Asthma and Lung Mechanics.

This article will discuss in detail the pathophysiology of asthma from the point of view of lung mechanics. In particular, we will explain how asthma is more than just airflow limitation resulting from airway narrowing but in fact involves multiple consequences of airway narrowing, including ventilation heterogeneity, airway closure, and airway hyperresponsiveness. In addition, the relationship between the airway and surrounding lung parenchyma is thought to be critically important in asthma, especially as related to the response to deep inspiration. Furthermore, dynamic changes in lung mechanics over time may yield important information about asthma stability, as well as potentially provide a window into future disease control. All of these features of mechanical properties of the lung in asthma will be explained by providing evidence from multiple investigative methods, including not only traditional pulmonary function testing but also more sophisticated techniques such as forced oscillation, multiple breath nitrogen washout, and different imaging modalities. Throughout the article, we will link the lung mechanical features of asthma to clinical manifestations of asthma symptoms, severity, and control. © 2020 American Physiological Society. Compr Physiol 10:975-1007, 2020

How harmless are E-cigarettes? Effects in the pulmonary system.

PURPOSE OF REVIEW:Electronic cigarettes have quickly risen to be the leading alternative nicotine source to tobacco. E-cigarette use is hard to research and regulate because of the novelty and rapid evolution of the devices and E-liquids. Epidemiological data on long-term usage is currently lacking, but in smaller cohort studies we are starting to understand the usage patterns and demographics of users, which differ depending on where the study takes place and the regulatory environment. The present review describes the current knowledge of the effects of E-cigarettes on the pulmonary system and knowledge of their usage patterns worldwide. RECENT FINDINGS:E-cigarette use is continuing to rise in young adults in United States and Canada, but not in United Kingdom. These suggest that regulation is influencing uptake in young adults. If E-cigarettes are to be considered as a harm minimisation smoking cessation product, use in young never smokers must be factored into the risk assessment. A recent surge in cases of lung injury associated with vaping in America has resulted in the definition of vaping associated pulmonary injury, although the exact cause remains unknown. SUMMARY:It is our opinion that E-cigarettes can no longer be defined as harmless. Further studies are needed to determine the risks for all populations as it is evident that a large proportion of E-cigarette users are never-smokers, meaning they cannot only be considered from a harm reduction perspective

Designing crossing and selection strategies to combine diagnostic markers and quantitative traits

Tese de doutoramento em Biociências, ramo de especialização em Toxicologia, apresentada à Faculdade de Ciências e Tecnologia da Universidade de CoimbraDoxorubicin (DOX) is one of the most potent antineoplastic drugs. Although possessing a superior anti-­‐‑cancer activity, a broader clinical use of DOX is limited by a dose-­‐‑dependent, constant and cumulative cardiomyopathy involving deterioration of mitochondrial function. Although acute effects of DOX treatment often disappear when treatment finishes, chronic effects often result in a persistent cardiotoxicity, including a progressive deterioration of mitochondrial metabolism, the development of cardiomyopathy and ultimately congestive heart failure. Important in the context of DOX-­‐‑induced cardiotoxicity, mitochondrial disruption has been observed in different models. This alteration of mitochondrial function is often sub-­‐‑clinical and is only manifested as cardiomyopathy when other factors are combined, including age or different types of cardiovascular stress. Also, metabolic alterations in the cardiac cell occur, which contribute to the ability of the heart to withstand increased workloads. Although mitochondrial disruption is an early and sensitive marker of DOX cardiotoxicity, how metabolic stress contributes to the development of cardiomyopathy remains to be determined. Because of this gap in knowledge, the objective of this work was to use of model of metabolic inhibition in perfused hearts from saline (SAL) and DOX-­‐‑ treated rats in order to identify metabolic alterations caused by an acute and sub-­‐‑ chronic treatment. Our assumption for this strategy is that a lower susceptibility to a determined inhibitor during perfusion, would be a sign of a more robust (i.e. more capacity) of the targeted pathway(s). XV For the acute treatment protocol, sixteen week-­‐‑old male Wistar rats were i.p. injected with 20mg/Kg DOX or 1mg/Kg 0.9%NaCl and sacrificed 24 hours later. For sub-­‐‑ chronic protocol, eight weeks-­‐‑old male Wistar rats received seven weekly s.c. injections with DOX(2mg/Kg) or equivalent SAL solution and sacrificed one week after the last injection. Following the protocol treatments, animals were sacrificed and hearts were removed and perfused using a Langendorff apparatus with distinct cardiac substrates (glucose, galactose plus glutamine -­‐‑ GG or octanoate plus malate – OM). Glycolytic (iodoacetate) and oxidative phosphorylation (rotenone-­‐‑ Rot or cyanide-­‐‑ KCN) inhibitors were separately added to the different metabolic perfusates, aiming to detect undercover mitochondrial defects in the DOX-­‐‑treated group. In non-­‐‑perfused hearts, or hearts perfused in the absence (time controls, TC) or presence of inhibitors, selected metabolic and mitochondrial proteins were semi-­‐‑ quantified by Western blotting, and mRNA levels were quantified by RT-­‐‑PCR. In the acute DOX treatment model, hearts perfused with glucose as substrate suffered a decline in the number of heart beat and rate pressure product (RPP) when iodoacetate was added, contrarily to Rot or KCN which had no effect. With GG, inhibitor titration decreased the heart rate, despite that the decrease in the RPP was more evident in SAL vs. DOX group with iodoacetate and KCN. Perfusion with OM resulted in decreased heart rate an RPP in the presence of the inhibitors, showing equal response between treatments. When glycolytic and mitochondrial proteins were semi-­‐‑quantified by Western blotting, alterations in proteins involved in mitochondrial biogenesis and autophagy were observed in DOX hearts perfused with inhibitors. The data from the acute protocol study, appears to suggest that hearts from DOX-­‐‑treated animals have improved function in the presence of XVI metabolic inhibitors, thus indicating that DOX triggers adaptations that allow the hearts to be less susceptible to mitochondrial and glycolytic inhibition. In the sub-­‐‑chronic model and using glucose as substrate, the DOX-­‐‑treated group showed again a better tolerability to inhibitors than SAL. With GG, titration with iodoacetate caused a decrease in heart beat and on RPP in DOX group, when rot or KCN was added the number of heart beat and RPP remains identical between the two groups. Glycolytic and mitochondrial proteins semi-­‐‑quantification suggested an impairment of autophagy in DOX perfused hearts perfused, more evident during GG perfusion. The presence of inhibitors in the perfusion also generally decreased the total amount of proteins detected by Western Blotting, although glycolytic proteins were increased when hearts were perfused with glucose, contrarily to GG perfusion. The results suggest that sub-­‐‑chronic DOX-­‐‑treated rats suffered a metabolic remodeling which is based on stronger glycolytic fluxes to maintain contractility, although no overt mitochondrial defect was uncovered. A surprising result is that regardless of the perfusion buffer used, no striking differences between SAL and DOX hearts in terms of hemodynamic parameters were found. The present work suggests that metabolic remodeling during DOX acute and sub-­‐‑ chronic treatment maintains cardiac function in the treated animals. This remodeling is apparently based in a stronger contribution of glycolysis to overall metabolism. Data from protein amount analyzed suggest that DOX treatment in both models affect important regulators of autophagy, mitochondrial biogenesis as well as the adenine nucleotide translocator. The results also suggest that a longer treatment XVII protocol or resting period should also be tested in order to uncover more profound differences.A doxorrubicina (DOX) é um dos fármacos antineoplásicos mais potentes. Apesar de possuir uma actividade anti-­‐‑cancro superior, uma mais ampla utilização clínica da DOX é limitada por uma dose-­‐‑dependente, constante e cumulativa cardiomiopatia que envolve a deterioração da função mitocondrial. Embora os efeitos agudos do tratamento DOX normalmente desaparece quando se conclui o tratamento, os efeitos crónicos resultam muitas vezes numa cardiotoxicidade persistente, incluindo a deterioração progressiva do metabolismo mitocondrial, o desenvolvimento de cardiomiopatia e por fim insuficiência cardíaca congestiva. Importante no contexto da cardiotoxicidade induzida pela DOX, perturbação mitocondrial foi observada em diferentes modelos. Esta alteração da função mitocondrial é muitas vezes sub-­‐‑clínica e só se manifesta como cardiomiopatia quando outros factores são combinados, incluindo a idade ou diferentes tipos de estresse cardiovascular. Além disso, ocorrem alterações metabólicas na célula cardíaca, o que contribui para a capacidade do coração resistir a maior demanda. Embora a perturbação mitocondrial seja um marcador precoce e sensível de DOX cardiotoxicidade, como o stress metabólico contribui para o desenvolvimento de cardiomiopatia permanece por determinar. Devido a essa lacuna no conhecimento, o objetivo deste trabalho foi a utilização de um modelo de inibição metabólica em corações perfundidos de ratos tratados com uma solução salina (SAL) e ratos tratados com DOX, a fim de identificar alterações metabólicas causadas por um tratamento agudo e sub-­‐‑crônico. XIX O nosso pressuposto para esta estratégia é que uma menor susceptibilidade a um determinado inibidor durante a perfusão, seria um sinal de uma forma mais robusta (ou seja, mais de capacidade) da via-­‐‑alvo (s). Para o protocolo de tratamento agudo, ratos machos Wistar de 16 semanas de idade foram injectados i.p. com 20 mg / kg de DOX ou de 1 mg / kg a 0,9% de NaCl e sacrificados 24 horas mais tarde. Para o protocolo sub-­‐‑crônico, ratos machos Wistar de oito semanas de idade, receberam sete injecções s.c. semanais com DOX (2 mg / kg) ou uma equivalente da solução SAL sendo sacrificados uma semana após a última injecção. Após o protocolo de tratamentos, os animais foram sacrificados e os corações foram perfundidos com um aparelho de Langendorff com substratos cardíacos distintos (glucose, galactose mais glutamina -­‐‑ GG ou octanoato mais malato -­‐‑ OM). Inibidores glicolíticos (iodoacetato) e inibidores da fosforilação oxidativa (Rot-­‐‑ rotenona ou KCN-­‐‑ cianeto) foram adicionados separadamente nos diferentes substratos metabólicos, com o objetivo de detectar defeitos mitocondriais no grupo tratado com DOX. Em corações não perfundidos, ou corações perfundidos na ausência (controlos de tempo, TC) ou na presença de inibidores, algumas proteínas metabólicas e proteínas mitocondriais foram semi-­‐‑quantificadas por Western blotting, e os níveis de mRNA foram quantificados por RT-­‐‑PCR. No modelo de tratamento agudo DOX, corações perfundidos com glucose como substrato sofreram um declínio no número de batimentos cardíacos e produto da taxa de pressão (RPP), quando iodoacetato foi adicionado, ao contrário da Rot ou KCN, que não teve nenhum efeito. Com GG, a titulação com o inibidor diminuiu a frequência cardíaca, apesar de que a diminuição da RPP foi mais evidente no grupo SAL vs. DOX com iodoacetato e KCN. Perfusão com OM resultou em diminuição da XX frequência cardíaca e do RPP na presença dos inibidores, mostrando uma resposta igual entre os tratamentos. Quando proteínas glicolíticas e mitocondriais foram semi-­‐‑ quantificadas por Western blotting, alterações de proteínas envolvidas na biogênese mitocondrial e autofagia foram observados em corações DOX perfundidos com inibidores. Os dados do protocolo de estudo agudo, parecem sugerir que os corações provenientes de animais tratados com DOX na presença de inibidores, têm a função metabólica melhorada, indicando assim que a DOX desencadeia adaptações que permitem que os corações sejam menos susceptíveis à inibição mitocondrial e glicolítica. No modelo sub-­‐‑crónica e utilizando glucose como substrato, o grupo tratado com DOX mostrou novamente um melhor tolerabilidade para inibidores que SAL. Com GG, a titulação com iodoacetato causou uma diminuição no batimento cardíaco e no RPP em grupo DOX, quando rot ou KCN foi adicionado o número de batimentos cardíacos e RPP permaneceram idênticos entre os dois grupos. A semi-­‐‑quantificação de proteínas glicolíticas e mitocondriais sugerem uma deficiência da autofagia em corações DOX perfundidos, mais evidente durante a perfusão com GG. A presença de inibidores da perfusão geralmente também reduziu a quantidade total de proteínas detectadas através de Western Blot, embora proteínas glicolíticas aumentaram quando os corações foram perfundidos com glucose, ao contrário da perfusão com GG. Os resultados sugerem que ratos tratados sub-­‐‑cronicamente com DOX sofreram uma remodelação metabólica, que é baseado em fluxos glicolíticos mais fortes para manter a contratilidade, embora nenhum defeito mitocondrial ostensivo foi descoberto. XXI Um resultado surpreendente é que, independentemente do tampão de perfusão utilizado, não foram encontradas diferenças marcantes entre SAL e DOX corações em termos de parâmetros hemodinâmicos. O presente trabalho sugere que o remodelação metabólica durante o tratamento agudo e sub-­‐‑crônico com DOX, mantém a função cardíaca nos animais tratados. Esta remodelação é, aparentemente, baseado numa contribuição mais forte da glicólise ao metabolismo geral. Os resultados de quantidade de proteína analisados sugerem que o tratamento com DOX em ambos os modelos afectam importantes reguladores da autofagia e biogénese mitocondrial, bem como o translocador de nucleótidos de adenina. Os resultados também sugerem que um protocolo de tratamento mais longo ou com um período de repouso também devem ser testados a fim de descobrir diferenças mais profundas

