Hydroxycobalamin Reveals the Involvement of Hydrogen Sulfide in the Hypoxic Responses of Rat Carotid Body Chemoreceptor Cells

Carotid body (CB) chemoreceptor cells sense arterial blood PO2, generating a neurosecretory response proportional to the intensity of hypoxia. Hydrogen sulfide (H2S) is a physiological gaseous messenger that is proposed to act as an oxygen sensor in CBs, although this concept remains controversial. In the present study we have used the H2S scavenger and vitamin B12 analog hydroxycobalamin (Cbl) as a new tool to investigate the involvement of endogenous H2S in CB oxygen sensing. We observed that the slow-release sulfide donor GYY4137 elicited catecholamine release from isolated whole carotid bodies, and that Cbl prevented this response. Cbl also abolished the rise in [Ca2+]i evoked by 50 µM NaHS in enzymatically dispersed CB glomus cells. Moreover, Cbl markedly inhibited the catecholamine release and [Ca2+]i rise caused by hypoxia in isolated CBs and dispersed glomus cells, respectively, whereas it did not alter these responses when they were evoked by high [K+]e. The L-type Ca2+ channel blocker nifedipine slightly inhibited the rise in CB chemoreceptor cells [Ca2+]i elicited by sulfide, whilst causing a somewhat larger attenuation of the hypoxia-induced Ca2+ signal. We conclude that Cbl is a useful and specific tool for studying the function of H2S in cells. Based on its effects on the CB chemoreceptor cells we propose that endogenous H2S is an amplifier of the hypoxic transduction cascade which acts mainly by stimulating non-L-type Ca2+ channels

High fat diet blunts the effects of leptin on ventilation and on carotid body activity

Funding : This study was supported by the Portuguese Foundation for Science and Technology grant PTDC/SAU-ORG/111417/2009 to S.C. and by Grants BFU2015-70616R from MINECO-FEDER, Spain. J.F.S. and B.F.M. are supported by PhD Grants from FCT, PD/BD/105890/2014 and PD/BD/128336/2017, respectively.Leptin plays a role in the control of breathing, acting mainly on central nervous structures. Leptin receptor is expressed in the carotid body (CB) and this finding has been associated with a putative physiological role of leptin in the regulation of CB function. Since, the CBs are implicated in energy metabolism herein we tested the effects of different concentrations of leptin administration on ventilatory parameters and on carotid sinus nerve (CSN) activity in control and high-fat (HF) diet fed rats, in order to clarify the role of leptin in ventilation control in metabolic disease states. We also investigated the expression of leptin receptors and the neurotransmitters involved in leptin signalling in the CBs. We found that in non-disease conditions, leptin increases minute ventilation both in basal and hypoxic conditions. However, in the HF model, the effect of leptin in ventilatory control is blunted. We also observed that HF rats display an increased frequency of CSN discharge in basal conditions that is not altered by leptin, in contrast to what is observed in control animals. Leptin did not modify intracellular Ca2+ in CB chemoreceptor cells, but it produced an increase in the release of adenosine from the whole CB. We conclude that CBs represent an important target for leptin signalling, not only to coordinate peripheral ventilatory chemoreflexive drive, but probably also to modulate metabolic variables. We also concluded that leptin signalling is mediated by adenosine release and that HF diets blunt leptin responses in the CB, compromising ventilatory adaptation. This article is protected by copyright. All rights reserved.publishersversionpublishe

Mentoria universitária na Espanha: um relato de experiencia com alunos de altas habilidades ou superdotação

