Eficacia y tolerabilidad Resultados del tratamiento para la fibrosis pulmonar idiopática. Experiencia de la vida real / Efficacy and Tolerability Outcomes of Treatment for Idiopathic Pulmonary Fibrosis. Real-life Experience

Introducción: la fibrosis pulmonar idiopática (FPI) es una enfermedad progresiva y cró-nica con muy mal pronóstico. Actualmente, existen dos fármacos para esta patología. El propósito de nuestro estudio es evaluar los efectos del tratamiento en los pacientes de una consulta en vida real.

Introduction: idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with a very poor prognosis. Two drugs are currently available for this disease. The purpo-se of our study is to evaluate the effects of treatment in patients in a real-life practice.

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Intermediate molecular phenotypes to identify genetic markers of anthracycline-induced cardiotoxicity risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex disease whose polygenic component is mainly unidentified. We propose that levels of intermediate molecular phenotypes in the myocardium associated with histopathological damage could explain CDA susceptibility; so that variants of genes encoding these intermediate molecular phenotypes could identify patients susceptible to this complication. A genetically heterogeneous cohort of mice generated by backcrossing (N = 165) was treated with doxorubicin and docetaxel. Cardiac histopathological damage was measured by fibrosis and cardiomyocyte size by an Ariol slide scanner. We determine intramyocardial levels of intermediate molecular phenotypes of CDA associated with histopathological damage and quantitative trait loci (ipQTLs) linked to them. These ipQTLs seem to contribute to the missing heritability of CDA because they improve the heritability explained by QTL directly linked to CDA (cda-QTLs) through genetic models. Genes encoding these molecular subphenotypes were evaluated as genetic markers of CDA in three cancer patient cohorts (N = 517) whose cardiac damage was quantified by echocardiography or Cardiac Magnetic Resonance. Many SNPs associated with CDA were found using genetic models. LASSO multivariate regression identified two risk score models, one for pediatric cancer patients and the other for women with breast cancer. Molecular intermediate phenotypes associated with heart damage can identify genetic markers of CDA risk, thereby allowing a more personalized patient management. A similar strategy could be applied to identify genetic markers of other complex trait diseases.

[Infectious Disease Prevention Group: Update on vaccines, 2022]. / Prevención de las enfermedades infecciosas. Actualización en vacunas PAPPS 2022.

The update of the preventive activities for this year 2022 in the field of infectious diseases is of special relevance due to the importance that prevention has gained and more specifically, vaccination as a tool to control the pandemic caused by the SARS-CoV-2 virus declared on March 11, 2020. The pandemic has focused much of the prevention efforts on its containment, but the importance of maintaining high vaccination coverage of the rest of the recommended vaccines to maintain good control of vaccine-preventable diseases and avoid complications in particularly vulnerable patients should not be forgotten. In this year's review we present a practical document with the aim of providing tools to primary care professionals who work with adults, to make the indication of each vaccine whether it is systematically recommended or if it is because the patient belongs to some risk group due to their condition or underlying pathology. In this way, throughout the document, we will comment on the most innovative aspects of systematic vaccination (flu, pneumococcus, meningococcal vaccines and vaccines against the human papillomavirus [HPV]), the new vaccines (pandemic vaccines against COVID-19, vaccines against herpes zoster of subunits, vaccines against monkeypox) and the recommended vaccines according to risk condition (pregnancy and lactation, travelers, patients with immunosuppression or underlying pathology).

Structural Ordering Supremacy on the Oxygen Reduction Reaction of Layered Iron-Perovskites.

