NFkB in the development of endothelial activation and damage in uremia: an in vitro approach

Impaired hemostasis coexists with accelerated atherosclerosis in patients with chronic kidney disease (CKD). The elevated frequency of atherothrombotic events has been associated with endothelial dysfunction. The relative contribution of the uremic state and the impact of the renal replacement therapies have been often disregarded. Plasma markers of endothelial activation and damage were evaluated in three groups of patients with CKD: under conservative treatment (predialysis), on hemodialysis, and on peritoneal dialysis. Activation of p38 MAPK and the transcription factor NFκB was assessed in endothelial cell (EC) cultures exposed to pooled sera from each group of patients. Most of the markers evaluated (VCAM-1, ICAM-1, VWF, circulating endothelial cells) were significantly higher in CDK patients than in controls, being significantly more increased in the group of peritoneal dialysis patients. These results correlated with the activation of both p38 MAPK and NFκB in EC cells exposed to the same sera samples, and also to the peritoneal dialysis fluids. Hemodialysis did not further contribute to the endothelial damage induced by the uremic state observed in predialysis patients, probably due to the improved biocompatibility of the hemodialysis technique in recent years, resulting in lower cellular activation. However, peritoneal dialysis seemed to exert a significant proinflammatory effect on the endothelium that could be related to the high glucose concentrations and glucose degradation products present in the dialysis fluid. Although peritoneal dialysis has been traditionally considered a more physiological technique, our results raise some doubts with respect to inflammation and EC damage

Management and follow-up of hip fracture. Do we follow the clinical guidelines?

Introducción: La osteoporosis supone un riesgo de padecer fracturas por fragilidad. Objetivos: Estudiar el perfil, manejo hospitalario y farmacológico posterior a una fractura de cadera. Material y métodos: Estudio descriptivo transversal de sujetos con fractura de cadera ingresados a nivel hospitalario Resultados: Se estudiaron 100 pacientes con media de edad de 82,31 ±11,5 años y predominio femenino. Un 17% había sufrido una fractura vertebral y el 30% una no vertebral previa (13% de cadera). El factor de riesgo más prevalente fue la menopausia (74%). Un 15% de los pacientes poseían un diagnóstico de osteoporosis antes de la fractura y un 50% al alta. Aunque tras el ingreso un 67% de los pacientes tenían prescrito un fármaco (vitamina D un 60% y suplementos de calcio un 14%), solo el 8% un fármacos antirresortivos o anabólicos. Conclusiones: El perfil del sujeto con fractura de cadera es el de una mujer de 82 años, sin diagnóstico de osteoporosis, pero con algún factor de riesgo de fragilidad ósea. El tratamiento antiresortivo posterior es muy escaso pese a ser pacientes de alto riesgo de re-fractura. Se debe reforzar la utilidad del uso de tratamientos para prevenir nuevas fracturas.Introduction: Osteoporosis poses a risk of suffering from fragility fractures. Objectives: Study the profile, hospital and pharmacological management after a hip fracture. Material and methods: Descriptive cross-sectional study of subjects with hip fracture admitted to hospital. Results: 100 patients with a mean age of 82.31 ± 11.5 years and a female predominance were studied. 17% had suffered a vertebral fracture and 30% a previous non-vertebral fracture (13% of the hip). The most common risk factor was menopause (74%). 15% of the patients had a diagnosis of osteoporosis before the fracture and 50% at discharge. Although 67% of the patients were prescribed a drug after admission (60% vitamin D and 14% calcium supplements), only 8% were prescribed antiresorptive or anabolic drugs. Conclusions: The profile of the subject with a hip fracture is that of an 82- year-old woman, without a diagnosis of osteoporosis, but with some risk factor for bone fragility. Subsequent antiresorptive treatment is very scarce despite being patients with a high risk of refracture. The utility of the use of treatments to prevent new fractures must be reinforced.Grado en Medicin

Role of sodium tungstate as a potential antiplatelet agent.

