17ß-estradiol induces hyperresponsiveness in guinea pig airway smooth muscle by inhibiting the plasma membrane Ca2+-ATPase.

High serum estrogen concentrations are associated with asthma development and severity, suggesting a link between estradiol and airway hyperresponsiveness (AHR). 17ß-estradiol (E2) has non-genomic effects via Ca2+ regulatory mechanisms; however, its effect on the plasma membrane Ca2+-ATPases (PMCA1 and 4) and sarcoplasmic reticulum Ca2+-ATPase (SERCA) is unknown. Hence, in the present study, we aim to demonstrate if E2 favors AHR by increasing intracellular Ca2+ concentrations in guinea pig airway smooth muscle (ASM) through a mechanism involving Ca2+-ATPases. In guinea pig ASM, Ca2+ microfluorometry, muscle contraction, and Western blot were evaluated. Then, we performed molecular docking analysis between the estrogens and Ca2+ ATPases. In tracheal rings, E2 produced AHR to carbachol. In guinea pig myocytes, acute exposure to physiological levels of E2 modified the transient Ca2+ peak induced by caffeine to a Ca2+ plateau. The incubation with PMCA inhibitors (lanthanum and carboxyeosin, CE) partially reversed the E2-induced sustained plateau in the caffeine response. In contrast, cyclopiazonic acid (SERCA inhibitor), U-0126 (an inhibitor of ERK 1/2), and choline chloride did not modify the Ca2+ plateau produced by E2. The mitochondrial uniporter activity and the capacitative Ca2+ entry were unaffected by E2. In guinea pig ASM, Western blot analysis demonstrated PMCA1 and PMCA4 expression. The results from the docking modeling demonstrate that E2 binds to both plasma membrane ATPases. In guinea pig tracheal smooth muscle, inhibiting the PMCA with CE, induced hyperresponsiveness to carbachol. 17ß-estradiol produces hyperresponsiveness by inhibiting the PMCA in the ASM and could be one of the mechanisms responsible for the increase in asthmatic crisis in women.

Potential of olfactory neuroepithelial cells as a model to study schizophrenia: A focus on GPCRs (Review).

Schizophrenia (SZ) is a multifactorial disorder characterized by volume reduction in gray and white matter, oxidative stress, neuroinflammation, altered neurotransmission, as well as molecular deficiencies such as punctual mutation in Disrupted­in­Schizophrenia 1 protein. In this regard, it is essential to understand the underlying molecular disturbances to determine the pathophysiological mechanisms of the disease. The signaling pathways activated by G protein­coupled receptors (GPCRs) are key molecular signaling pathways altered in SZ. Convenient models need to be designed and validated to study these processes and mechanisms at the cellular level. Cultured olfactory stem cells are used to investigate neural molecular and cellular alterations related to the pathophysiology of SZ. Multipotent human olfactory stem cells are undifferentiated and express GPCRs involved in numerous physiological functions such as proliferation, differentiation and bioenergetics. The use of olfactory stem cells obtained from patients with SZ may identify alterations in GPCR signaling that underlie dysfunctional processes in both undifferentiated and specialized neurons or derived neuroglia. The present review aimed to analyze the role of GPCRs and their signaling in the pathophysiology of SZ. Culture of olfactory epithelial cells constitutes a suitable model to study SZ and other psychiatric disorders at the cellular level.

Hypoxic Effects on Matrix Metalloproteinases' Expression in the Tumor Microenvironment and Therapeutic Perspectives.

