Sleep apnea-COPD overlap syndrome is associated with larger left carotid atherosclerotic plaques.

Background: Little is known about whether the overlap syndrome (OS) combining features of chronic obstructive pulmonary disease (COPD) and sleep apnea-hypopnea syndrome increases the risk of stroke associated with COPD itself. Methods: We prospectively studied 74 COPD patients and 32 subjects without lung disease. Spirometry and cardiorespiratory polygraphy were used to assess the pulmonary function of the study population and ultrasound measurements of intima media thickness (IMT) as well as the volume of plaques in both carotid arteries were also evaluated. Results: Polygraphic criteria of OS were met in 51% of COPD patients. We found that 79% of patients with OS and 50% of COPD patients without OS had atherosclerotic plaques in the left carotid artery (p = 0.0509). Interestingly, the mean volume of atherosclerotic plaques was significantly higher in the left carotid artery of COPD patients with OS (0.07 ± 0.02 ml) than in those without OS (0.04 ± 0.02 ml, p = 0.0305). However, regardless of the presence of OS, no significant differences were observed in both presence and volume of atherosclerotic plaques in the right carotid artery of COPD patients. Adjusted-multivariate linear regression revealed age, current smoking and the apnea/hypopnea index (OR = 4.54, p = 0.012) as independent predictors of left carotid atherosclerotic plaques in COPD patients. Conclusions: This study suggests that the presence of OS in COPD patients is associated with larger left carotid atherosclerotic plaques, indicating that OS might be screened in all COPD patients to identify those with higher risk of stroke.

Reduced miR-146a-5p Is a Biomarker of Infant Respiratory Diseases Contributing to Immune Dysregulation in Small Airway Epithelial Cells.

Respiratory diseases such as bronchiolitis, and those with wheezing episodes, are highly important during infancy due to their potential chronicity. Immune response dysregulation is critical in perpetuating lung damage. Epigenetic modifications including microRNA (miRNA) post-transcriptional regulation are among the factors involved in alleviating inflammation. We evaluated the expression of miR-146a-5p, a previously described negative regulator of immunity, in infants with respiratory diseases, in order to study epigenetic regulation of the immune response. Nasopharyngeal aspirate (NPA) was obtained from infants with bronchiolitis (ongoing and post-disease) or with wheezing episodes in addition to healthy controls. Virus presence was determined by nested PCR, while miRNA and gene expression were studied in cells from NPAs using qPCR. Healthy small airway epithelial cells (SAECs) were used as an in vitro model. We observe a reduction in miR-146a-5p expression in infants with either of the two diseases compared to controls, suggesting the potential of this miRNA as a disease biomarker. Post-bronchiolitis, miR-146a-5p expression increases, though without reaching levels of healthy controls. MiR-146a-5p expression correlates inversely with the immune-related gene PTGS2, while its expression correlates directly with TSLP. When heathy donor SAECs are stimulated by poly:IC, we observe an increase in miR-146a-5p, with wounds having a synergistic effect. In conclusion, infants with respiratory diseases present reduced miR-146a-5p expression, possibly affecting immune dysregulation.

Passive targeting of high-grade gliomas via the EPR effect: a closed path for metallic nanoparticles?

Passive tumor targeting via the enhanced permeability and retention (EPR) effect has long been considered the most effective mechanism for the accumulation of nanoparticles inside solid tumors. However, several studies have demonstrated that the EPR effect is largely dependent on the tumor type and location. Particularly complex is the situation in brain tumors, where the presence of the blood-brain tumor barrier (BBTB) adds an extra limiting factor in reaching the tumor interstitium. However, it remains unclear whether these restraints imposed by the BBTB prevent the EPR effect from acting as an efficient tumor targeting mechanism for metallic nanoparticles. In this work, we have studied the EPR effect of metallic magnetic nanoparticles (MMNPs) in a glioblastoma (GBM) model by parametric MRI. Our results showed that only MMNPs ≤50 nm could reach the tumor interstitium, whereas larger MMNPs were unable to cross the BBTB. Furthermore, even for MMNPs around 30-50 nm, the amount of them found within the tumor was scarce and restricted to the vicinity of large tumor vessels, indicating that the BBTB strongly limits the passive accumulation of metallic nanoparticles in brain tumors. Therefore, active targeting becomes the most reasonable strategy to target metallic nanoparticles to GBMs.

Excerpts from the documents of Mexican positions and recommendations in cardiovascular diseases and COVID-19.

