Inter-annual variation of physiological traits between urban and forest great tits.

Urbanization is characterized by rapid environmental changes such as an increase in building surface, in pollution, or a decrease in invertebrate abundance. For many bird species, morphological and physiological differences have been observed between urban and rural individuals that seem to reflect a negative impact of urban life on the health and fitness of individuals. Studies on passerine birds also showed important differences between populations and species in their responses to the urban environment. We propose to test physiological differences between urban and forest individuals over 3 years to understand whether the observed patterns are constant or subject to variations across years. For this purpose, we assessed the health parameters of adults and fledgling of great tits, Parus major, living in an urban and in a forest site in the Eurometropole of Strasbourg, for three years. Bird health was estimated with morphological parameters (body condition and size) and also with physiological parameters (oxidative status and telomere length). Our results showed lower body condition of urban fledglings regardless of the year, but no site effects on telomere length. On the contrary, for adult breeders, urban individuals had longer telomeres than forest ones except for one year which coincide with bad weather conditions during reproduction where no difference was detected. Urban birds also had higher antioxidant capacity whatever the years. These results suggest that cities act as a filter in which only good quality individuals survive and achieve successful reproduction regardless of year, whereas in the forest the selection occurs only during harsh weather years.

Interactions between miRNAs and Double-Strand Breaks DNA Repair Genes, Pursuing a Fine-Tuning of Repair.

The repair of DNA damage is a crucial process for the correct maintenance of genetic information, thus, allowing the proper functioning of cells. Among the different types of lesions occurring in DNA, double-strand breaks (DSBs) are considered the most harmful type of lesion, which can result in significant loss of genetic information, leading to diseases, such as cancer. DSB repair occurs through two main mechanisms, called non-homologous end joining (NHEJ) and homologous recombination repair (HRR). There is evidence showing that miRNAs play an important role in the regulation of genes acting in NHEJ and HRR mechanisms, either through direct complementary binding to mRNA targets, thus, repressing translation, or by targeting other genes involved in the transcription and activity of DSB repair genes. Therefore, alteration of miRNA expression has an impact on the ability of cells to repair DSBs, which, in turn, affects cancer therapy sensitivity. This latter gives account of the importance of miRNAs as regulators of NHEJ and HRR and places them as a promising target to improve cancer therapy. Here, we review recent reports demonstrating an association between miRNAs and genes involved in NHEJ and HRR. We employed the Web of Science search query TS ("gene official symbol/gene aliases*" AND "miRNA/microRNA/miR-") and focused on articles published in the last decade, between 2010 and 2021. We also performed a data analysis to represent miRNA-mRNA validated interactions from TarBase v.8, in order to offer an updated overview about the role of miRNAs as regulators of DSB repair.

As-Cd-Pb Mixture Induces Cellular Transformation via Post-Transcriptional Regulation of Rad51c by miR-222.

BACKGROUND/AIMS: Exposure to heavy metals is today a threat to society. The understanding of the molecular processes related to diseases related to exposure to metals mixture involve changes in the expression of microRNAs. Changes on microRNAs expression may alter several cellular processes, among them, DNA repair inhibition has been described as an essential event leading to the initiation of metal-induced carcinogenesis. METHODS: We evaluate the miR-222 expression in the two-stage transformation Balb/c 3T3 cell assay treated with As-Cd-Pb mixture. RESULTS: We could appreciate that up-regulation of miR-222 reduces the expression both gene and as a protein expression of Rad51c by RT-PCR and immunoblot, respectively. CONCLUSION: Here, we demonstrate that the mixture of As-Cd-Pb at epidemiologically relevant concentrations induces miR-222 up-regulation, which directly negatively regulates Rad51c expression and impairs homologous recombination of DNA during the initiation stage of cell transformation. This inhibition triggers morphological transformation in a murine two-stage Balb/c 3T3 cell assay, suggesting that this small RNA acts as an initiator of the carcinogenesis process.

Glutathione depletion triggers actin cytoskeleton changes via actin-binding proteins.

The importance of glutathione (GSH) in alternative cellular roles to the canonically proposed, were analyzed in a model unable to synthesize GSH. Gene expression analysis shows that the regulation of the actin cytoskeleton pathway is strongly impacted by the absence of GSH. To test this hypothesis, we evaluate the effect of GSH depletion via buthionine sulfoximine (5 and 12.5 mM) in human neuroblastoma MSN cells. In the present study, 70% of GSH reduction did not induce reactive oxygen species, lipoperoxidation, or cytotoxicity, which enabled us to evaluate the effect of glutathione in the absence of oxidative stress. The cells with decreasing GSH levels acquired morphology changes that depended on the actin cytoskeleton and not on tubulin. We evaluated the expression of three actin-binding proteins: thymosin ß4, profilin and gelsolin, showing a reduced expression, both at gene and protein levels at 24 hours of treatment; however, this suppression disappears after 48 hours of treatment. These changes were sufficient to trigger the co-localization of the three proteins towards cytoplasmic projections. Our data confirm that a decrease in GSH in the absence of oxidative stress can transiently inhibit the actin binding proteins and that this stimulus is sufficient to induce changes in cellular morphology via the actin cytoskeleton.

Assessing genotoxicity of diuron on Drosophila melanogaster by the wing-spot test and the wing imaginal disk comet assay.

The aim of this study was to evaluate the genotoxicity of the herbicide diuron in the wing-spot test and a novel wing imaginal disk comet assay in Drosophila melanogaster. The wing-spot test was performed with standard (ST) and high-bioactivation (HB) crosses after providing chronic 48 h treatment to third instar larvae. A positive dose-response effect was observed in both crosses, but statistically reduced spot frequencies were registered for the HB cross compared with the ST. This latter finding suggests that metabolism differences play an important role in the genotoxic effect of diuron. To verify diuron's ability to produce DNA damage, a wing imaginal disk comet assay was performed after providing 24 h diuron treatment to ST and HB third instar larvae. DNA damage induced by the herbicide had a significantly positive dose-response effect even at very low concentrations in both strains. However, as noted for the wing-spot test, a significant difference between strains was not observed that could be related to the duration of exposure between both assays. A positive correlation between the comet assay and the wing-spot test was found with regard to diuron genotoxicity.

Metal mixture (As-Cd-Pb)-induced cell transformation is modulated by OLA1.

Environmental pollutants are complex mixtures in which metals are ubiquitous. Metal mixtures of arsenic, cadmium and lead are present in the occupational environment and generate health effects such as cardiovascular, renal and cancer diseases. Cell transformation induced by metal mixtures that depend on reactive oxygen species (ROS) generation, cell viability maintenance and avoidance of senescence was previously reported by our group. The aim of the present study was to explore the role of a Obg-like ATPase1 (OLA1) in the cell transformation of BALB/c 3T3 A31-1-1 clonal cells induced by a metal mixture (2 µM NaAsO2, 2 µM CdCl2 and 5 µM Pb(C2H3O2)2 3H2O) through ROS generation. The interest in OLA1 is justified because this protein has been proposed to be a negative regulator of the cellular antioxidant response. Small interfering RNA (siRNA) was used to knockdown OLA1 before the initiation stage of the transformation assay. We evaluated (ROS) and OLA1 protein expression throughout the initiation and promotion stages of transformation. OLA1 knockdown modulated metal mixture-induced cell transformation more strongly when the metal mixture was an initiator stimulus than when it was a promoter. The ability of the metal mixture to initiate cell transformation was diminished by OLA1 knockdown, an effect that depended on intracellular ROS levels. The effect of OLA1 was synergistic with N-Acetyl-l-cysteine (NAC) co-treatment. Oxidative stress-associated transcription factors Egr1 and Smad were also down-regulated by the OLA1 knockdown, contributing to the rescue of metal mixture cell transformation.

Oxidative stress during courtship affects male and female reproductive effort differentially in a wild bird with biparental care.