The tumor microenvironment (TME) is characterized by an acidic pH and low oxygen concentrations. Hypoxia induces neoplastic cell evasion of the immune surveillance, rapid DNA repair, metabolic reprogramming, and metastasis, mainly as a response to the hypoxic inducible factors (HIFs). Likewise, cancer cells increase matrix metalloproteinases' (MMPs) expression in response to TME conditions, allowing them to migrate from the primary tumor to different tissues. Since HIFs and MMPs are augmented in the hypoxic TME, it is easy to consider that HIFs participate directly in their expression regulation. However, not all MMPs have a hypoxia response element (HRE)-HIF binding site. Moreover, different transcription factors and signaling pathways activated in hypoxia conditions through HIFs or in a HIF-independent manner participate in MMPs' transcription. The present review focuses on MMPs' expression in normal and hypoxic conditions, considering HIFs and a HIF-independent transcription control. In addition, since the hypoxic TME causes resistance to anticancer conventional therapy, treatment approaches using MMPs as a target alone, or in combination with other therapies, are also discussed.

Hypoxia Induces Alterations in the Circadian Rhythm in Patients with Chronic Respiratory Diseases.

The function of the circadian cycle is to determine the natural 24 h biological rhythm, which includes physiological, metabolic, and hormonal changes that occur daily in the body. This cycle is controlled by an internal biological clock that is present in the body's tissues and helps regulate various processes such as sleeping, eating, and others. Interestingly, animal models have provided enough evidence to assume that the alteration in the circadian system leads to the appearance of numerous diseases. Alterations in breathing patterns in lung diseases can modify oxygenation and the circadian cycles; however, the response mechanisms to hypoxia and their relationship with the clock genes are not fully understood. Hypoxia is a condition in which the lack of adequate oxygenation promotes adaptation mechanisms and is related to several genes that regulate the circadian cycles, the latter because hypoxia alters the production of melatonin and brain physiology. Additionally, the lack of oxygen alters the expression of clock genes, leading to an alteration in the regularity and precision of the circadian cycle. In this sense, hypoxia is a hallmark of a wide variety of lung diseases. In the present work, we intended to review the functional repercussions of hypoxia in the presence of asthma, chronic obstructive sleep apnea, lung cancer, idiopathic pulmonary fibrosis, obstructive sleep apnea, influenza, and COVID-19 and its repercussions on the circadian cycles.

Phytoestrogen-Based Hormonal Replacement Therapy Could Benefit Women Suffering Late-Onset Asthma.

It has been observed that plasmatic concentrations of estrogens, progesterone, or both correlate with symptoms in asthmatic women. Fluctuations in female sex steroid concentrations during menstrual periods are closely related to asthma symptoms, while menopause induces severe physiological changes that might require hormonal replacement therapy (HRT), that could influence asthma symptoms in these women. Late-onset asthma (LOA) has been categorized as a specific asthmatic phenotype that includes menopausal women and novel research regarding therapeutic alternatives that might provide relief to asthmatic women suffering LOA warrants more thorough and comprehensive analysis. Therefore, the present review proposes phytoestrogens as a promising HRT that might provide these females with relief for both their menopause and asthma symptoms. Besides their well-recognized anti-inflammatory and antioxidant capacities, phytoestrogens activate estrogen receptors and promote mild hormone-like responses that benefit postmenopausal women, particularly asthmatics, constituting therefore a very attractive potential therapy largely due to their low toxicity and scarce side effects.

Operation Diversify Plastic Surgery: An Innovative Strategy to Increase Diversity in Plastic and Reconstructive Surgery.

Healthcare disparities remain a significant problem facing the US healthcare system with recent evidence of persistent racial and ethnic disparities especially among patients from minority backgrounds. Recent studies have documented advantages to a racially and ethnically diverse surgical workforce such as higher patient satisfaction scores, superior patient compliance with physician recommendations, and increased participation in clinical research studies by minority patients. In plastic and reconstructive surgery (PRS), there is a noted deficit among residents and faculty that come from ethnically underrepresented in medicine (URiM) backgrounds despite recent efforts to increase diversity in PRS surgeons. URiM medical students from three of the four historically Black medical universities organized to discuss pathways to PRS. Operation Diversify Plastic Surgery is a student-led organization that was developed to address the lack of diversity in PRS, challenges faced by students from institutions that lack PRS residency training programs, and unique factors that affect URiM students interested in PRS. Available studies note that mentoring relationships and research opportunities were instrumental in recruiting URiM students into PRS residency programs. Operation Diversify Plastic Surgery is an innovative solution to the insufficient URiM PRS residency candidate pool by increasing medical student exposure to PRS via educational lectures, virtual mentoring opportunities, and insights into research fellowships.