The recommendations in which the Mexican Society of Cardiology (SMC) in conjunction with the National Association of Cardiologists of Mexico (ANCAM) as well as different Mexican medical associations linked to cardiology are presented, after a comprehensive and consensual review and analysis of the topics related to cardiovascular diseases in the COVID-19 pandemic. Scientific positions are analyzed and responsible recommendations on general measures are given to patients, with personal care, healthy eating, regular physical activity, actions in case of cardio-respiratory arrest, protection of the patient and health personnel as well as precise indications in the use of non-invasive cardiovascular imaging, prescription of medications, care in specific topics such as systemic arterial hypertension, heart failure, arrhythmias and acute coronary syndromes, in addition to emphasizing electrophysiology, interventionism, cardiac surgery and in cardiac rehabilitation. The main interest is to provide the medical community with a general orientation on what to do in daily practice and patients with cardiovascular diseases in the setting of this unprecedented epidemiological crisis of COVID-19.

Se presentan las recomendaciones en las cuales la Sociedad Mexicana de Cardiología (SMC) en conjunto con la Asociación Nacional de Cardiólogos de México (ANCAM), así como diferentes asociaciones médicas mexicanas vinculadas con la cardiología, después de una revisión y análisis exhaustivo y consensuado sobre los tópicos relacionados con las enfermedades cardiovasculares en la pandemia de COVID-19, se analizan posturas científicas y se dan recomendaciones responsables sobre medidas generales a los pacientes, con cuidados personales, alimentación saludable, actividad física regular, acciones en caso de paro cardiorrespiratorio, la protección del paciente y del personal de salud así como las indicaciones precisas en el uso de la imagen cardiovascular no invasiva, la prescripción de medicamentos, cuidados en tópicos específicos como en la hipertensión arterial sistémica, insuficiencia cardiaca, arritmias y síndromes coronarios agudos, además de hacer énfasis en los procedimientos de electrofisiología, intervencionismo, cirugía cardiaca y en la rehabilitación cardiaca. El interés principal es brindar a la comunidad médica una orientación general sobre el quehacer en la práctica cotidiana y pacientes con enfermedades cardiovasculares en el escenario esta crisis epidemiológica sin precedentes de COVID-19.

MicroRNAs as Potential Regulators of Immune Response Networks in Asthma and Chronic Obstructive Pulmonary Disease.

Chronic respiratory diseases (CRDs) are an important factor of morbidity and mortality, accounting for approximately 6% of total deaths worldwide. The main CRDs are asthma and chronic obstructive pulmonary disease (COPD). These complex diseases have different triggers including allergens, pollutants, tobacco smoke, and other risk factors. It is important to highlight that although CRDs are incurable, various forms of treatment improve shortness of breath and quality of life. The search for tools that can ensure accurate diagnosis and treatment is crucial. MicroRNAs (miRNAs) are small non-coding RNAs and have been described as promising diagnostic and therapeutic biomarkers for CRDs. They are implicated in multiple processes of asthma and COPD, regulating pathways associated with inflammation, thereby showing that miRNAs are critical regulators of the immune response. Indeed, miRNAs have been found to be deregulated in several biofluids (sputum, bronchoalveolar lavage, and serum) and in both structural lung and immune cells of patients in comparison to healthy subjects, showing their potential role as biomarkers. Also, miRNAs play a part in the development or termination of histopathological changes and comorbidities, revealing the complexity of miRNA regulation and opening up new treatment possibilities. Finally, miRNAs have been proposed as prognostic tools in response to both conventional and biologic treatments for asthma or COPD, and miRNA-based treatment has emerged as a potential approach for clinical intervention in these respiratory diseases; however, this field is still in development. The present review applies a systems biology approach to the understanding of miRNA regulatory networks in asthma and COPD, summarizing their roles in pathophysiology, diagnosis, and treatment.

Extractos de los documentos de posicionamientos y recomendaciones mexicanas en enfermedades cardiovasculares y COVID-19 / Excerpts from the documents of Mexican positions and recommendations in cardiovascular diseases and COVID-19

Resumen Se presentan las recomendaciones en las cuales la Sociedad Mexicana de Cardiología (SMC) en conjunto con la Asociación Nacional de Cardiólogos de México (ANCAM), así como diferentes asociaciones médicas mexicanas vinculadas con la cardiología, después de una revisión y análisis exhaustivo y consensuado sobre los tópicos relacionados con las enfermedades cardiovasculares en la pandemia de COVID-19, se analizan posturas científicas y se dan recomendaciones responsables sobre medidas generales a los pacientes, con cuidados personales, alimentación saludable, actividad física regular, acciones en caso de paro cardiorrespiratorio, la protección del paciente y del personal de salud así como las indicaciones precisas en el uso de la imagen cardiovascular no invasiva, la prescripción de medicamentos, cuidados en tópicos específicos como en la hipertensión arterial sistémica, insuficiencia cardiaca, arritmias y síndromes coronarios agudos, además de hacer énfasis en los procedimientos de electrofisiología, intervencionismo, cirugía cardiaca y en la rehabilitación cardiaca. El interés principal es brindar a la comunidad médica una orientación general sobre el quehacer en la práctica cotidiana y pacientes con enfermedades cardiovasculares en el escenario esta crisis epidemiológica sin precedentes de COVID-19.