Purpose: Platelet inhibition is a key strategy in the management of atherothrombosis. However, the large variability in response to current strategies leads to the search for alternative inhibitors. The antiplatelet effect of the inorganic salt sodium tungstate (Na2O4W), a protein tyrosine phosphatase 1B (PTP1B) inhibitor, has been investigated in this study.Methods: Wild-type (WT) and PTP1B knockout (PTP1B-/-) mice were treated for 1 week with Na2O4W to study platelet function with the platelet function analyzer PFA-100, a cone-and-plate analyzer, a flat perfusion chamber, and thrombus formation in vivo. Human blood aliquots were incubated with Na2O4W for 1 hour to measure platelet function using the PFA-100 and the annular perfusion chamber. Aggregometry and thromboelastometry were also performed.Results: In WT mice, Na2O4W treatment prolonged closure times in the PFA-100 and decreased the surface covered (%SC) by platelets on collagen. Thrombi formed in a thrombosis mice model were smaller in animals treated with Na2O4W (4.6±0.7 mg vs 8.9±0.7 mg; P<0.001). Results with Na2O4W were similar to those in untreated PTP1B -/- mice (5.0±0.3 mg). Treatment of the PTP1B-/- mice with Na2O4W modified only slightly this response. In human blood, a dose-dependent effect was observed. At 200 mM, closure times in the PFA-100 were prolonged. On denuded vessels, %SC and thrombi formation (%T) decreased with Na2O4W. Neither the aggregating response nor the viscoelastic clot properties were affected.Conclusion: Na2O4W decreases consistently the hemostatic capacity of platelets, inhibiting their adhesive and cohesive properties under flow conditions in mice and in human blood, resulting in smaller thrombi. Although Na2O4W may be acting on platelet PTP1B, other potential targets should not be disregarded © 2015 Fernández-Ruiz et al.This work was supported by the Secretaría de Estado de Investigación, Desarrollo e Innovación, and the Ministerio de Economía y Competitividad of Spain (SAF2011-28214 and SAF2010-19527); the Red de Investigación Cardiovascular, Instituto de Salud Carlos III, of Spain (RD12/0042/0016); and the Government of Catalonia (2009 SGR 1426). BH is a recipient of a Juan de la Ciervas’ grant from the Instituto de Salud Carlos III (JCI-2011-10417)Peer Reviewe

Patient-derived heterogeneous breast phantoms for advanced dosimetry in mammography and tomosynthesis

Background: Understanding the magnitude and variability of the radiation dose absorbed by the breast fibroglandular tissue during mammography and digital breast tomosynthesis (DBT) is of paramount importance to assess risks versus benefits. Although homogeneous breast models have been proposed and used for decades for this purpose, they do not accurately reflect the actual heterogeneous distribution of the fibroglandular tissue in the breast, leading to biases in the estimation of dose from these modalities. Purpose: To develop and validate a method to generate patient-derived, heterogeneous digital breast phantoms for breast dosimetry in mammography and DBT. Methods: The proposed phantoms were developed starting from patient-based models of compressed breasts, generated for multiple thicknesses and representing the two standard views acquired in mammography and DBT, that is, cranio-caudal (CC) and medio-lateral-oblique (MLO). Internally, the breast phantoms were defined as consisting of an adipose/fibroglandular tissue mixture, with a nonspatially uniform relative concentration. The parenchyma distributions were obtained from a previously described model based on patient breast computed tomography data that underwent simulated compression. Following these distributions, phantoms with any glandular fraction (1%–100%) and breast thickness (12–125 mm) can be generated, for both views. The phantoms were validated, in terms of their accuracy for average normalized glandular dose (DgN) estimation across samples of patient breasts, using 88 patient-specific phantoms involving actual patient distribution of the fibroglandular tissue in the breast, and compared to that obtained using a homogeneous model similar to those currently used for breast dosimetry. Results: The average DgN estimated for the proposed phantoms was concordant with that absorbed by the patient-specific phantoms to within 5% (CC) and 4% (MLO). These DgN estimates were over 30% lower than those estimated with the homogeneous models, which overestimated the average DgN by 43% (CC), and 32% (MLO) compared to the patient-specific phantoms. Conclusions: The developed phantoms can be used for dosimetry simulations to improve the accuracy of dose estimates in mammography and DBT

Monte Carlo study on optimal breast voxel resolution for dosimetry estimates in digital breast tomosynthesis

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Patient-derived heterogeneous breast phantoms for advanced dosimetry in mammography and tomosynthesis.

BackgroundUnderstanding the magnitude and variability of the radiation dose absorbed by the breast fibroglandular tissue during mammography and digital breast tomosynthesis (DBT) is of paramount importance to assess risks versus benefits. Although homogeneous breast models have been proposed and used for decades for this purpose, they do not accurately reflect the actual heterogeneous distribution of the fibroglandular tissue in the breast, leading to biases in the estimation of dose from these modalities.PurposeTo develop and validate a method to generate patient-derived, heterogeneous digital breast phantoms for breast dosimetry in mammography and DBT.MethodsThe proposed phantoms were developed starting from patient-based models of compressed breasts, generated for multiple thicknesses and representing the two standard views acquired in mammography and DBT, that is, cranio-caudal (CC) and medio-lateral-oblique (MLO). Internally, the breast phantoms were defined as consisting of an adipose/fibroglandular tissue mixture, with a nonspatially uniform relative concentration. The parenchyma distributions were obtained from a previously described model based on patient breast computed tomography data that underwent simulated compression. Following these distributions, phantoms with any glandular fraction (1%-100%) and breast thickness (12-125&nbsp;mm) can be generated, for both views. The phantoms were validated, in terms of their accuracy for average normalized glandular dose (Dg N) estimation across samples of patient breasts, using 88 patient-specific phantoms involving actual patient distribution of the fibroglandular tissue in the breast, and compared to that obtained using a homogeneous model similar to those currently used for breast dosimetry.ResultsThe average Dg N estimated for the proposed phantoms was concordant with that absorbed by the patient-specific phantoms to within 5% (CC) and 4% (MLO). These Dg N estimates were over 30% lower than those estimated with the homogeneous models, which overestimated the average Dg N by 43% (CC), and 32% (MLO) compared to the patient-specific phantoms.ConclusionsThe developed phantoms can be used for dosimetry simulations to improve the accuracy of dose estimates in mammography and DBT

NFκB in the development of endothelial activation and damage in uremia: an in vitro approach.

Impaired hemostasis coexists with accelerated atherosclerosis in patients with chronic kidney disease (CKD). The elevated frequency of atherothrombotic events has been associated with endothelial dysfunction. The relative contribution of the uremic state and the impact of the renal replacement therapies have been often disregarded. Plasma markers of endothelial activation and damage were evaluated in three groups of patients with CKD: under conservative treatment (predialysis), on hemodialysis, and on peritoneal dialysis. Activation of p38 MAPK and the transcription factor NFκB was assessed in endothelial cell (EC) cultures exposed to pooled sera from each group of patients. Most of the markers evaluated (VCAM-1, ICAM-1, VWF, circulating endothelial cells) were significantly higher in CDK patients than in controls, being significantly more increased in the group of peritoneal dialysis patients. These results correlated with the activation of both p38 MAPK and NFκB in EC cells exposed to the same sera samples, and also to the peritoneal dialysis fluids. Hemodialysis did not further contribute to the endothelial damage induced by the uremic state observed in predialysis patients, probably due to the improved biocompatibility of the hemodialysis technique in recent years, resulting in lower cellular activation. However, peritoneal dialysis seemed to exert a significant proinflammatory effect on the endothelium that could be related to the high glucose concentrations and glucose degradation products present in the dialysis fluid. Although peritoneal dialysis has been traditionally considered a more physiological technique, our results raise some doubts with respect to inflammation and EC damage

Main demographic characteristics and biochemical parameters.

<p>Main demographic characteristics and biochemical parameters.</p