Hemostatic Effects of Raloxifene in Ovariectomized Rats.

This study aimed to explore the effects of raloxifene (Rx) and estradiol (E2) on prothrombin time (PT), partial thromboplastin time (APTT), coagulation factors (VII, X, XI), and fibrinogen concentrations in rats. Female rats were ovariectomized 11 days prior to starting the treatment. Afterward, they received Rx or E2 (1, 10, 100, and 1000 µg/kg) or propylene glycol (0.3 mL; vehicle, V) subcutaneously for 3 consecutive days. Plasma was collected to measure the hemostatic parameters. Rx significantly increased PT (8%, at 1000 µg/kg; p < 0.05) and APTT at all doses evaluated (32, 70, 67, 30%; p < 0.05, respectively). Rx (1, 10, 100, and 1000 µg/kg) decreased the activity of factor VII by -20, -40, -37, and -17% (p < 0.05), respectively, and E2 increased it by 9, 34, 52, and 29%. Rx reduced factor X activity at 10 and 100 µg/kg doses (-30, and -30% p < 0.05), and E2 showed an increment of 24% with 1000 µg/kg dose only. Additionally, Rx (1, 10, 100 µg/kg) diminished FXI activity (-71, -62, -66; p < 0.05), E2 (1 and 10 µg/kg) in -60 and -38, respectively (p < 0.05), and Rx (1000 µg/kg) produced an increment of 29% (p < 0.05) in fibrinogen concentration, but not E2. Our findings suggest that raloxifene has a protective effect on hemostasis in rats.

Barriers and Facilitators for Under-Represented in Medicine (URiM) Medical Students Interested in Surgical Sub-specialties.

Background: Little is known on drivers and detractors underrepresented in medicine (URiM) medical students face. Methods: Using the nominal group technique (NGT), we explored experiences that strengthen or weaken the enthusiasm to pursue a career in surgery among URiM medical students (October 2021- April 2022); participants voted on the three most important experiences (weight of 3= top rated, = 1 for the lowest rated). Responses from NGT with at least one vote were weighted, ranked, and categorized. Results: Seventeen students participated. Experiences that strengthen enthusiasm (36 responses with at least one vote) involved mentorship and role models (weighted sum percentage, 35%), demonstrating grit (15%), lifestyle (15%), patient interactions (14%), technical skills (11%), community and team (10%), and intellectual stimulation (1%). Experiences that weaken enthusiasm (33 responses with at least one vote) include the minority experience (weighted sum percentage, 51%), quality of life (25%), toxic environment (13%), lack of information (7%), and finances (5%). Conclusions: Mentorship, demonstrating grit, and feeling a sense of community were important positive experiences or attitudes. The minority experience, toxic environment, perceptions of self-worth, and lifestyle misconceptions perceived by URiM must be addressed to increase diversity, equity, and inclusion.

A Systematic Review of Microsurgical Pedicle Lengthening in Free Tissue Transfer.