Abstract The recommendations in which the Mexican Society of Cardiology (SMC) in conjunction with the National Association of Cardiologists of Mexico (ANCAM) as well as different Mexican medical associations linked to cardiology are presented, after a comprehensive and consensual review and analysis of the topics related to cardiovascular diseases in the COVID-19 pandemic. Scientific positions are analyzed and responsible recommendations on general measures are given to patients, with personal care, healthy eating, regular physical activity, actions in case of cardio-respiratory arrest, protection of the patient and health personnel as well as precise indications in the use of non-invasive cardiovascular imaging, prescription of medications, care in specific topics such as systemic arterial hypertension, heart failure, arrhythmias and acute coronary syndromes, in addition to emphasizing electrophysiology, interventionism, cardiac surgery and in cardiac rehabilitation. The main interest is to provide the medical community with a general orientation on what to do in daily practice and patients with cardiovascular diseases in the setting of this unprecedented epidemiological crisis of COVID-19.

Surface-Functionalization of Zr-Fumarate MOF for Selective Cytotoxicity and Immune System Compatibility in Nanoscale Drug Delivery.

Metal-organic frameworks (MOFs), network structures wherein metal ions or clusters link organic ligands into porous materials, are being actively researched as nanoscale drug delivery devices as they offer tunable structures with high cargo loading that can easily be further functionalized for targeting and enhanced physiological stability. The excellent biocompatibility of Zr has meant that its MOFs are among the most studied to date, in particular the archetypal Zr terephthalate UiO-66. In contrast, the isoreticular analog linked by fumarate (Zr-fum) has received little attention, despite the endogenous linker being part of the Krebs cycle. Herein, we report a comprehensive study of Zr-fum in the context of drug delivery. Reducing particle size is shown to increase uptake by cancer cells while reducing internalization by macrophages, immune system cells that remove foreign objects from the bloodstream. Zr-fum is compatible with defect loading of the drug dichloroacetate (DCA) as well as surface modification during synthesis, through coordination modulation and postsynthetically. DCA-loaded, PEGylated Zr-fum shows selective in vitro cytotoxicity toward HeLa and MCF-7 cancer cells, likely as a consequence of its enhanced caveolae-mediated endocytosis compared to uncoated precursors, and it is well tolerated by HEK293 kidney cells, J774 macrophages, and human peripheral blood lymphocytes. Compared to UiO-66, Zr-fum is more efficient at transporting the drug mimic calcein into HeLa cells, and DCA-loaded, PEGylated Zr-fum is more effective at reducing HeLa and MCF-7 cell proliferation than the analogous UiO-66 sample. In vitro examination of immune system response shows that Zr-fum samples induce less reactive oxygen species than UiO-66 analogs, possibly as a consequence of the linker being endogenous, and do not activate the C3 and C4 complement cascade pathways, suggesting that Zr-fum can avoid phagocytic activation. The results show that Zr-fum is an attractive alternative to UiO-66 for nanoscale drug delivery, and that a wide range of in vitro experiments is available to greatly inform the design of drug delivery systems prior to early stage animal studies.

Mechanistic Investigation into the Selective Anticancer Cytotoxicity and Immune System Response of Surface-Functionalized, Dichloroacetate-Loaded, UiO-66 Nanoparticles.

