achieved correction of anemia, while the CRF200NR group developed anemia, after an initial response (1st week) to rHuEPO therapy. CRF and CRF200NR groups presented a trend to higher serum CRP levels; CRF200NR showed also high levels of renal inflammatory markers, such as interleukin (IL)-6, IL-1β, nuclear factor kappa B, connective tissue growth factor (CTGF) and transforming growth factor beta 1 (TGF-β1); no changes were found in iron metabolism. Our data suggest that the development of anemia/rHuEPO hyporesponsiveness is associated with a higher systemic and renal inflammatory condition, favoring hypoxia and triggering an increase in renal expression of HIF-1α, TGF-β1 and CTGF that will further aggravate renal fibrosis, which will enhance the inflammatory response, creating a cycle that promotes disease progression. New therapeutic strategies to reduce inflammation in CKD patients could improve the response to rHuEPO therapy and reduce hyporesponsiveness., (Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Aim: To determine the effects of a school-based exercise intervention programme on cardiovascular risk factors, including body fat (BF), metabolic profile and physical activity (PA) in children with and without individualised dietary counselling approach (IDC and WIDC)., Subjects and Methods: Forty-six overweight children from 6-16 years old (25 girls, 54.3%; age = 10.3 ± 2.8) of six schools took part in an 8-month interdisciplinary, school-based intervention programme. All children were engaged in PA classes, but only one group was exposed to individualised counselling. Blood pressure (BP), lipids and lipoproteins, accelerometer-based PA, percentage of body fat (%BF) and trunk fat (%TF) measures were taken before and after intervention. General Linear Model (Repeated Measures ANOVA) adjusted for age, maturation and height change was used to analyse the longitudinal effect of individualised counselling between two evaluations in each group., Results: Favourable changes were observed for %BF, %TF, systolic BP and total cholesterol in the IDC group. Subjects WIDC only increased light and moderate-vigorous PA. In IDC, significant effects for time * group interactions were found for systolic BP, total cholesterol and LDL-cholesterol, indicating that counselling might add favourable changes in these markers, beyond those explained by PA and growth., Conclusion: School-based interventions can contribute to counteracting obesity in youth, particularly when individualised dietary counselling is provided. Therefore, the link between schools and professional counselling should be strengthened to ensure consolidated changes towards healthy behaviours.

Hepcidin is the major central regulator of iron metabolism, controlling iron absorption and mobilization. Considering its interaction with several factors that are altered in chronic kidney disease (CKD), particularly in hyporesponsive CKD patients under therapy with high recombinant human erythropoietin (rHuEPO) doses, it was aimed to study the impact of increasing rHuEPO doses on the regulation of iron-hepcidin metabolism. The blood, cellular, and tissue studies, using the remnant kidney rat model of CKD induced by 5/6 nephrectomy, under rHuEPO (100, 200, 400, and 600 IU/Kg body weight [BW]/week) treatment during 3 weeks were performed. It was found that the rHuEPO stimulus triggered a first wave to achieve correction of anemia, by inhibiting hepcidin synthesis, favoring erythropoiesis and iron absorption; this continuous stimulus enhanced iron absorption leading to iron overload, as showed by the hepatic iron deposits found in rats treated with higher rHuEPO dose that seems to trigger the upregulation of hepcidin synthesis through the activation of the BMP6/SMAD pathway. The data suggested that liver iron overload was an important stimuli for hepcidin synthesis, stronger than the inhibitory effect of high rHuEPO doses; moreover, the findings raised the hypothesis that when high inflammation (triggering hepcidin expression) was associated with increased iron stores in hemodialysis patients, hepcidin expression was also upregulated via BMP6, enhancing hepcidin synthesis, leading, therefore, to worsening of anemia and, eventually, to a hyporesponse/resistance to rHuEPO therapy. © 2016 BioFactors, 42(3):296-306, 2016., (© 2016 International Union of Biochemistry and Molecular Biology.)