INTRODUCTION: Traumatic injuries that require free tissue flaps for reconstruction may require vascular pedicle extension between the flap and recipient vessels to form a clear anastomosis. Currently, a variety of techniques are used, each with their own potential benefits and harms. In addition, reports in the literature conflict on the reliability of pedicle extensions of vessels in free flap (FF) surgery. The objective of this study is to systematically assess the available literature about outcomes of pedicle extensions in FF reconstruction. METHODS: A comprehensive search was performed for relevant studies published up to January 2020. Study quality was assessed using the Cochrane Collaboration risk of bias assessment tool and a set of predetermined parameters was extracted by 2 investigators independently for further analysis. The literature review yielded 49 studies investigating pedicled extension of FF. Studies meeting inclusion criteria underwent data extraction focusing on demographics, conduit type, microsurgical technique, and postoperative outcomes. RESULTS: The search yielded 22 retrospective studies totaling 855 procedures from 2007 to 2018 in which 159 complications (17.1%) were reported in patients aged between 39 and 78 years. Overall heterogeneity of articles included in this study was high. Free flap failure and thrombosis were the 2 most prevalent major complications noted: vein graft extension technique had the highest rate of flap failure (11%) in comparison with the arterial graft (9%) and arteriovenous loops (8%). Arteriovenous loops had a rate of thrombosis of 5% versus 6% in arterial grafts and 8% in venous grafts. Bone flaps maintained the highest overall complication rates per tissue type at 21%. The overall success rate of pedicle extensions in FFs was 91%. Arteriovenous loop extension resulted in a 63% decrease in the odds of vascular thrombosis and a 27% decrease in the odds of FF failure when compared with venous graft extensions (P < 0.05). Arterial graft extension resulted in a 25% decrease in the odds of venous thrombosis and a 19% decrease in the odds of FF failure when compared with venous graft extensions (P < 0.05). CONCLUSIONS: This systematic review strongly suggests that pedicle extensions of the FF in a high-risk complex setting are a practical and effective option. There may be a benefit to using arterial versus venous conduits, although further examination is warranted given the small number of reconstructions reported in the literature.

Do Socioeconomic Status and Race Impact the Safety and Efficacy of Breast Reconstruction?

INTRODUCTION: Immediate breast reconstruction after mastectomy has increased in recent years when compared with delayed reconstruction. Despite this encouraging trend, racial and socioeconomic disparities in the receipt of postmastectomy breast reconstruction have been well documented. We sought to assess the effect of race, socioeconomic status, and patient comorbidities on muscle sparing transverse rectus abdominis myocutaneous outcomes at our safety net hospital institution in the southeast. METHODS: The database of a tertiary referral center was queried for patients who received free transverse rectus abdominis myocutaneous flaps for immediate reconstruction after mastectomy meeting inclusion criteria from 2006 to 2020. Patient demographics and outcomes were compared based on socioeconomic status. The primary outcome (reconstructive success) was defined as breast reconstruction without flap loss. Statistical analysis included analysis of variance and χ2 tests were appropriate using Rstudio. RESULTS: Three-hundred fourteen patients were included in the study, with 76% White, 16% Black, and 8% other. Overall complication rate at our institution was 17% and reconstructive success was 94%. Non-White race, older age at time of breast cancer diagnosis, higher body mass index, and presence of comorbid conditions including current smoking and hypertension were all associated with low socioeconomic status. Despite this, surgical complication rates were not predicted by non-White race, older age, or presence of diabetes mellitus. When analyzing major and minor complications based on radiation received or reconstructive success, there was no significant difference regardless of radiation treatment with the group overall achieving a 94% success rate (P = 0.229). CONCLUSIONS: This study aimed to characterize the impact of socioeconomic status and race/ethnic status of patients on breast reconstruction outcomes at an institution in the South. We found that despite the greater morbidity in low income and ethnic/minority patients that when treated by a comprehensive safety net institution, they had excellent reconstructive outcomes due to low complications and minimal reoperations.

Examination of the Novel National Institutes of Health-Supported Relative Citation Ratio, a Measure of Research Productivity, Among Academic Plastic Surgeons.

BACKGROUND: Considerable interest has been devoted to quantifying research productivity for the purposes of academic appointment and promotion in plastic surgery. A novel bibliometric, the relative citation ratio (RCR), integrates features unavailable in prior metrics, such as the h-index, including the ability to compare researchers in distinct fields. This investigation examines the RCR in relation to established measures of academic productivity and provides the benchmark data in plastic surgery. METHODS: Online sources were queried to identify the characteristics of 955 academic plastic surgeons from 94 programs, ie, academic rank, gender, degrees, and fellowships. Bibliometric data were acquired using the iCite and Scopus databases. Comparative and correlational analyses of variables were performed. RESULTS: Academic plastic surgeons were exceptionally productive, with a mean RCR of 1.20 (interquartile range, 0.79-1.67) and a weighted RCR of 17.68 (interquartile range, 5.14-52.48). Increased mean RCR was significantly associated with advanced academic rank and fellowship training. Increased weighted RCR was significantly associated with advanced academic rank, male gender, PhD acquisition, publication experience, and fellowship training. The h-index was weakly correlated with mean RCR but strongly correlated with weighted RCR and publication experience. CONCLUSIONS: The RCR was associated with established markers of academic productivity, indicating its validity as a reliable field-normalized measure for the evaluation of plastic surgery faculty. Because scholarly output is a potential factor with respect to decisions of hiring, promotion, and allocation of funding, this modality of standardized comparison is paramount for plastic surgeons who exist within a larger general surgery department.

Estrogenic Modulation of Ionic Channels, Pumps and Exchangers in Airway Smooth Muscle.

To preserve ionic homeostasis (primarily Ca2+, K+, Na+, and Cl-), in the airway smooth muscle (ASM) numerous transporters (channels, exchangers, and pumps) regulate the influx and efflux of these ions. Many of intracellular processes depend on continuous ionic permeation, including exocytosis, contraction, metabolism, transcription, fecundation, proliferation, and apoptosis. These mechanisms are precisely regulated, for instance, through hormonal activity. The lipophilic nature of steroidal hormones allows their free transit into the cell where, in most cases, they occupy their cognate receptor to generate genomic actions. In the sense, estrogens can stimulate development, proliferation, migration, and survival of target cells, including in lung physiology. Non-genomic actions on the other hand do not imply estrogen's intracellular receptor occupation, nor do they initiate transcription and are mostly immediate to the stimulus. Among estrogen's non genomic responses regulation of calcium homeostasis and contraction and relaxation processes play paramount roles in ASM. On the other hand, disruption of calcium homeostasis has been closely associated with some ASM pathological mechanism. Thus, this paper intends to summarize the effects of estrogen on ionic handling proteins in ASM. The considerable diversity, range and power of estrogens regulates ionic homeostasis through genomic and non-genomic mechanisms.

An assessment of mental health of Mexican and Colombian medical students during the COVID-19 pandemic / Una evaluación de la salud mental de estudiantes de medicina Mexicanos y Colombianos durante la pandemia de COVID-19

Abstract Introduction The COVID-19 pandemic caused the cessation of academic activities from the face-to-face format to confinement and virtual classes, in which little is studied about its effect on mental health. Objective Determine levels of depression, anxiety, and stress in medical students in Mexico and Colombia during the COVID-19 pandemic. Furthermore, depression, anxiety, and stress were compared by gender, education status, and country. Method A cross-sectional study was carried out with 426 medical students. Data was collected using an online survey containing the Depression, Anxiety, Stress Scale (DASS-21) questionnaire. Results Overall scores for depression, anxiety, and stress were 6.7 ± 1.2, 8.8 ± 1.2, and 5.6 ± 1.2, respectively. Females had significantly higher overall scores for depression (.24-fold increase), anxiety (.25-fold increase), and stress (.40-fold increase) than males (p ≤ .01). The risk for anxiety and stress by school year showed that basic years were associated with higher scores than advanced years (.25 and .38-fold increase, respectively). For females, starting medical school did show an increased risk of depression when compared to male students in their basic years (.38-fold increase). Lastly, students from Mexico had an increased risk for depression and anxiety (p ≤ .022 and p ≤ .004, respectively) but not for stress (p ≤ .402), when compared to students from Colombia. Discussion and conclusion Significant anxiety and depression were observed in medical students from Mexico and Colombia. Factors associated with an increased risk of depression and anxiety are students in their basic years as well as being female.