Oxidative stress has been suggested as one of the physiological mechanisms modulating reproductive effort, including investment in mate choice. Here, we evaluated whether oxidative stress influences breeding decisions by acting as a cost of or constraint on reproduction in the brown booby (Sula leucogaster), a long-lived seabird with prolonged biparental care. We found that during courtship, levels of lipid peroxidation (LP) of males and females were positively associated with gular skin color, a trait presumably used in mate choice, while levels of reactive oxygen species (ROS) were higher as laying approached and in early breeding pairs. Evidence of a constraining effect of oxidative stress for females was suggested by the fact that females with higher ROS during courtship laid smaller first eggs and had chicks with lower rates of body mass gain, and higher female LP was associated with lower offspring attendance time. No evidence of an oxidative cost of parental effort was found; from courtship to parental care, levels of ROS in males and females decreased, and changes in LP levels were non-significant. Finally, using a cross-fostering experiment we found that offspring ROS was unrelated to rearing and genetic parents' ROS. Interestingly, offspring LP was positively associated with the LP during courtship of both the rearing parents and the genetic father, suggesting that offspring LP might have both a genetic and an environmental component. Hence, in the brown booby, oxidative stress may be a cost of investment in reproductive traits before egg laying and constrain females' investment in eggs and parental care.

Causes of genome instability: the effect of low dose chemical exposures in modern society.

Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis.

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

The comet assay as a tool for human biomonitoring studies: the ComNet project.

The comet assay is widely used in human biomonitoring to measure DNA damage as a marker of exposure to genotoxic agents or to investigate genoprotective effects. Studies often involve small numbers of subjects, and design may be sub-optimal in other respects. In addition, comet assay protocols in use in different laboratories vary significantly. In spite of these difficulties, it is appropriate to carry out a pooled analysis of all available comet assay biomonitoring data, in order to establish baseline parameters of DNA damage, and to investigate associations between comet assay measurements and factors such as sex, age, smoking status, nutrition, lifestyle, etc. With this as its major objective, the ComNet project has recruited almost 100 research groups willing to share datasets. Here we provide a background to this project, discussing the history of the comet assay and practical issues that can critically affect its performance. We survey its diverse applications in biomonitoring studies, including environmental and occupational exposure to genotoxic agents, genoprotection by dietary and other factors, DNA damage associated with various diseases, and intrinsic factors that affect DNA damage levels in humans. We examine in depth the quality of data from a random selection of studies, from an epidemiological and statistical point of view.

Genetic structure and diversity of animal populations exposed to metal pollution.

Studying the genetic diversity of wild populations that are affected by pollution provides a basis for estimating the risks of environmental contamination to both wildlife, and indirectly to humans. Such research strives to produce both a better understanding of the underlying mechanisms by which genetic diversity is affected,and the long-term effects of the pollutants involved.In this review, we summarize key aspects of the field of genetic ecotoxicology that encompasses using genetic patterns to examine metal pollutants as environmental stressors of natural animal populations. We address genetic changes that result from xenobiotic exposure versus genetic alterations that result from natural ecological processes. We also describe the relationship between metal exposure and changes in the genetic diversity of chronically exposed populations, and how the affected populations respond to environmental stress. Further, we assess the genetic diversity of animal populations that were exposed to metals, focusing on the literature that has been published since the year 2000.Our review disclosed that the most common metals found in aquatic and terrestrial ecosystems were Cd, Zn, Cu and Pb; however, differences in the occurrence between aquatic (Cd=Zn>Cu>Pb>Hg) and terrestrial (Cu>Cd>Pb>Zn>Ni)environments were observed. Several molecular markers were used to assess genetic diversity in impacted populations, the order of the most common ones of which were SSR's > allozyme > RAPD's > mtDNA sequencing> other molecular markers.Genetic diversity was reduced for nearly all animal populations that were exposed to a single metal, or a mixture of metals in aquatic ecosystems (except in Hyalella azteca, Littorina littorea, Salmo trutta, and Gobio gobio); however, the pattern was less clear when terrestrial ecosystems were analyzed.We propose that future research in the topic area of this paper emphasizes seven key areas of activity that pertain to the methodological design of genetic ecotoxicological studies. Collectively, these points are designed to provide more accurate data and a deeper understanding of the relationship between alterations in genetic diversity of impacted populations and metal exposures. In particular, we believe that the exact nature of all tested chemical pollutants be clearly described, biomarkers be included, sentinel organisms be used, testing be performed at multiple experimental sites, reference populations be sampled in close geographical proximity to where pollution occurs, and genetic structure parameters and high-throughput technology be more actively employed. Furthermore, we propose a new class of biomarkers,termed "biomarkers of permanent effect," which may include measures of genetic variability in impacted populations.