Our aim was to study the effect of a broad range of recombinant human erythropoietin (rHuEPO) doses on hematological and biochemical parameters, blood pressure (BP), renal function and damage in the rat, focusing on endothelial nitric oxide synthase (eNOS) and hypoxia-inducible factors (HIFs). Male Wistar rats were divided in 5 groups receiving different doses of rHuEPO (100, 200, 400 and 600IU/kg body weight (BW)/week) and saline solution (control), during 3weeks. Blood and 24h urine were collected to perform hematological and biochemical analysis. BP was measured by the tail-cuff method. Kidney tissue was collected to mRNA and protein expression assays and to characterize renal lesions. A dose-dependent increase in red blood cells count, hematocrit and hemoglobin levels was found with rHuEPO therapy, in rHuEPO200, rHuEPO400 and rHuEPO600 groups. Increased reticulocyte count was found in rHuEPO400 and rHuEPO600 groups. BP raised in all groups receiving rHuEPO. The rHuEPO200 and rHuEPO600 groups presented increased kidney protein levels of HIF2α, a reduction in kidney protein levels of eNOS, and the highest grade of vascular and tubular renal lesions. Our study showed that rHuEPO-induced hypertension is present before significant hematological changes occur and, therefore, might involve direct (renal) and indirect (hematological) effects, which varies according to the dose used. The presence of renal hypoxia reduces eNOS activity. Excessive erythrocytosis increases blood hyperviscosity, which can be modulated by an increase in reticulocytes. Hypertension leads to early renal damage without alterations in traditional markers of renal function, thus underestimating the serious adverse effects and risks., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Clinical studies showed that high doses of recombinant human erythropoietin (rHuEPO) used to correct anaemia in chronic kidney disease (CKD) hyporesponsive patients may lead to deleterious effects. The aim of this study was to analyze the effects of rHuEPO in doses usually used to correct CKD-anaemia (100, 200 IU/kg body weight (BW) per week) and in higher doses used in the treatment of hyporesponsive patients (400, 600 IU/kg BW per week), focusing on renal damage, hypoxia, inflammation and fibrosis. Male Wistar rats with chronic renal failure (CRF) induced by 5/6 nephrectomy were treated with rHuEPO or with vehicle, over a 3-week period. Haematological, biochemical and renal function analyses were performed. Kidney and liver mRNA levels were evaluated by quantitative real-time polymerase chain reaction (qPCR) and protein expression by Western blot and immunohistochemistry. Kidney histopathological evaluations were also performed. The CRF group developed anaemia, hypertension and a high score of renal histopathologic lesions. Correction of anaemia was achieved with all rHuEPO doses, with improvement in hypertension, renal function and renal lesions. In addition, the higher rHuEPO doses also improved inflammation. Blood pressure was reduced in all rHuEPO-treated groups, compared to the CRF group, but increased in a dose-dependent manner. The current study showed that rHuEPO treatment corrected anaemia and improved urinary albumin excretion, particularly at lower doses. In addition, it is suggested that a short-term treatment with high doses, used to overcome an episode of hyporesponsiveness to rHuEPO therapy, can present benefits by reducing inflammation, without worsening of renal lesions; however, the pro-hypertensive effect should be considered, and carefully managed to avoid a negative cardiorenal impact., (© 2016 John Wiley & Sons Australia, Ltd.)

Anemia is a common complication in patients with chronic kidney disease (CKD), mainly due to inadequate renal production of erythropoietin. In hemodialysis (HD) patients this condition may be aggravated by iron deficiency (absolute or functional). The correction of this anemia is usually achieved by treatment with erythropoiesis stimulating agents (ESAs) and iron (oral or intravenous). Studies questioning the safety of ESAs (especially at higher doses) changed the pattern of anemia treatment in CKD patients. According to the new guidelines, when transferrin saturation is lower than 30% and ferritin lower than 500 ng/mL, a trial with iron should be started, to avoid therapy with ESAs or at least to reduce the doses needed to treat the anemia. Recent reports showed increasing ferritin levels, towards values above 800 ng/mL, in CKD patients treated according to the guidelines. In this review we focus on the risks of the increased iron use to treat CKD anemia, namely, iron overload and toxicity, increased risk of infections, as well as mortality.

This study aimed to elucidate the mechanisms explaining the persistence of anemia and resistance to recombinant human erythropoietin (rHuEPO) therapy in a rat model of chronic kidney disease (CKD)-associated anemia with formation of anti-rHuEPO antibodies. The remnant kidney rat model of CKD induced by 5/6 nephrectomy was used to test a long-term (nine weeks) high dose of rHuEPO (200 UI/kg bw/week) treatment. Hematological and biochemical parameters were evaluated as well as serum and tissue (kidney, liver and/or duodenum) protein and/or gene expression of mediators of erythropoiesis, iron metabolism and tissue hypoxia, inflammation, and fibrosis. Long-term treatment with a high rHuEPO dose is associated with development of resistance to therapy as a result of antibodies formation. In this condition, serum EPO levels are not deficient and iron availability is recovered by increased duodenal absorption. However, erythropoiesis is not stimulated, and the resistance to endogenous EPO effect and to rHuEPO therapy results from the development of a hypoxic, inflammatory and fibrotic milieu in the kidney tissue. This study provides new insights that could be important to ameliorate the current therapeutic strategies used to treat patients with CKD-associated anemia, in particular those that become resistant to rHuEPO therapy.

Anemia is a common complication of chronic kidney disease (CKD) that develops early and its severity increases as renal function declines. It is mainly due to a reduced production of erythropoietin (EPO) by the kidneys; however, there are evidences that iron metabolism disturbances increase as CKD progresses. Our aim was to study the mechanisms underlying the development of anemia of CKD, as well as renal damage, in the remnant kidney rat model of CKD induced by 5/6 nephrectomy. This model of CKD presented a sustained degree of renal dysfunction, with mild and advanced glomerular and tubulointerstitial lesions. Anemia developed 3 weeks after nephrectomy and persisted throughout the protocol. The remnant kidney was still able to produce EPO and the liver showed an increased EPO gene expression. In spite of the increased EPO blood levels, anemia persisted and was linked to low serum iron and transferrin levels, while serum interleukin (IL)-6 and high sensitivity C-reactive protein (hs-CRP) levels showed the absence of systemic inflammation. The increased expression of duodenal ferroportin favours iron absorption; however, serum iron is reduced which might be due to iron leakage through advanced kidney lesions, as showed by tubular iron accumulation. Our data suggest that the persistence of anemia may result from disturbances in iron metabolism and by an altered activity/function of EPO as a result of kidney cell damage and a local inflammatory milieu, as showed by the increased gene expression of different inflammatory proteins in the remnant kidney. In addition, this anemia and the associated kidney hypoxia favour the development of fibrosis, angiogenesis and inflammation that may underlie a resistance to EPO stimuli and reduced iron availability. These findings might contribute to open new windows to identify putative therapeutic targets for this condition, as well as for recombinant human EPO (rHuEPO) resistance, which occurs in a considerable percentage of CKD patients.

