Oxidative stress in hemodialysis patients: Is NADPH oxidase complex the culprit?

Oxidative stress in hemodialysis patients: Is NADPH oxidase complex the culprit?Oxidative stress results from an imbalance between oxidant production, including reactive oxygen species (ROS), reactive nitrogen species (RNS), chlorinated compounds, and antioxidant defense mechanisms. Most reports prove that oxidative stress is present in ESRD patients. Several studies tend to accreditate the hypothesis by which oxidative stress is a strong co-factor for the development of complications related to long-term HD such as atherosclerosis, amyloidosis, malnutrition, anemia, and infection.In order to evaluate the rationale for curative action against oxidative damage in chronic renal failure patients, we reviewed the putative factors involved in this process. Antioxidant systems are severely impaired in uremic patients and gradually altered with the degree of renal failure. Moreover, the inflammatory state caused by the hemoincompatibility of the dialysis system plays a critical role in the activation of NADPH oxidase, aggravating the pro-oxidant status of uremic patients.Prevention of ROS overproduction by improvement of dialysis biocompatibility, an important component of adequate dialysis, might be completed by antioxidant supplementation

Fluid Overload and Tissue Sodium Accumulation as Main Drivers of Protein Energy Malnutrition in Dialysis Patients

International audienceProtein energy malnutrition is recognized as a leading cause of morbidity and mortality in dialysis patients. Protein–energy-wasting process is observed in about 45% of the dialysis population using common biomarkers worldwide. Although several factors are implicated in protein energy wasting, inflammation and oxidative stress mechanisms play a central role in this pathogenic process. In this in-depth review, we analyzed the implication of sodium and water accumulation, as well as the role of fluid overload and fluid management, as major contributors to protein–energy-wasting process. Fluid overload and fluid depletion mimic a tide up and down phenomenon that contributes to inducing hypercatabolism and stimulates oxidation phosphorylation mechanisms at the cellular level in particular muscles. This endogenous metabolic water production may contribute to hyponatremia. In addition, salt tissue accumulation likely contributes to hypercatabolic state through locally inflammatory and immune-mediated mechanisms but also contributes to the perturbation of hormone receptors (i.e., insulin or growth hormone resistance). It is time to act more precisely on sodium and fluid imbalance to mitigate both nutritional and cardiovascular risks. Personalized management of sodium and fluid, using available tools including sodium management tool, has the potential to more adequately restore sodium and water homeostasis and to improve nutritional status and outcomes of dialysis patients

Determination of protein composition in milk by mid-infrared spectrometry

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How to interpret cardiac biomarkers in renal failure and elderly?

International audienceNew highly sensitive (hs) assays have challenged the interpretation of cardiac troponins (cTn) as markers of injury while natriuretic peptides remain the markers of choice for myocardial dysfunction. However, variability extracardiac factors such as age, gender and renal function may alter circulating levels. In chronic kidney disease (CKD), the increase in circulating levels of these biomarkers in the absence of cardiac disease underlines the problem of discriminative value for diagnosis as well as the need to redefine the thresholds. In addition, these biomarkers are of potential interest to stratify cardiovascular risk, the leading cause of death in CKD. The aim of this work is to clarify the effect of age and renal function on circulating levels of high-sensitivity troponins and natriuretic peptides

Standardized Method to Measure Muscle Force at the Bedside in Hemodialysis Patients

International audienceIn hemodialysis, diminution of muscle strength constitutes a major prognostic factor of mortality. Currently, measurement of quadriceps isometric maximal voluntary force (MVF) represents the reference method to investigate muscle strength. However, reduction of MVF is rarely detected in these patients due to the absence of portative bedside tools in clinical practice. The purposes of this study were therefore to assess the agreement of a belt-stabilized handheld dynamometer (HHD) with the dynamometer chair (reference method) and to determine intratester and intertester reliability of the quadriceps MVF measurements using belt-stabilized HHD in healthy subjects and in hemodialysis patients.Not applicable

Tumor cells educate mesenchymal stromal cells to release chemoprotective and immunomodulatory factors

International audienceFactors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. In this study, we characterize the mechanisms by which naïve mesenchymal stromal cells (MSCs) can acquire a CA-MSCs phenotype. Ovarian tumor cells trigger the transformation of MSCs to CA-MSCs by expressing pro-tumoral genes implicated in the chemoresistance of cancer cells, resulting in the secretion of high levels of CXC chemokine receptors 1 and 2 (CXCR1/2) ligands such as chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and interleukin 8 (IL-8). CXCR1/2 ligands can also inhibit the immune response against ovarian tumor cells. Indeed, through their released factors, CA-MSCs promote the differentiation of monocytes towards M2 macrophages, which favors tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 properties and acquire an anti-tumoral phenotype. Both ex vivo and in vivo, we used a CXCR1/2 inhibitor to sensitize ovarian tumor cells to carboplatin and circumvent the pro-tumoral effects of CA-MSCs. Since high concentrations of CXCR1/2 ligands in patients' blood are associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert carboplatin resistance

Reduced reticulum–mitochondria Ca2+ transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy

International audienceType 2 diabetic cardiomyopathy features Ca2+ signaling abnormalities, notably an altered mitochondrial Ca2+ handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca2+ homeostasis, the reticulum-mitochondrial Ca2+ coupling, and/or the mitochondrial Ca2+ entry through the uniporter. Following a 16-week high-fat high-sucrose diet (HFHSD), mice developed cardiac insulin resistance, fibrosis, hypertrophy, lipid accumulation, and diastolic dysfunction when compared to standard diet. Ultrastructural and proteomic analyses of cardiac reticulum-mitochondria interface revealed tighter interactions not compatible with Ca2+ transport in HFHSD cardiomyocytes. Intramyocardial adenoviral injections of Ca2+ sensors were performed to measure Ca2+ fluxes in freshly isolated adult cardiomyocytes and to analyze the direct effects of in vivo type 2 diabetes on cardiomyocyte function. HFHSD resulted in a decreased IP3R-VDAC interaction and a reduced IP3-stimulated Ca2+ transfer to mitochondria, with no changes in reticular Ca2+ level, cytosolic Ca2+ transients, and mitochondrial Ca2+ uniporter function. Disruption of organelle Ca2+ exchange was associated with decreased mitochondrial bioenergetics and reduced cell contraction, which was rescued by an adenovirus-mediated expression of a reticulum-mitochondria linker. An 8-week diet reversal was able to restore cardiac insulin signaling, Ca2+ transfer, and cardiac function in HFHSD mice. Therefore, our study demonstrates that the reticulum-mitochondria Ca2+ miscoupling may play an early and reversible role in the development of diabetic cardiomyopathy by disrupting primarily the mitochondrial bioenergetics. A diet reversal, by counteracting the MAM-induced mitochondrial Ca2+ dysfunction, might contribute to restore normal cardiac function and prevent the exacerbation of diabetic cardiomyopathy

Comparison of Two Methods for Estimating MS-Related Mortality: The Excess Mortality vs. the Cause-Specific Frameworks

Background and objective: Determining whether multiple sclerosis (MS) causes death is challenging. Our objective was to contrast two frameworks to estimate probabilities of death attributed to MS (PMS) and to other causes (POther): the cause-specific framework (CSF) which requires the causes of death and the excess mortality framework (EMF) which does not.Methods: We used data from the Observatoire Français de la Sclérose en Plaques (OFSEP, n=37,524) and from a comparative subset where causes of death was available (4,004 women with relapsing onset (R-MS)). In CSF, the probabilities were estimated using Aalen-Johansen method. In EMF, they were estimated from the excess mortality hazard, which is the additional mortality among MS patients as compared to the expected mortality in the matched general population. PMS were estimated at 30 years of follow-up, i) with both frameworks in the comparative subset, by age group at onset, and ii) with EMF only in the OFSEP population, by initial phenotype, sex and age at onset.Results: In the comparative subset, the estimated 30-year PMS were greater using EMF than CSF: respectively 10.9% [95%CI 8.3-13.6] vs 8.7% [6.4-11.8] among the youngest, and 20.4% [11.3-29.5] vs 16.2% [8.7-30.2] for the oldest groups. In the CSF, probabilities of death from unknown causes ranged from 1.5% [0.7-3.0] to 6.4% [2.5-16.4], and even after their reallocation, PMS remained lower with CSF than with EMF. The estimated probabilities of being alive were close using the two frameworks and the estimated POther (EMF vs CSF) were 2.6% [2.5-2.6] vs 2.1% [1.2-3.9] and 18.1% [16.9-19.3] vs 26.4% [16.5-42.2] respectively for the youngest and oldest groups. In the OFSEP population, the estimated 30-year PMS ranged from 7.5 [6.4-8.7] to 24.0% [19.1-28.9] in R-MS patients and from 25.4 [21.1-29.7] to 36.8% [28.3-45.3] in primary progressive patients, depending on sex and age.Discussion: EMF has the strong advantage of not requiring death certificates, which quality is sub-optimal. Conceptually, it also appears more relevant as it avoids having to state, for each individual, if death was directly or indirectly caused by MS or if it would have occurred anyway, which is especially difficult in such chronic diseases

Multivariate analyses of (A) main determinants of maximal voluntary force and of (B) variables associated with muscle torque.

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