A metal mixture induces transformation upon antioxidant depletion in a hepatic cell line.

INTRODUCTION: Metals are ubiquitous soil, air, and water pollutants. A mixture of arsenic cadmium and lead, in particular, has commonly been found in the vicinity of smelter areas. The mixture of As-Cd-Pb has been shown to be carcinogenic, and transforming potential and oxidative stress have been proposed as principal mechanisms involved in this process. The aim of this work was to explore the role of the antioxidant barrier in the establishment of cell transformation upon chronic exposure to a metal mixture containing 2 µM NaAsO(2), 2 µM. CdCl(2), and 5 µM Pb(C(2)H(3)O(2))(2)∙3H(2)O in WRL-68 cells-a non-transformed human hepatic cell line. MATERIAL AND METHODS: In this study, we used a WRL-68 cell model of human embryonic hepatic origin treated with antioxidant inhibitors (L-Buthionine-sulfoxamine and aminotriazole) to test the role of the antioxidant barrier in the establishment of cell transformation upon chronic exposure to a metal mixture of As-Cd-Pb (2 µM NaAsO(2), 2 µM CdCl(2) and 5 µM Pb(C(2)H(3)O(2))(2)∙3H(2)O). We evaluated oxidative damage markers, including reactive oxygen species, lipid peroxidation, and genotoxicity, as well as antioxidant response markers, including glutathione concentration, catalase activity, and superoxide dismutase activity, which promote morphological transformation, which can be quantified by foci formation. RESULTS: As expected, we found an increase in the intracellular concentration of the metals after treatment with the metal mixture. In addition, treatment with the metal mixture in addition to inhibitors resulted in a large increase in the intracellular concentration of cadmium and lead. Our results describe the generation of reactive oxygen species, cytotoxicity, genotoxicity, and oxidative damage to macromolecules that occurred exclusively in cells that were morphologically transformed upon exposure to a metal mixture and antioxidant barrier inhibition. CONCLUSION: Our results show the importance of the antioxidant barrier role in the protection of cellular integrity and the transformation potential of this metal mixture via free radicals.

Effect of Air Pollution on the Basal DNA Damage of Mother-Newborn Couples of México City.

Environmental pollution of megacities can cause early biological damage such as DNA strand breaks and micronuclei formation. Comet assay tail length (TL) reflects exposure in the uterus to high levels of air pollution, primarily ozone and air particles (PM10), including mothers' smoking habits during pregnancy, conditions which can lead to low birth weight. In this biomonitoring study, we evaluated basal DNA damage in the cord blood cells of newborn children from Mexico City. We found a correlation between DNA damage in mothers and their newborns, including various parameters of environmental exposure and complications during pregnancy, particularly respiratory difficulties, malformations, obstetric trauma, neuropathies, and nutritional deficiencies. Mothers living in the southern part of the city showed double DNA damage compared to those living in the northern part (TL 8.64 µm vs. 4.18 µm, p < 0.05). Additionally, mothers' DNA damage correlates with exposure to NOx (range 0.77-1.52 ppm) and PM10 (range 58.32-75.89 µg/m3), as well maternal age >29. These results highlight the sensitivity of the comet assay in identifying differential in utero exposure for newborns whose mothers were exposed during pregnancy. They also suggest the importance of antioxidants during pregnancy and the role of the placental barrier in protecting the newborn from the DNA-damaging effects of oxidative pollution.

Role of Ape1 in Impaired DNA Repair Capacity in Battery Recycling Plant Workers Exposed to Lead.

Exposure to lead in environmental and occupational settings continues to be a serious public health problem. At environmentally relevant doses, two mechanisms may underlie lead exposition-induced genotoxicity, disruption of the redox balance and an interference with DNA repair systems. The aim of the study was to evaluate the ability of lead exposition to induce impaired function of Ape1 and its impact on DNA repair capacity of workers chronically exposed to lead in a battery recycling plant. Our study included 53 participants, 37 lead exposed workers and 16 non-lead exposed workers. Lead intoxication was characterized by high blood lead concentration, high lipid peroxidation and low activity of delta-aminolevulinic acid dehydratase (δ-ALAD). Relevantly, we found a loss of DNA repair capacity related with down-regulation of a set of specific DNA repair genes, showing specifically, for the first time, the role of Ape1 down regulation at transcriptional and protein levels in workers exposed to lead. Additionally, using a functional assay we found an impaired function of Ape1 that correlates with high blood lead concentration and lipid peroxidation. Taken together, these data suggest that occupational exposure to lead could decrease DNA repair capacity, inhibiting the function of Ape1, as well other repair genes through the regulation of the ZF-transcription factor, promoting the genomic instability.

Fusion of the ß2-adrenergic receptor with either Gαs or ßarrestin-2 produces constitutive signaling by each pathway and induces gain-of-function in BEAS-2B cells.

The ß2AR is a prototypical G protein-coupled receptor (GPCR) known to orchestrate different cellular responses by the stimulation of specific signaling pathways. The best-established signaling pathways for the ß2AR are the canonical Gs pathway and the alternative ß arrestin 2 (ßarr2) pathway. Exploring each pathway separately remains a challenging task due to the dynamic nature of the receptor. Here, we fused the ß2AR with its cognate transducers, Gαs and ßarr2, using short linkers as a novel approach for restricting the conformation of the receptor and preferentially activating one of its two signaling pathways. We characterized the behavior of our fusion proteins ß2AR-Gαs and ß2AR-ßarr2 in HEK293 cells by measuring their constitutive activity, transducer recruitment, and pharmacological modulation. Our fusion proteins show (a) steric hindrance from the reciprocal endogenous transducers, (b) constitutive activity of the ß2AR for the signaling pathway activated by the tethered transducer, and (c) pharmacologic modulation by ß2AR ligands. Based on these characteristics, we further explored the possibility of a gain-of-function mechanism in the human lung non-tumorigenic epithelial cell line, BEAS-2B cells. This immortalized human bronchial epithelial cell line has immunomodulatory properties through cytokine release mediated by ß2AR stimulation. Our findings suggest that each signaling pathway of the ß2AR is biased toward either the Th1 or Th2 inflammatory response suggesting a role in regulating the immune phenotype of respiratory diseases. Our data imply that our fusion proteins can be used as tools to isolate the function elicited by a single signaling pathway in physiologically relevant cell types.

A NanoBiT assay to monitor membrane proteins trafficking for drug discovery and drug development.

Internalization of membrane proteins plays a key role in many physiological functions; however, highly sensitive and versatile technologies are lacking to study such processes in real-time living systems. Here we describe an assay based on bioluminescence able to quantify membrane receptor trafficking for a wide variety of internalization mechanisms such as GPCR internalization/recycling, antibody-mediated internalization, and SARS-CoV2 viral infection. This study represents an alternative drug discovery tool to accelerate the drug development for a wide range of physiological processes, such as cancer, neurological, cardiopulmonary, metabolic, and infectious diseases including COVID-19.

Induction of oxidative stress by low doses of lead in human hepatic cell line WRL-68.

Even though the molecular mechanisms by which lead induces toxicity and cancer have been intensely studied for many years, its carcinogenic mechanisms are not well understood yet. Several possible mechanisms have been examined to gain understanding on the carcinogenic properties of lead, which include mitogenesis, alteration of gene expression, and oxidative damage, among others. The aim of the present study was to explore the induction of oxidative damage at low lead concentrations using human embryonic hepatic cells WRL-68. Our results showed induction of reactive oxygen species, changes in the superoxide dismutase and catalase activity, as well as an induction of lipidperoxidation and DNA damage. However, after 5 weeks of exposure, these alterations returned to their basal levels. These results taking together indicate that at low concentrations, lead is able to establish an oxidative stress scenario; however under optimal antioxidant defense the oxidative scenario could be abolished through an adaptative process.

miR-27b-3p a Negative Regulator of DSB-DNA Repair.