The high drug-loading and excellent biocompatibilities of metal-organic frameworks (MOFs) have led to their application as drug-delivery systems (DDSs). Nanoparticle surface chemistry dominates both biostability and dispersion of DDSs while governing their interactions with biological systems, cellular and/or tissue targeting, and cellular internalization, leading to a requirement for versatile and reproducible surface functionalization protocols. Herein, we explore not only the effect of introducing different surface functionalities to the biocompatible Zr-MOF UiO-66 but also the efficacy of three surface modification protocols: (i) direct attachment of biomolecules [folic acid (FA) and biotin (Biot)] introduced as modulators for UiO-66 synthesis, (ii) our previously reported "click-modulation" approach to covalently attach polymers [poly(ethylene glycol) (PEG), poly-l-lactide, and poly-N-isopropylacrylamide] to the surface of UiO-66 through click chemistry, and (iii) surface ligand exchange to postsynthetically coordinate FA, Biot, and heparin to UiO-66. The innovative use of a small molecule with metabolic anticancer activity, dichloroacetate (DCA), as a modulator during synthesis is described, and it is found to be compatible with all three protocols, yielding surface-coated, DCA-loaded (10-20 w/w %) nano-MOFs (70-170 nm). External surface modification generally enhances the stability and colloidal dispersion of UiO-66. Cellular internalization routes and efficiencies of UiO-66 by HeLa cervical cancer cells can be tuned by surface chemistry, and anticancer cytotoxicity of DCA-loaded MOFs correlates with the endocytosis efficiency and mechanisms. The MOFs with the most promising coatings (FA, PEG, poly-l-lactide, and poly-N-isopropylacrylamide) were extensively tested for selectivity of anticancer cytotoxicity against MCF-7 breast cancer cells and HEK293 healthy kidney cells as well as for cell proliferation and reactive oxygen species production against J774 macrophages and peripheral blood lymphocytes isolated from the blood of human donors. DCA-loaded, FA-modified UiO-66 selectively kills cancer cells without harming healthy ones or provoking immune system response in vitro, suggesting a significant targeting effect and great potential in anticancer drug delivery. The results provide mechanistic insight into the design and functionalization of MOFs for drug delivery and underline the availability of various in vitro techniques to potentially minimize early-stage in vivo animal studies following the three Rs: reduction, refinement, and replacement.

The expression of oxidative stress response genes is modulated by a combination of resveratrol and N-acetylcysteine to ameliorate ototoxicity in the rat cochlea.

Aminoglycoside antibiotics are used widely in medicine despite their ototoxic side-effects. Oxidative stress and inflammation are key mechanisms determining the extent and severity of the damage. Here we evaluate the protective effect of a treatment with resveratrol plus N-acetylcysteine on the ototoxic actions of kanamycin and furosemide in the rat. Resveratrol (10 mg/kg) and N-acetylcysteine (400 mg/kg) were administered together to Wistar rats on 5 consecutive days. The second day, a concentrated solution of kanamycin and furosemide was placed on the round window to induce ototoxicity. Hearing was assessed by recording auditory brainstem responses before and 5, 16 and 23 days after the beginning of the treatment. Cochlear samples were taken at day 5 (end of the treatment) and at day 23, and targeted PCR arrays or RT-qPCR were performed to analyze oxidative balance and inflammation related genes, respectively. In addition, the cytoarchitecture and the presence of apoptosis, oxidative stress and inflammation markers were evaluated in cochlear sections. Results indicate that administration of resveratrol plus N-acetylcysteine reduced the threshold shifts induced by ototoxic drugs at high frequencies (≈10 dB), although this protective effect fades after the cessation of the treatment. Gene expression analysis showed that the treatment modulated the expression of genes involved in the cellular oxidative (Gpx1, Sod1, Ccs and Noxa1) and inflammatory (Il1b, Il4, Mpo and Ncf) responses to injury. Thus, co-administration of resveratrol and NAC, routinely used individually in patients, could reduce the ototoxic secondary effects of aminoglycosides.

Developmental trajectories of aggressive behavior in children from ages 8 to 10: The role of sex and hormones.

OBJECTIVES: This study explored the developmental trajectory of aggressive behavior from age 8 to age 10 in school-aged children, taking into account possible sex differences, as well as the involvement of certain hormones. METHODS: Participants were 90 children (49 boys and 41 girls) from four schools. At the beginning of the study, the children were 8-year old and were in 3rd grade of primary school. The second data collection phase was carried out two years later (at age 10) when the children were in 5th grade (primary). Their aggressive behavior was measured by the Direct and Indirect Aggression Scale, an instrument which uses peer rating. Hormone levels, testosterone, cortisol and estradiol were analyzed using an enzymoimmunoassay technique in saliva samples. RESULTS: The results revealed a difference in aggressive behavior between the ages of 8 and 10, in boys only, who were found to be more aggressive at age 10. A regression analysis revealed that cortisol and estradiol contributed to explaining the changes observed in aggressive behavior in boys. Boys whose cortisol levels rose most between the ages of 8 and 10 were also those whose aggressive behavior increased most during the same timeframe. Moreover, boys whose estradiol levels rose most between the ages of 8 and 10 were also those whose aggressive behavior decreased most during the same timeframe. CONCLUSIONS: Our results highlight the importance of studying aggressive behavior from a longitudinal perspective, taking into account sex differences and biological measures.