Trata-se de um relato de experiência vinculada à experiência profissional e acadêmica no Amentúrate Programa de Mentorias Universitárias. Programa do departamento de Educação da Universidade da Cantábria - UC – Santander – Espanha, que oferece a estudantes dos anos finais do ensino fundamental ou ensino médio com altas habilidades ou superdotação – AH/SD, uma experiência de mentoria  universitária. A mentoria é entendida como uma relação didática, relativamente estável ao longo do tempo, entre um mentor experiente (professor) e um mentee (pupilo,estudante AH/SD) menos experiente. O programa está no seu quarto ano de funcionamento e já atendeu mais de 90 estudantes da região. Destacamos a importância do Relato de Experiência – RE, como mais uma possibilidade de criação de narrativa científica, especialmente no campo das pesquisas capazes de englobar processos e produções subjetivas, como é o caso da psicologia. Nesse sentido, e considerando que essa experiência compõe uma trajetória acadêmica de uma doutoranda, foi possível identificar a repetição de um discurso científico sobre a educação de superdotados, no que se refere a quatro questões: a) dificuldade em nomear e conceituar o fenômeno; b) maior participação masculina no programa; c) pouca ou nenhuma participação de estrangeiros como latinos ou africanos no programa e (d) estratégias educativas mais desafiadoras, complexas e que promovam a autonomia dos estudantes. Essas questões nos colocam frente a barreiras sociais e ideológicas, como o sexismo, o racismo e o classicismo que interferem no bem estar e na qualidade de vida da pessoa superdotada. A invisibilidade de mulheres com AH/SD em programas de desenvolvimento de talentos nos provoca a questionar: por onde andam essas mulheres

Characterization of methicillin-resistant Staphylococcus aureus strains colonizing the nostrils of Spanish children

Objective: To characterize the Staphylococcus aureus strains colonizing healthy Spanish children. Methods: Between March and July 2018, 1876 Spanish children younger than 14 years attending primary healthcare centers were recruited from rural and urban areas. Staphylococcus aureus colonization of the anterior nostrils was analyzed. MecA and mecC genes, antibiotic susceptibility, and genotyping according to the spa were determined in all strains, and the following toxins were examined: Panton-Valentine leucocidin (pvl), toxic shock syndrome toxin (tst), and exfoliative toxins (eta, etb, etd). Multilocus sequence typing (MLST) and staphylococcal cassette chromosome (SCCmec) typing were performed on methicillin-resistant Staphylococcus aureus (MRSA) strains, as well as pulsed-field gel electrophoresis (PFGE). Results: 619 strains were isolated in 1876 children (33%), and 92% of them were sent for characterization to the Spanish National Centre of Microbiology (n = 572). Twenty (3.5%) of these strains were mecA-positive. Several spa types were detected among MRSA, being t002 the most frequently observed (30%), associating with SCCmec IVc. Among MSSA, 33% were positive for tst, while only 0.73% were positive for pvl. The 20 MRSA strains were negative for pvl, and 6 (30%) harbored the tst gene. Conclusions: methicillin-resistant Staphylococcus aureus nasal colonization in Spanish children is rare, with t002 being the most observed spa type, associated with SCCmec IVc. None of the MRSA strains produced pvl, but up to 30% of S. aureus strains were positive for tst

Characterization of methicillin-resistant Staphylococcus aureus strains colonizing the nostrils of Spanish children

Objective: To characterize the Staphylococcus aureus strains colonizing healthy Spanish children. Methods: Between March and July 2018, 1876 Spanish children younger than 14 years attending primary healthcare centers were recruited from rural and urban areas. Staphylococcus aureus colonization of the anterior nostrils was analyzed. MecA and mecC genes, antibiotic susceptibility, and genotyping according to the spa were determined in all strains, and the following toxins were examined: Panton-Valentine leucocidin (pvl), toxic shock syndrome toxin (tst), and exfoliative toxins (eta, etb, etd). Multilocus sequence typing (MLST) and staphylococcal cassette chromosome (SCCmec) typing were performed on methicillin-resistant Staphylococcus aureus (MRSA) strains, as well as pulsed-field gel electrophoresis (PFGE). Results: 619 strains were isolated in 1876 children (33%), and 92% of them were sent for characterization to the Spanish National Centre of Microbiology (n = 572). Twenty (3.5%) of these strains were mecA-positive. Several spa types were detected among MRSA, being t002 the most frequently observed (30%), associating with SCCmec IVc. Among MSSA, 33% were positive for tst, while only 0.73% were positive for pvl. The 20 MRSA strains were negative for pvl, and 6 (30%) harbored the tst gene. Conclusions: methicillin-resistant Staphylococcus aureus nasal colonization in Spanish children is rare, with t002 being the most observed spa type, associated with SCCmec IVc. None of the MRSA strains produced pvl, but up to 30% of S. aureus strains were positive for tst.Sociedad Española Infectologia Pediatrica, Grant/Award Number: José María Corretger. Grant 2018; Spanish Association of Paediatric Primary Care, Grant/Award Number: Grant 2018; European Society for Paediatric Infectious Diseases, Grant/Award Number: Small Grant Award 2018; Instituto de Salud Carlos III, Grant/Award Number: PI18CIII/00372S