Understanding the regulation of DNA repair mechanisms is of utmost importance to identify altered cellular processes that lead to diseases such as cancer through genomic instability. In this sense, miRNAs have shown a crucial role. Specifically, miR-27b-3 biogenesis has been shown to be induced in response to DNA damage, suggesting that this microRNA has a role in DNA repair. In this work, we show that the overexpression of miR-27b-3p reduces the ability of cells to repair DNA lesions, mainly double-stranded breaks (DSB), and causes the deregulation of genes involved in homologous recombination repair (HRR), base excision repair (BER), and the cell cycle. DNA damage was induced in BALB/c-3T3 cells, which overexpress miR-27b-3p, using xenobiotic agents with specific mechanisms of action that challenge different repair mechanisms to determine their reparative capacity. In addition, we evaluated the expression of 84 DNA damage signaling and repair genes and performed pathway enrichment analysis to identify altered cellular processes. Taken together, our results indicate that miR-27b-3p acts as a negative regulator of DNA repair when overexpressed.

Hypoxia Inducible Factors as Central Players in the Pathogenesis and Pathophysiology of Cardiovascular Diseases.

Cardiovascular (CV) diseases are the major cause of death in industrialized countries. The main function of the CV system is to deliver nutrients and oxygen to all tissues. During most CV pathologies, oxygen and nutrient delivery is decreased or completely halted. Several mechanisms, including increased oxygen transport and delivery, as well as increased blood flow are triggered to compensate for the hypoxic state. If the compensatory mechanisms fail to sufficiently correct the hypoxia, irreversible damage can occur. Thus, hypoxia plays a central role in the pathogenesis and pathophysiology of CV diseases. Hypoxia inducible factors (HIFs) orchestrate the gene transcription for hundreds of proteins involved in erythropoiesis, glucose transport, angiogenesis, glycolytic metabolism, reactive oxygen species (ROS) handling, cell proliferation and survival, among others. The overall regulation of the expression of HIF-dependent genes depends on the severity, duration, and location of hypoxia. In the present review, common CV diseases were selected to illustrate that HIFs, and proteins derived directly or indirectly from their stabilization and activation, are related to the development and perpetuation of hypoxia in these pathologies. We further classify CV diseases into acute and chronic hypoxic states to better understand the temporal relevance of HIFs in the pathogenesis, disease progression and clinical outcomes of these diseases. We conclude that HIFs and their derived factors are fundamental in the genesis and progression of CV diseases. Understanding these mechanisms will lead to more effective treatment strategies leading to reduced morbidity and mortality.

[Blue Lungs in Covid-19 Patients: A Step beyond the Diagnosis of Pulmonary Thromboembolism using MDCT with Iodine Mapping]. / Pulmones azules en pacientes COVID-19: un paso más allá del diagnóstico de tromboembolismo pulmonar mediante TCMD con mapa de yodo.

OBJECTIVE: To evaluate the diagnostic capacity of pulmonary angiography with multidetector computed tomography (MDCT) and iodine mapping in the diagnosis of pulmonary thromboembolism (PTE) in patients with Covid-19 disease. METHODS: Retrospective observational study of 81 consecutive patients admitted with Covid-19 respiratory infection who underwent MDCT for clinical suspicion of PTE (sudden dyspnea, chest pain, hemoptysis, severe respiratory failure (SRF) not corrected with high O2 flow) and/or raised D-dimer. RESULTS: Of the 81 patients studied [64 (79.01%) men], acute PTE was identified in 22 (27.16%), bilaterally in 13 (59.09%), and 13 (59,09%) showed areas of hypoperfusion. Of the 59 (72.83%) patients without PTE, hypoperfusion was observed in 41 (69.49%) (attributable in one case to pulmonary emphysema). In 18 (22.2%) of the total number of patients, neither PTE nor hypoperfusion were seen. A crazy paving pattern is a risk factor for developing PTE (OR 1.94; 95% CI 0.28-13.57), as are consolidations (OR 1.44; 95% CI 0.24-8.48) and septal thickening/bronchiectasis (OR 1.47; 95% CI 0.12-17.81).Patients with O2-refractory SRF showed a 6.36-fold higher risk for hypoperfusion on the iodine map. CONCLUSION: By adding the functional image to the anatomical image, pulmonary angiography with MDCT and iodine mapping can demonstrate not only PTE in main, lobar and segmental arteries, but also the presence of hypoperfusion in distal vessels. This makes it a highly useful tool for the accurate diagnosis and therapeutic orientation of patients with Covid-19 lung involvement.