Resumen Introducción La pandemia de COVID-19 provocó el cese de las actividades académicas desde el formato presencial al confinamiento de las clases virtuales, de las que poco se ha estudiado sobre su efecto en la salud mental. Objetivo Determinar los niveles de depresión, ansiedad y estrés en estudiantes de medicina de México y Colombia durante la pandemia de COVID-19; además de comparar depresión, ansiedad y estrés por género, nivel educativo y país. Método Se realizó un estudio transversal con 426 estudiantes de medicina. Los datos se recopilaron mediante una encuesta en línea que contenía el cuestionario DASS-21. Resultados Las puntuaciones generales de depresión, ansiedad y estrés fueron 6.7 ± 1.2, 8.8 ± 1.2 y 5.6 ± 1.2, respectivamente. Las mujeres tuvieron puntajes generales significativamente más altos para depresión (.24-fold increase), ansiedad (.25-fold increase) y estrés (.40-fold increase). El riesgo de ansiedad y estrés por año escolar mostró que los años básicos se asociaron con puntajes más altos que los estudiantes en años los avanzados (.25 y .38-fold increase). Para las mujeres, cursar años básicos mostró un mayor riesgo de depresión en comparación con los estudiantes varones (.38-fold increase). Por último, los estudiantes mexicanos tuvieron un mayor riesgo de depresión y ansiedad (p ≤ .022 y p ≤ .004, respectivamente) pero no de estrés (p ≤ .402) en comparación con los estudiantes Colombianos. Discusión y conclusión Se observó ansiedad y depresión significativas en estudiantes de medicina mexicanos y colombianos. Los factores asociados a un mayor riesgo de depresión y ansiedad fueron; ser estudiante en años básicos además de ser mujer.

Outcomes of Ventral Hernia Repair After Orthotopic Liver Transplant Using Component Separation and Onlay Biologic Mesh.

INTRODUCTION: The management of ventral hernias (VHs) after orthotopic liver transplant (OLT) can be uniquely challenging because of immunosuppression coupled with large laparotomy size that can compromise the quality of the abdominal wall. The component separation with multipoint suture onlay acellular dermis fixation technique has proven to be effective in high-risk abdominal wall reconstructions. The goal of this study was to elucidate the factors that affect safety and efficacy of VH repair in post-OLT patients. METHODS: A retrospective review of 345 patients who underwent repair of VH with compartment separation and onlay acellular dermal matrix reinforcement from a single surgeon from 2012 to 2020 was conducted. Of these, 27 patients were identified with a history of OLT and were stratified based on whether the defect was a initial or recurrent hernia repair. The majority of patients had a standard chevron incision (70%). Data abstraction was performed for preoperative risk factors, hernia characteristics, surgical site complications, and postoperative course including hernia recurrence. RESULTS: A majority of cases in the study period were initial hernia repairs (59%) with no significant differences in the patient demographics and size of VH defects (190 ± 112.69 cm 2 ). Comorbidities were similar between the groups with the exception of a significantly higher baseline creatinine levels and higher history of smoking in the recurrent hernia repair group ( P < 0.05). Of the 27 cases, there were no demonstrable hernia recurrences noted and an overall 11% complication rate. Univariate analysis noted a statistically significant difference in surgical site complication rate ( P = 0.017), with the initial hernia repair group having the lowest rate of surgical site complications. CONCLUSIONS: In complex post-OLT patients with large VH, modified component separation with onlay acellular mesh was shown to have acceptable medium-term results. Further studies investigating the factors leading to postoperative complications are necessary to reduce recurrence in this evolving patient population.

Pediatric Cranioplasty Patients With Hostile Reconstructive Environments: Split Calvarial Versus Prosthetic Implant.