Staphylococcus aureus Nasal Colonization in Spanish Children. The COSACO Nationwide Surveillance Study

Objective: To assess the prevalence and risk factors for S. aureus and methicillin-resistant S. aureus (MRSA) nasal colonization in Spanish children. Methods: Cross-sectional study of patients <14 years from primary care centers all over Spain. Clinical data and nasal aspirates were collected from March to July 2018. Results: A total of 1876 patients were enrolled. Prevalence of S. aureus and MRSA colonization were 33% (95% CI 30.9-35.1) and 1.44% (95% CI 0.9-2), respectively. Thirty-three percent of the children (633/1876) presented chronic conditions, mainly atopic dermatitis, asthma and/or allergy (524/633). Factors associated with S. aureus colonization were age ≥5 years (OR 1.10, 95% CI 1.07-1.12), male sex (OR 1.43, 95% CI 1.17-1.76), urban setting (OR 1.46, 95% CI 1.08-1.97) and the presence of asthma, atopic dermatitis or allergies (OR 1.25; 95% CI: 1.093-1.43). Rural residence was the only factor associated with MRSA colonization (OR 3.62, 95% CI 1.57-8.36). MRSA was more frequently resistant than methicillin-susceptible S. aureus to ciprofloxacin [41.2% vs 2.6%; p<0.0001], clindamycin [26% vs 16.9%; p=0.39], and mupirocin [14.3% vs 6.7%; p=0.18]. None of the MRSA strains was resistant to tetracycline, fosfomycin, vancomycin or daptomycin. Conclusions: The main risk factors for S. aureus colonization in Spanish children are being above five years of age, male gender, atopic dermatitis, asthma or allergy, and residence in urban areas. MRSA colonization is low, but higher than in other European countries and is associated with rural settings.This study has been supported by The Spanish Ministry of Science and Innovation – Instituto de Salud Carlos III, and Fondos FEDER of the EU, Grant Nº PI18CIII/00372 [Fondo de Investigaciones Sanitarias-Spanish Health Research Fund (ISCIII)]; Grant Award “Jose María Corretger” from the Spanish Society for Pediatric Infectious Diseases; Grant Research Award from the Spanish Association of Pediatric Primary Care; and a Small Grant Award from the European Society for Pediatric Infectious Diseases.S

Case-Control Analysis of the Impact of Anemia on Quality of Life in Patients with Cancer: A Qca Study Analysis

The impact of anemia on the quality of life (QoL) in cancer patients has been studied previously; however, the cut-off point used to define anemia differed among studies, thus providing inconsistent results. Therefore, we analysed the clinical impact of anemia on QoL using the same cut-off point for hemoglobin level to define anemia as that used in ESMO clinical practice guidelines. This post-hoc analysis aimed to determine the impact of anemia on QoL in cancer patients through the European Organization for Research and Treatment of Cancer Quality of life questionnaire version 3.0 (EORTC QLQ-C30) and Euro QoL 5-dimension 3-level (EQ-5D-3L) questionnaire. We found that cancer patients with anemia had significantly worse QoL in clinical terms. In addition, anemic patients had more pronounced symptoms than those in non-anemic patients. Anemia is a common condition in cancer patients and is associated with a wide variety of symptoms that impair quality of life (QoL). However, exactly how anemia affects QoL in cancer patients is unclear because of the inconsistencies in its definition in previous reports. We aimed to examine the clinical impact of anemia on the QoL of cancer patients using specific questionnaires. We performed a post-hoc analysis of a multicenter, prospective, case-control study. We included patients with cancer with (cases) or without (controls) anemia. Participants completed the European Organization for Research and Treatment of Cancer Quality of Life questionnaire version 3.0 (EORTC QLQ-C30) and Euro QoL 5-dimension 3-level (EQ-5D-3L) questionnaire. Statistically significant and clinically relevant differences in the global health status were examined. From 2015 to 2018, 365 patients were included (90 cases and 275 controls). We found minimally important differences in global health status according to the EORTC QLQ-C30 questionnaire (case vs. controls: 45.6 vs. 58%, respectively; mean difference: -12.4, p < 0.001). Regarding symptoms, cancer patients with anemia had more pronounced symptoms in six out of nine scales in comparison with those without anemia. In conclusion, cancer patients with anemia had a worse QoL both clinically and statistically

