Hospital Universitario La Paz

About: Hospital Universitario La Paz is a healthcare organization based out in Madrid, Spain. It is known for research contribution in the topics: Population & Medicine. The organization has 8960 authors who have published 11499 publications receiving 191509 citations.

Visfatin/eNampt induces endothelial dysfunction in vivo: a role for Toll-Like Receptor 4 and NLRP3 inflammasome.

Abstract: Visfatin/extracellular-nicotinamide-phosphoribosyltranferase-(eNampt) is a multifaceted adipokine enhanced in type-2-diabetes and obesity. Visfatin/eNampt cause in vitro endothelial dysfunction and vascular inflammation, although whether the same effects are achieved in vivo is unknown. Toll-like receptor-4 (TLR4), a main surface pattern recognition receptor of innate immune system is a potential target for visfatin/eNampt. We studied its capacity to generate vascular dysfunction in vivo, focusing on TLR4 role and downstream activation of nod-like-receptor-protein-3 (NLRP3)-inflammasome. 4 month-old C57BL/6 mice were exposed to 7 days infusion of visfatin/eNampt, alone or together with FK 866 (Nampt enzymatic inhibitor), CLI 095 (TLR4 blocker), MCC 950 (NLRP3-inflammasome inhibitor), or anakinra (interleukin(IL)-1-receptor antagonist). Endothelial dysfunction was tested in isolated microvessels. In human umbilical endothelial cells (HUVEC), proteins related to the NLRP3-inflammasome phosphorylated p-65, NLRP3, caspase-1, pro-IL-1β, and mature IL-1β were determined by Western blot, while the inflammasome related apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC-specks) was studied by immunofluorescence. Impaired endothelium-dependent relaxations were observed in isolated mesenteric microvessels from visfatin/eNampt-infused mice. This effect was attenuated by co-treatment with FK 866 or CLI 095, supporting a role for Nampt enzymatic activity and TLR4 activation. Moreover, cultured HUVEC exposed to visfatin/eNampt showed higher expression and activation of NLRP3-inflammasome. Again, this effect relied on Nampt enzymatic activity and TLR4 activation, and it was abrogated by the inflammasome assembly blockade with MCC 950. The endothelial dysfunction evoked by visfatin/eNampt infusion in vivo was also sensitive to both MCC 950 and anakinra treatments, suggesting that the NLRP3-inflammasome-driven tissular release of IL-1β is the final mediator of endothelial damage. We conclude that Visfatin/eNampt produces in vivo vascular dysfunction in mice by a Nampt-dependent TLR4-mediated pathway, involving NLRP3-inflammasome and paracrine IL-1β. Thus, those targets may become therapeutic strategies for attenuating the adipokine-mediated vascular dysfunction associated to obesity and/or type-2-diabetes.

Atypical Hemolytic Uremic Syndrome-Associated Variants and Autoantibodies Impair Binding of Factor H and Factor H-Related Protein 1 to Pentraxin 3

Abstract: Atypical hemolytic uremic syndrome (aHUS) is a renal disease associated with complement alternative pathway dysregulation and is characterized by endothelial injury. Pentraxin 3 (PTX3) is a soluble pattern recognition molecule expressed by endothelial cells and upregulated under inflammatory conditions. PTX3 activates complement, but it also binds the complement inhibitor factor H. In this study, we show that native factor H, factor H-like protein 1, and factor H-related protein 1 (CFHR1) bind to PTX3 and that PTX3-bound factor H and factor H-like protein 1 maintain their complement regulatory activities. PTX3, when bound to extracellular matrix, recruited functionally active factor H. Residues within short consensus repeat 20 of factor H that are relevant for PTX3 binding were identified using a peptide array. aHUS-associated factor H mutations within this binding site caused a reduced factor H binding to PTX3. Similarly, seven of nine analyzed anti-factor H autoantibodies isolated from aHUS patients inhibited the interaction between factor H and PTX3, and five autoantibodies also inhibited PTX3 binding to CFHR1. Moreover, the aHUS-associated CFHR1*B variant showed reduced binding to PTX3 in comparison with CFHR1*A. Thus, the interactions of PTX3 with complement regulators are impaired by certain mutations and autoantibodies affecting factor H and CFHR1, which could result in an enhanced local complement-mediated inflammation, endothelial cell activation, and damage in aHUS.

Multidetector CT in the evaluation of potential living donors for liver transplantation.

Abstract: Living donor liver transplantation is increasingly being used to help compensate for the increasing shortage of cadaveric liver grafts. However, the extreme variability of the hepatic vascular systems can impede this surgical procedure. Evaluation of potential living donors was conducted in which a two-detector-row computed tomographic (CT) scanner was used to obtain arterial phase and portal dominant phase images following the intravenous injection of contrast material, after which three-dimensional maximum-intensity-projection and volume-rendered images were created. The vascular anatomy was evaluated, with special attention given to the origin and course of the artery to segment IV and the presence of variants, especially those considered relative or absolute contraindications for donation, those requiring reconstruction, or those potentially altering the surgical approach. In addition, graft and remnant liver volumes were determined and the liver parenchyma evaluated. Multidetector CT is proving to be valuable in the evaluation of potential living liver donors, contributing to donor safety and providing comprehensive information about the hepatic vascular anatomy, the liver parenchyma, and graft and remnant liver volume. This information is critical in choosing the most suitable potential donor, in surgical planning, and in obtaining an optimal graft that maintains the balance between blood supply and venous drainage.

Annual direct medical costs of bronchiectasis treatment Impact of severity, exacerbations, chronic bronchial colonization and chronic obstructive pulmonary disease coexistence

Abstract: Patients with bronchiectasis (BE) present exacerbations that increase with severity of the disease. We aimed to determine the annual cost of BE treatment according to its severity, determined by FACED score, as well as the parameters associated with higher costs. Multicentre historical cohorts study with patients from six hospitals in Spain. The costs arising during the course of a year from maintenance treatment, exacerbations, emergency visits and hospital admissions were analysed. In total, 456 patients were included (56.4% mild BE, 26.8% moderate BE and 16.9% severe BE). The mean cost was €4671.9 per patient, which increased significantly with severity. In mild BE, most of the costs were due to bronchodilators and inhaled steroids; in severe BE, most were due to exacerbations and inhaled antibiotics. Forced expiratory volume in 1 second (FEV1%), age, colonization by Pseudomonas aeruginosa and the number of admissions were independently related to higher costs. The highest costs were found in patients with BE associated with chronic obstructive pulmonary disease, with the most exacerbations and with chronic bronchial colonization by Pseudomonas aeruginosa (PA). In conclusion, BE patients gave rise to high annual costs, and these were doubled on each advance in severity on the FACED score. FEV1%, age, colonization by PA and the number of admissions were independently related to higher costs.

SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes.

Abstract: C1 inhibitor (C1Inh) deficiency is responsible for hereditary angioedema (C1-INH-HAE) and caused by variants of the SERPING1/C1INH/C1NH gene. C1Inh is the major control of kallikrein-kinin system. C1Inh deficiency leads to its uncontrolled activation, with subsequent generation of the vasoactive peptide bradykinin. This update documents 748 different SERPING1 variants, including published variants and additional 120 unpublished ones. They were identified as heterozygous variants (n = 729), as homozygous variants in 10 probands and as compound heterozygous variants (nine combinations). Six probands with heterozygous variants exhibited gonadal mosaicism. Probands with heterozygous (n = 72) and homozygous (n = 1) variants were identified as de novo cases. Overall, 58 variants were found at positions showing high residue conservation among serpins, and have been referred to as a mousetrap function of C1Inh: reactive center loop, gate, shutter, breach, and hinge. C1Inh phenotype analysis identified dysfunctional serpin variants with failed serpin-protease association and a residual 105-kDa species after incubation with target protease. Regarding this characteristic, in conditions with low antigenic C1Inh, 74 C1-INH-HAE probands presented with an additional so-called intermediate C1-INH-HAE phenotype. The present update addresses a comprehensive SERPING1 variant spectrum that facilitates genotype-phenotype correlations, highlighting residues of strategic importance for serpin function and for identification of C1Inh deficiency as serpinopathy.