Background: Growth-curves are an important tool for evaluating the anthropometric development in pediatrics. The different growth-curves available are based in different populations, what leads to different cut-offs. Pediatric obesity tracks into adulthood and is associated with increased cardiovascular risk. The accurate assessment of a child nutritional status using growth-curves can indicate individuals that are either obese or in risk of becoming obese, allowing an early intervention. Moreover, the association between the data obtained from growth-curves with specific metabolic risk factors further highlights the importance of these charts. This study aimed to evaluate the associations between body mass index z-score (BMIzsc), determined using the growth-curves from the Centre for Disease Control and Prevention (CDC) and from the World Health Organization (WHO), with cardiovascular risk factors, represented here by metabolic syndrome (MS) and insulin resistance (IR) related parameters. The study involved 246 obese adolescents (10-18 years, 122 females). MS was defined according to the International Diabetes Federation. IR was considered for HOMA-IR greater than 2.5., Findings: No difference between both BMIzsc in identifying MS was noticeable by a ROC analysis. For both indexes the area-under-the-curve increased for older groups, particularly for males. CDC-BMIzsc was the best predictor of MS by logistic regression when all population was considered, however MS was better predicted by WHO-BMIzsc for females and by CDC-BMIzsc for males. Younger girls and older boys were in increased risk for MS. Similar results were obtained for IR., Conclusions: A significant difference between the two BMIzsc regarding their association with MS and IR was not clear, being these associations weaker in younger individuals.

Toxic effects of ultraviolet (UV) radiation on skin include protein and lipid oxidation, and DNA damage. The latter is known to play a major role in photocarcinogenesis and photoaging. Many plant extracts and natural compounds are emerging as photoprotective agents. Castanea sativa leaf extract is able to scavenge several reactive species that have been associated to UV-induced oxidative stress. The aim of this work was to analyze the protective effect of C. sativa extract (ECS) at different concentrations (0.001, 0.01, 0.05 and 0.1 μg/mL) against the UV mediated-DNA damage in a human keratinocyte cell line (HaCaT). For this purpose, the cytokinesis-block micronucleus assay was used. Elucidation of the protective mechanism was undertaken regarding UV absorption, influence on (1)O₂ mediated effects or NRF2 activation. ECS presented a concentration-dependent protective effect against UV-mediated DNA damage in HaCaT cells. The maximum protection afforded (66.4%) was achieved with the concentration of 0.1 μg/mL. This effect was found to be related to a direct antioxidant effect (involving (1)O₂) rather than activation of the endogenous antioxidant response coordinated by NRF2. Electrochemical studies showed that the good antioxidant capacity of the ECS can be ascribed to the presence of a pool of different phenolic antioxidants. No genotoxic or phototoxic effects were observed after incubation of HaCaT cells with ECS (up to 0.1 μg/mL). Taken together these results reinforce the putative application of this plant extract in the prevention/minimization of UV deleterious effects on skin., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Bilirubin can prevent lipid oxidation in vitro, but the association in vivo with oxidized low-density lipoprotein (Ox-LDL) levels has been poorly explored. Our aim is to the association of Ox-LDL with total bilirubin (TB) levels and with variables related with metabolic syndrome and inflammation, in young obese individuals., Findings: 125 obese patients (13.4 years; 53.6% females) were studied. TB, lipid profile including Ox-LDL, markers of glucose metabolism, and levels of C-reactive protein (CRP) and adiponectin were determined. Anthropometric data was also collected. In all patients, Ox-LDL correlated positively with BMI, total cholesterol, LDLc, triglycerides (TG), CRP, glucose, insulin and HOMAIR; while inversely with TB and HDLc/Total cholesterol ratio (P < 0.05 for all). In multiple linear regression analysis, LDLc, TG, HDLc and TB levels were significantly associated with Ox-LDL (standardized Beta: 0.656, 0.293, -0.283, -0.164, respectively; P < 0.01 for all). After removing TG and HDLc from the analysis, HOMAIR was included in the regression model. In this new model, LDLc remained the best predictor of Ox-LDL levels (β = 0.665, P < 0.001), followed by TB (β = -0.202, P = 0.002) and HOMAIR (β = 0.163, P = 0.010)., Conclusions: Lower bilirubin levels may contribute to increased LDL oxidation in obese children and adolescents, predisposing to increased cardiovascular risk.