INTRODUCTION: Pediatric cranial defects can be preceded by prior infection, radiation therapy, failed prior cranioplasty, or cerebrospinal fluid leak, leading to a complex reconstructive environment. The primary aim of this study was to investigate differences in outcomes between pediatric patients with hostile reconstructive environments who received split-calvarial autologous grafts as opposed to prosthetic grafts in cranioplasty. METHODS: We performed an institutional review board-approved retrospective chart review of 51 patients younger than 18 years who underwent cranioplasty with a hostile setting between 1998 and 2020. Patients were then stratified into prosthetic (45%) and autologous groups (54%). The primary outcome measured was postoperative complication, defined as requirement of a subsequent surgery or revision. RESULTS: Overall, there were no significant differences in age, sex, type of hostile setting, etiology of cranial defect, or side of the cranial defect between the 2 groups. Complication rate among the 2 graft groups was 18%. However, there were no significant differences in complications, defined as infection, failure or resorption of the graft, wound breakdown or necrosis, resulting bone defect, or hematoma, between the 2 populations. There was a significant difference in etiology between patients with complications, with patients who required a cranioplasty due to previous hemicraniectomy being nearly 5 times as likely to face a complication ( P = 0.045). CONCLUSIONS: In our study, there was no significant difference observed in complications between prosthetic and split-thickness autologous grafts in pediatric patients with hostile settings. It does, however, seem that patients who had a previous hemicraniectomy are more likely to face complications as a result of cranioplasty.

Data-Driven Approaches Used for Compound Library Design for the Treatment of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease in older individuals worldwide. Pharmacological treatment for such a disease consists of drugs such as monoamine oxidase B (MAO-B) inhibitors to increase dopamine concentration in the brain. However, such drugs have adverse reactions that limit their use for extended periods; thus, the design of less toxic and more efficient compounds may be explored. In this context, cheminformatics and computational chemistry have recently contributed to developing new drugs and the search for new therapeutic targets. Therefore, through a data-driven approach, we used cheminformatic tools to find and optimize novel compounds with pharmacological activity against MAO-B for treating PD. First, we retrieved from the literature 3316 original articles published between 2015-2021 that experimentally tested 215 natural compounds against PD. From such compounds, we built a pharmacological network that showed rosmarinic acid, chrysin, naringenin, and cordycepin as the most connected nodes of the network. From such compounds, we performed fingerprinting analysis and developed evolutionary libraries to obtain novel derived structures. We filtered these compounds through a docking test against MAO-B and obtained five derived compounds with higher affinity and lead likeness potential. Then we evaluated its antioxidant and pharmacokinetic potential through a docking analysis (NADPH oxidase and CYP450) and physiologically-based pharmacokinetic (PBPK modeling). Interestingly, only one compound showed dual activity (antioxidant and MAO-B inhibitors) and pharmacokinetic potential to be considered a possible candidate for PD treatment and further experimental analysis.

Premisas, aportes y desafíos metodológicos de la investigación etnográfica en salud mental / Premises, contributions and methodological challenges ethnographic research in mental health

La reflexividad metodológica como centro articulador de la investigación cualitativa permite definir y consolidar el posicionamiento epistemológico, teórico y ético-político de los investigadores. Este artículo reflexiona sobre los aportes y desafíos de la etnogra-fía como herramienta teórica metodológica y escritural para acercarse a la comprensión de la atención de la salud mental en el Primer Nivel de Atención, en el estado de Tabasco, México. El ejercicio presenta la toma de decisiones y dilemas hallados en el trabajo de campo; discute las implicaciones ético-políticas de trabajar con diseños etnográficos y expresa una serie de posicionamientos asumidos a lo largo de la investigación. Finalmente, plantea la urgencia de reflexionar ética, cultural y afectivamente en la investigación etnográfica en salud metal y llama la atención sobre los desafíos emocionales de trabajar con poblaciones en situación de vulnerabilidad, como los pueblos originarios y los enfermos mentales.(AU)

Methodological reflexivity as an articulator center in qualitative research allows us to define and consolidate the epistemological, theoretical and ethical-political positioning of researchers. This paper reflects about contributions and challenges of ethnography as theoretical, methodological and scriptural tool to approach the understanding about mental healthcare at First Level of Care in Tabasco state, Mexico. This exercise is about decisions and dilemmas faced at field work arguing about ethical-political implications of working using ethnographic al designs and expressing a series of position in assumed through this researching. Finally, it shows the urgent need of ethical, cultural and emotional reflection in to the ethnographic al researching in mental health besides to draw attention to emotional challenges of working with vulnerable populations such as native people and mental ills.(AU)

Functional Repercussions of Hypoxia-Inducible Factor-2α in Idiopathic Pulmonary Fibrosis.