Analysis of the association between CD40 and CD40 ligand polymorphisms and systemic sclerosis.

Introduction: The aim of the present study was to investigate the possible role of CD40 and CD40 ligand (CD40LG) genes in the susceptibility and phenotype expression of systemic sclerosis (SSc). Methods: In total, 2,670 SSc patients and 3,245 healthy individuals from four European populations (Spain, Germany, The Netherlands, and Italy) were included in the study. Five single-nucleotide polymorphisms (SNPs) of CD40 (rs1883832, rs4810485, rs1535045) and CD40LG (rs3092952, rs3092920) were genotyped by using a predesigned TaqMan allele-discrimination assay technology. Meta-analysis was assessed to determine whether an association exists between the genetic variants and SSc or its main clinical subtypes. Results: No evidence of association between CD40 and CD40LG genes variants and susceptibility to SSc was observed. Similarly, no significant statistical differences were observed when SSc patients were stratified by the clinical subtypes, the serologic features, and pulmonary fibrosis. Conclusions: Our results do not suggest an important role of CD40 and CD40LG gene polymorphisms in the susceptibility to or clinical expression of SSc

Effect of viral storm in patients admitted to intensive care units with severe COVID-19 in Spain: a multicentre, prospective, cohort study

Background: The contribution of the virus to the pathogenesis of severe COVID-19 is still unclear. We aimed to evaluate associations between viral RNA load in plasma and host response, complications, and deaths in critically ill patients with COVID-19. Methods: We did a prospective cohort study across 23 hospitals in Spain. We included patients aged 18 years or older with laboratory-confirmed SARS-CoV-2 infection who were admitted to an intensive care unit between March 16, 2020, and Feb 27, 2021. RNA of the SARS-CoV-2 nucleocapsid region 1 (N1) was quantified in plasma samples collected from patients in the first 48 h following admission, using digital PCR. Patients were grouped on the basis of N1 quantity: VIR-N1-Zero ([removed]2747 N1 copies per mL). The primary outcome was all-cause death within 90 days after admission. We evaluated odds ratios (ORs) for the primary outcome between groups using a logistic regression analysis. Findings: 1068 patients met the inclusion criteria, of whom 117 had insufficient plasma samples and 115 had key information missing. 836 patients were included in the analysis, of whom 403 (48%) were in the VIR-N1-Low group, 283 (34%) were in the VIR-N1-Storm group, and 150 (18%) were in the VIR-N1-Zero group. Overall, patients in the VIR-N1-Storm group had the most severe disease: 266 (94%) of 283 patients received invasive mechanical ventilation (IMV), 116 (41%) developed acute kidney injury, 180 (65%) had secondary infections, and 148 (52%) died within 90 days. Patients in the VIR-N1-Zero group had the least severe disease: 81 (54%) of 150 received IMV, 34 (23%) developed acute kidney injury, 47 (32%) had secondary infections, and 26 (17%) died within 90 days (OR for death 0·30, 95% CI 0·16–0·55; p<0·0001, compared with the VIR-N1-Storm group). 106 (26%) of 403 patients in the VIR-N1-Low group died within 90 days (OR for death 0·39, 95% CI 0·26–0·57; p[removed]11 página

Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort

Background Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster.Methods Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3.Results Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3.Conclusions During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis