El reto del envejecimiento y la complejidad farmacoterapéutica en el paciente VIH+

Objective: To describe the current knowledge and management of aging and pharmacotherapeutic complexity in HIV + patients. Method: A review of literature was carried out, including articles, originals or reviews, published in English or Spanish, from 2007 to 2017, which analysed the aging and pharmacotherapeutic complexity in HIV + patients. The terms «Polypharmacy»/«Polifarmacia», «Aging»/«Envejecimiento», «Frailty»/«Fragilidad», «Complejidad Farmacotera péutica»/«Medication Regimen Complexity» and «HIV»/«VIH» were combined. The review was carried out independently by two authors. The degree of agreement, according to the Kappa index, was analysed. Results: A total of 208 references were analysed, including, finally, only 68. An aging of the population and an increase in associated comorbidities have been identified, especially over 50 years-old. Immunological changes similar to those that are generated in a non-infected elderly population have been described. These conditions influencing the prescription of antiretroviral treatment, according to studies identified. In parallel, polypharmacy is increasingly present, being defined exclusively by the concomitant use of five drugs. Pharmacotherapeutic complexity, through the Medication Regimen Complexity Index, has begun to analyse and relate to health outcomes. There has been a need to know and apply concepts already known in non-HIV-aged population, such as deprescription, potentially inappropriate medication, cholinergic risk, although few results are available. Conclusions: There is a growing interest to know about the relationship between HIV and aging. Pharmacotherapeutic complexity is beginning to be used as a pharmacotherapeutic follow-up criterion due to its influence on health outcomes. It is necessary to manage and incorporate new concepts that help pharmacotherapeutic optimization in this population

Caveolin-1 Modulates Mechanotransduction Responses to Substrate Stiffness through Actin-Dependent Control of YAP

The transcriptional regulator YAP orchestrates many cellular functions, including tissue homeostasis, organ growth control, and tumorigenesis. Mechanical stimuli are a key input to YAP activity, but the mechanisms controlling this regulation remain largely uncharacterized. We show that CAV1 positively modulates the YAP mechanoresponse to substrate stiffness through actin-cytoskeleton-dependent and Hippo-kinase-independent mechanisms. RHO activity is necessary, but not sufficient, for CAV1-dependent mechanoregulation of YAP activity. Systematic quantitative interactomic studies and image-based small interfering RNA (siRNA) screens provide evidence that this actin-dependent regulation is determined by YAP interaction with the 14-3-3 protein YWHAH. Constitutive YAP activation rescued phenotypes associated with CAV1 loss, including defective extracellular matrix (ECM) remodeling. CAV1-mediated control of YAP activity was validated in vivo in a model of pancreatitis-driven acinar-to-ductal metaplasia. We propose that this CAV1-YAP mechanotransduction system controls a significant share of cell programs linked to these two pivotal regulators, with potentially broad physiological and pathological implications. Moreno-Vicente et al. report that CAV1, a key component of PM mechanosensing caveolae, mediates adaptation to ECM rigidity by modulating YAP activity through the control of actin dynamics and phosphorylation-dependent interaction of YAP with the 14-3-3-domain protein YWHAH. Cav1-dependent YAP regulation drives two pathophysiological processes: ECM remodeling and pancreatic ADM. © 2018 The Author

The optimal method to make inferences about a linear combination of proportions

Asymptotic inferences about a linear combination of K independent binomial proportions are very frequent in applied research. Nevertheless, until quite recently research had been focused almost exclusively on cases of K≤2 (particularly on cases of one proportion and the difference of two proportions). This article focuses on cases of K>2, which have recently begun to receive more attention due to their great practical interest. In order to make this inference, there are several procedures which have not been compared: the score method (S0) and the method proposed by Martín Andrés et al. (W3) for adjusted Wald (which is a generalization of the method proposed by Price and Bonett) on the one hand and, on the other hand, the method of Zou et al. (N0) based on the Wilson confidence interval (which is a generalization of the Newcombe method). The article describes a new procedure (P0) based on the classic Peskun method, modifies the previous methods giving them continuity correction (methods S0c, W3c, N0c and P0c, respectively) and, finally, a simulation is made to compare the eight aforementioned procedures (which are selected from a total of 32 possible methods). The conclusion reached is that the S0c method is the best, although for very small samples (n i ≤ 10, ∀ i) the W3 method is better. The P0 method would be the optimal method if one needs a method which is almost never too liberal, but this entails using a method which is too conservative and which provides excessively wide CIs. The W3 and P0 methods have the additional advantage of being very easy to apply. A free programme which allows the application of the S0 and S0c methods (which are the most complex) can be obtained at http://www.ugr.es/local/bioest/Z_LINEAR_K.EXE

Molecular genetics of naringenin biosynthesis, a typical plant secondary metabolite produced by Streptomyces clavuligerus

Background: Some types of flavonoid intermediates seemed to be restricted to plants. Naringenin is a typical plant metabolite, that has never been reported to be produced in prokariotes. Naringenin is formed by the action of a chalcone synthase using as starter 4-coumaroyl-CoA, which in dicotyledonous plants derives from phenylalanine by the action of a phenylalanine ammonia lyase. Results: A compound produced by Streptomyces clavuligerus has been identified by LC-MS and NMR as naringenin and coelutes in HPLC with a naringenin standard. Genome mining of S. clavuligerus revealed the presence of a gene for a chalcone synthase (ncs), side by side to a gene encoding a P450 cytochrome (ncyP) and separated from a gene encoding a Pal/Tal ammonia lyase (tal). Deletion of any of these genes results in naringenin non producer mutants. Complementation with the deleted gene restores naringenin production in the transformants. Furthermore, naringenin production increases in cultures supplemented with phenylalanine or tyrosine. Conclusion: This is the first time that naringenin is reported to be produced naturally in a prokariote. Interestingly three non-clustered genes are involved in naringenin production, which is unusual for secondary metabolites. A tentative pathway for naringenin biosynthesis has been proposedThis work was supported by Grant BIO2012-34723 from the Spanish Ministry of Economy and Competitivity. R. Álvarez-Álvarez received a FPU fellowship from the Spanish Ministry of Education, Culture and Sport

Topological defects and misfit strain in magnetic stripe domains of lateral multilayers with perpendicular magnetic anisotropy

Stripe domains are studied in perpendicular magnetic anisotropy films nanostructured with a periodic thickness modulation that induces the lateral modulation of both stripe periods and inplane magnetization. The resulting system is the 2D equivalent of a strained superlattice with properties controlled by interfacial misfit strain within the magnetic stripe structure and shape anisotropy. This allows us to observe, experimentally for the first time, the continuous structural transformation of a grain boundary in this 2D magnetic crystal in the whole angular range. The magnetization reversal process can be tailored through the effect of misfit strain due to the coupling between disclinations in the magnetic stripe pattern and domain walls in the in-plane magnetization configuration

Regulación epigenética del IFN-y en tuberculosis

M. tuberculosis (Mtb) es el principal asesino microbiológico en el mundo. Las modificaciones epigenéticas son claves en la plasticidad del sistema inmune y como mediadores entre el ambiente y los fenotipos celulares. El IFN-v, media la respuesta protectiva frente a Mtb, pero se desconocen los mecanismos epigenéticos que regularían su activación y mediarían la susceptibilidad a la tuberculosis.Área: Ciencias Biológicas, Ambiente y Salud