Hypoxia and hypoxia-inducible factors (HIFs) are essential in regulating several cellular processes, such as survival, differentiation, and the cell cycle; this adaptation is orchestrated in a complex way. In this review, we focused on the impact of hypoxia in the physiopathology of idiopathic pulmonary fibrosis (IPF) related to lung development, regeneration, and repair. There is robust evidence that the responses of HIF-1α and -2α differ; HIF-1α participates mainly in the acute phase of the response to hypoxia, and HIF-2α in the chronic phase. The analysis of their structure and of different studies showed a high specificity according to the tissue and the process involved. We propose that hypoxia-inducible transcription factor 2a (HIF-2α) is part of the persistent aberrant regeneration associated with developing IPF.

Effect of Hypoxia in the Transcriptomic Profile of Lung Fibroblasts from Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by exacerbated extracellular matrix deposition that disrupts oxygen exchange. Hypoxia and its transcription factors (HIF-1α and 2α) influence numerous circuits that could perpetuate fibrosis by increasing myofibroblasts differentiation and by promoting extracellular matrix accumulation. Therefore, this work aimed to elucidate the signature of hypoxia in the transcriptomic circuitry of IPF-derived fibroblasts. To determine this transcriptomic signature, a gene expression analysis with six lines of lung fibroblasts under normoxia or hypoxia was performed: three cell lines were derived from patients with IPF, and three were from healthy donors, a total of 36 replicates. We used the Clariom D platform, which allows us to evaluate a huge number of transcripts, to analyze the response to hypoxia in both controls and IPF. The control's response is greater by the number of genes and complexity. In the search for specific genes responsible for the IPF fibroblast phenotype, nineteen dysregulated genes were found in lung fibroblasts from IPF patients in hypoxia (nine upregulated and ten downregulated). In this sense, the signaling pathways revealed to be affected in the pulmonary fibroblasts of patients with IPF may represent an adaptation to chronic hypoxia.

Matrix Metalloproteinases and Stress Hormones in Lung Cancer Progression.

Several matrix metalloproteinases (MMPs) and psychological stress are associated with poor cancer prognosis. The current work goal was to determine MMPs' and stress hormones' blood concentrations from lung adenocarcinoma (LAC) patients. Patients were divided into the following groups: tobacco smokers (TS), wood smoke-exposed (W), passive smokers (PS), TS exposed to wood smoke (TW), and patients with no recognizable risk factor (N). MMPs, tissue inhibitors of metalloproteinases (TIMPs), adrenaline, noradrenaline, and cortisol blood concentrations were measured by ELISA. Zymography and Western blot assays were performed to determine MMP-2 and MMP-9 active and latent forms. MMP-2, MMP-3, MMP-9, and TIMP-1 blood concentrations, and MMP-9 gelatinase activity were augmented, while MMP-12, MMP-14, and TIMP-2 were diminished in LAC patients. Cortisol was increased in LAC samples. Adrenaline concentrations were higher in W, TS, and TW, and noradrenaline was increased in W and N groups. Positive correlations were observed among cortisol and TIMP-1 (r s = 0.392) and TIMP-2 (r s = 0.409) in the W group and between noradrenaline and MMP-2 (r s = 0.391) in the N group. MMPs' blood concentration increments can be considered as lung cancer progression markers. Although stress hormones were also augmented, only weak correlations were observed between them and MMPs and TIMPs.