Layered perovskites of the Gd0.8-xBa0.8Ca0.4+xFe2O5+δ system show oxygen reduction reaction (ORR) activity. The layered crystal structure of these oxides is established by the interplay of the Gd3+, Ba2+, and Ca2+ locations with the ordering of the coordination polyhedra of the Fe3+ cations. Substitution of Gd3+ by Ca2+ increases the oxygen deficiency that is accommodated by the formation of layers of FeO5-squared pyramids intercalated with A-O layers containing mainly Gd3+. The presence of FeO5-squared pyramids in the crystal structure promotes the oxygen diffusion and then the ORR activity. Therefore, GdBa2Ca2Fe5O13 is the oxide of the system which presents lower area specific resistance (ASR) values when it is applied as an electrode in symmetrical cells using Ce0.9Gd0.1O2-δ as an electrolyte.

Up-regulation of HDACs, a harbinger of uraemic endothelial dysfunction, is prevented by defibrotide.

Endothelial dysfunction is an earlier contributor to the development of atherosclerosis in chronic kidney disease (CKD), in which the role of epigenetic triggers cannot be ruled out. Endothelial protective strategies, such as defibrotide (DF), may be useful in this scenario. We evaluated changes induced by CKD on endothelial cell proteome and explored the effect of DF and the mechanisms involved. Human umbilical cord vein endothelial cells were exposed to sera from healthy donors (n = 20) and patients with end-stage renal disease on haemodialysis (n = 20). Differential protein expression was investigated by using a proteomic approach, Western blot and immunofluorescence. HDAC1 and HDAC2 overexpression was detected. Increased HDAC1 expression occurred at both cytoplasm and nucleus. These effects were dose-dependently inhibited by DF. Both the HDACs inhibitor trichostatin A and DF prevented the up-regulation of the endothelial dysfunction markers induced by the uraemic milieu: intercellular adhesion molecule-1, surface Toll-like receptor-4, von Willebrand Factor and reactive oxygen species. Moreover, DF down-regulated HDACs expression through the PI3/AKT signalling pathway. HDACs appear as key modulators of the CKD-induced endothelial dysfunction as specific blockade by trichostatin A or by DF prevents endothelial dysfunction responses to the CKD insult. Moreover, DF exerts its endothelial protective effect by inhibiting HDAC up-regulation likely through PI3K/AKT.

Mixed-Valence Iron Dumortierite Fe13.52.22+(As5+O4- x)8(OH)6 and Its Intricate Topotactic Exsolution at Mild Temperatures.

The mixed-valent iron arsenate hydroxide Fe13.52.22+(AsO4- x)8(OH)6, x = 0.25, was prepared using the reaction of iron metal with arsenate in aqueous solution and autogenous pressure. Its crystal structure reveals a dumortierite-like framework with mixed-valent Fe2+/Fe3+ in double chains creating channel walls. Remarkably, hexagonal channels consist of chains of face-sharing Fe2+O6 octahedra, 3/4th occupied, whereas AsO4 tetrahedra occupy triangular ones with a single " up" orientation according to the polar P63 mc symmetry. We have analyzed the transformation of this phase upon heating, in which several chemical processes interact, including dehydroxylation, arsenate to arsenite reduction, and oxidative exsolution of a significant part of iron (ca. 15%) found at the surface as hematite and amorphous Fe-rich surficial layer. It leaves a strongly disordered composite structure between several Fe3+-based subunits, in which ∼80% of them is ordered in a complex supercell. Because of the high degree of disorder, the crystal chemistry of the individual subunits and their plausible imbrication were considered to unravel the most plausible ideal 3D model.

Effectiveness of two interventions based on improving patient-practitioner communication on diabetes self-management in patients with low educational level: study protocol of a clustered randomized trial in primary care.

BACKGROUND: In the last decades the presence of social inequalities in diabetes care has been observed in multiple countries, including Spain. These inequalities have been at least partially attributed to differences in diabetes self-management behaviours. Communication problems during medical consultations occur more frequently to patients with a lower educational level. The purpose of this cluster randomized trial is to determine whether an intervention implemented in a General Surgery, based in improving patient-provider communication, results in a better diabetes self-management in patients with lower educational level. A secondary objective is to assess whether telephone reinforcement enhances the effect of such intervention. We report the design and implementation of this on-going study. METHODS/DESIGN: The study is being conducted in a General Practice located in a deprived neighbourhood of Granada, Spain. Diabetic patients 18 years old or older with a low educational level and inadequate glycaemic control (HbA1c > 7%) were recruited. General Practitioners (GPs) were randomised to three groups: intervention A, intervention B and control group. GPs allocated to intervention groups A and B received training in communication skills and are providing graphic feedback about glycosylated haemoglobin levels. Patients whose GPs were allocated to group B are additionally receiving telephone reinforcement whereas patients from the control group are receiving usual care. The described interventions are being conducted during 7 consecutive medical visits which are scheduled every three months. The main outcome measure will be HbA1c; blood pressure, lipidemia, body mass index and waist circumference will be considered as secondary outcome measures. Statistical analysis to evaluate the effectiveness of the interventions will include multilevel regression analysis with three hierarchical levels: medical visit level, patient level and GP level. DISCUSSION: The results of this study will provide new knowledge about possible strategies to promote a better diabetes self-management in a particularly vulnerable group. If effective, this low cost intervention will have the potential to be easily incorporated into routine clinical practice, contributing to decrease health inequalities in diabetic patients. TRIAL REGISTRATION: Clinical Trials U.S. National Institutes of Health, NCT01849731.

Francisco Xavier Balmis y las Juntas de Vacuna, un ejemplo pionero para implementar la vacunación / Francisco Xavier Balmis and the vaccine network, a pioneering example of vaccination implementation

La primera campaña mundial de vacunación organizada fue efectuada en América y las Filipinas por la Real Expedición Filantrópica de la Vacuna (1803-1810). La labor de Balmis como director y de Salvany, subdirector, no se limitó al mero transporte del fluido vacunal a través de los niños vacuníferos sino también al sistema organizativo que aplicaron. Las Juntas de Vacuna fueron una red de centros creados para preservar y transportar el fluido vacuno en buenas condiciones hasta los lugares de vacunación. Disponían de un Reglamento con instrucciones sobre las características del puesto de vacunación o cómo efectuar el censo de vacunados. Para mejorar la aceptabilidad vacunal integraron a los sanitarios locales y utilizaron la prensa para difundir noticias. La estrategia desarrollada constituye un antecedente que, transcurridos doscientos años, guarda una indudable similitud con modelos de planificación sanitaria como el de Pineault y Daveluy utilizados en los modernos programas de inmunización.

The first organised global immunization campaign was undertaken in America and the Philippines by the 'Royal Philanthropic Expedition of the Vaccine' (1803-1810). The work of Balmis as director of the Expedition and Salvany, his Assistant Director, not only included vaccinating children but also the development of an organised model for its application. The model was based on a network of centres created to protect and transport the vaccine fluids in good condition until they reached their vaccination sites and how to conduct a census of vaccinated people. In order to improve vaccine acceptability, local health workers were incorporated and the press was used to disseminate news. The strategy developed served as an antecedent that, two hundred years later, is unquestionably similar to health planning models such as Pineault and Daveluy, used in modern vaccination campaigns.

Low doses of urban air particles from Buenos Aires promote oxidative stress and apoptosis in mice lungs.

UNLABELLED: Air pollution consists of a wide range of gaseous and particulate pollutants. Exposure to particulate matter (PM) can cause oxidative stress within the lung, which in turn can negatively impact health. The mechanisms by which PM causes oxidative stress include the release of trace metals or organic components from the particle. Previously, we have characterized urban air particles from downtown Buenos Aires (UAP-BA) and, by using in vivo animal studies, found that they are able to generate lung inflammation. PURPOSE: We studied lung responses to low doses of UAP-BA (15 µg), with special emphasis on oxidative balance. METHODS: We assessed cell viability, total cell number (TCN) and cell differential (CD) on bronchoalveolar lavages (BAL), oxidative metabolism in lung homogenates by tertbutylhydroperoxide-initiated chemiluminescence (CL), thiobarbituric reactive substances (TBARS), total reactive antioxidant potential (TRAP), reduced glutathione (GSH), and apoptosis in lung sections. RESULTS: We found that low UAP-BA exposure increases TCN, modifies CD, and decreases cell viability in the BAL. In lung homogenates, TBARS and CL rose while TRAP and GSH showed no alteration when compared to controls. Occurrence of apoptosis evaluated by TUNEL assay was markedly augmented in UAP-BA exposed animals. CONCLUSIONS: Our data further implicate oxidative stress as a possible inducer of apoptosis in lungs from animals exposed to low concentrations of this urban environmental contaminant.

[Trends in drug consumption among immigrants between 2004 and 2008]. / Evolución del consumo de drogas por inmigrantes entre los años 2004 y 2008.

OBJECTIVE: To determine the sociodemographic and drug use profile of immigrants attended in Castile-Leon (Spain). METHODS: We performed a retrospective descriptive study comparing sociodemographic profiles and drug use variables through Pearson's chi-square test. RESULTS: A total of 80.8% of drug users were men, with a mean age 33.8 years (SD: 9.0); 72.3% were from Latin America, Portugal and eastern Europe and 51.6% had lived for 5 years or less in Spain. The main drug used was heroine (43.8%), via smoking (43.5%); most drug users started using in the country of origin (64.3%). Comparisons between 2008 and 2004 showed the following significant differences: for men: mean age (33.8 vs 30.9); length of main drug use: > or =21 years (19.2% vs 8.3%); for women: main drug use: heroin plus cocaine (25.6% vs 3.6%); length of main drug use: 16-20 years (27.9% vs 4.0%). CONCLUSIONS: The pattern of drug use differed by country of origin. The most commonly used drug was heroin, and injection was a frequent route of administration. We identified a need to strengthen harm-reduction interventions in this collective, enhance surveillance and adapt health services.

Gene expression profiling reveals overexpression of TSPAN13 in prostate cancer.

Prostate cancer is one of the most frequent malignancies in the Western world. The identification of additional molecular markers is needed to refine the diagnosis of prostate cancer and to develop more effective therapies. In order to identify molecular abnormalities involved in prostate cancer progression, we performed gene expression analysis of prostate cancer samples compared to matched normal tissue from the same patient using a cancer-related microarray. Amplified RNA was hybridized to a cDNA microarray containing 6386 genes and tissue microarrays were used to study protein expression levels. Using significance analysis of microarrays, we identified >1300 genes differentially expressed in prostate cancer compared to normal tissue. Forty-two of these genes were highly upregulated in prostate cancer while 169 were highly repressed. We found that the gene coding for tspan13 was upregulated >2-fold in 75% of the samples analyzed. Immunohistochemistry analysis of prostate cancer tissue microarrays showed that tspan13 is overexpressed in 80% of prostate cancer samples analyzed. We found that tspan13 expression inversely correlates with Gleason score (p=0.01) and PSA preoperative levels (p=0.11) and directly correlates with presence of prostatic intraepithelial neoplasia in tumor tissue (p=0.04). Moreover, we detected tspan13 expression in low-grade prostatic intraepithelial neoplasia. Thus, our results show that tspan13 is overexpressed in prostate cancer and its expression correlates with factors of favourable outcome. Therefore we suggest that tspan13 may have an important role in the progression of prostate cancer.

Development of a full-genome cDNA clone of Citrus leaf blotch virus and infection of citrus plants.

Citrus leaf blotch virus (CLBV), a member of the family Flexiviridae, has a ~9-kb single-stranded, positive-sense genomic RNA encapsidated by a 41-kDa coat protein. CLBV isolates are associated with symptom production in citrus including leaf blotching of Dweet tangor and stem pitting in Etrog citron (Dweet mottle disease), and some isolates are associated with bud union crease on trifoliate rootstocks, but Koch's postulates for this virus were not fulfilled. A full-genome cDNA of CLBV isolate SRA-153, which induces bud union crease, was placed under the T7 promoter (clone T7-CLBV), or between the 35S promoter and the Nos-t terminator, with or without a ribozyme sequence downstream of the CLBV sequence (clones 35SRbz-CLBV and 35S-CLBV). RNA transcripts from T7-CLBV failed to infect Etrog citron and Nicotiana occidentalis and N. benthamiana plants, whereas agro-inoculation with binary vectors carrying 35SRbz-CLBV or 35S-CLBV, and the p19 silencing suppressor, caused systemic infection and production of normal CLBV virions. Virus accumulation was similar in citron plants directly agro-infiltrated, or mechanically inoculated with wild-type or 35SRbz-CLBV-derived virions from Nicotiana, and the three sources incited the symptoms characteristic of Dweet mottle disease, but not bud union crease. Our results show that (1) virions derived from an infectious clone show the same replication, movement and pathogenicity characteristics as the wild-type CLBV; (2) CLBV is the causal agent of Dweet mottle disease but not of the bud union crease syndrome; and (3) for the first time an RNA virus could be successfully agro-inoculated on citrus plants. This infectious clone may become a useful viral vector for citrus genomic studies.

From hypo- to hypersuppression: effect of amino acid substitutions on the RNA-silencing suppressor activity of the Tobacco etch potyvirus HC-Pro.

RNA silencing participates in several important functions: from the regulation of cell metabolism and organism development to sequence-specific antiviral defense. Most plant viruses have evolved proteins that suppress RNA silencing and that in many cases are multifunctional. Tobacco etch potyvirus (TEV) HC-Pro protein suppresses RNA silencing and participates in aphid-mediated transmission, polyprotein processing, and genome amplification. In this study, we have generated 28 HC-Pro amino acid substitution mutants and quantified their capacity as suppressors of RNA silencing in a transient expression assay. Most mutations either had no quantitative effect or completely abolished silencing suppression (10 in each class), 3 caused a significant decrease in the activity, and 5 significantly increased it, revealing an unexpected high frequency of mutations conferring hypersuppressor activity. A representative set of the mutant alleles, containing both hypo- and hypersuppressors, was further analyzed for their effect on TEV accumulation and the strength of induced symptoms. Whereas TEV variants with hyposuppressor mutants were far less virulent than wild-type TEV, those with hypersuppressor alleles induced symptoms that were not more severe than those characteristic of the wild-type virus, suggesting that there is not a perfect match between suppression and virulence.

Structure of Mn-Zr mixed oxides catalysts and their catalytic performance in the gas-phase oxidation of chlorocarbons.

The catalytic activity and selectivity of manganese zirconia mixed oxides were evaluated for the oxidation of two common chlorinated pollutants found in waste streams, namely 1,2-dichloroethane (DCE) and trichloroethylene (TCE). Mixed oxides with varying Mn-Zr content were prepared by coprecipitation via nitrates, and subsequent calcination at 600 degrees C for 4 h in air. These catalysts were characterised by means of several techniques such as atomic emission spectrometry, N2 adsorption-desorption, powder X-ray diffraction, temperature-programmed desorption of ammonia, pyridine adsorption followed by diffuse reflectance infrared spectroscopy and temperature-programmed reduction with hydrogen. The active catalytic behaviour of Mn-Zr mixed oxides was ascribed to a substantial surface acidity combined with readily accessible active oxygen species. Hence, the mixed oxide with 40 mol% manganese content was found to be an optimum catalyst for the combustion of both chlorocarbons with a T50 value around 305 and 315 degrees C for DCE and TCE oxidation, respectively. The major oxidation products were carbon dioxide, hydrogen chloride and chlorine. It was observed that the formation of both CO2 and Cl2 was promoted with Mn loading.