Systematic Review and Meta-analysis of Nonsteroidal Anti-inflammatory Drugs to Improve GI Recovery After Colorectal Surgery

BACKGROUND: The management of delayed GI recovery after surgery is an unmet challenge. Uncertainty over its pathophysiology has limited previous research, but recent evidence identifies intestinal inflammation and activation of µ-opioid receptors as key mechanisms. Nonsteroidal anti-inflammatory drugs are recommended by enhanced recovery protocols for their opioid-sparing and anti-inflammatory properties. OBJECTIVES: The purpose of this study was to explore the safety and efficacy of nonsteroidal anti-inflammatory drugs to improve GI recovery and to identify opportunities for future research. DATA SOURCES: MEDLINE, Embase, and the Cochrane Library were systematically searched from inception up to January 2018. STUDY SELECTION: Randomized controlled trials assessing the effect of nonsteroidal anti-inflammatory drugs on GI recovery after elective colorectal surgery were eligible. MAIN OUTCOME MEASURES: Postoperative GI recovery, including first passage of flatus, stool, and oral tolerance, were measured. RESULTS: Six randomized controlled trials involving 563 participants were identified. All of the participants received patient-controlled morphine and either nonsteroidal anti-inflammatory drug (nonselective: n = 4; cyclooxygenase-2 selective: n = 1; either: n = 1) or placebo. Patients receiving the active drug had faster return of flatus (mean difference: –17.73 h (95% CI, –21.26 to –14.19 h); p < 0.001), stool (–9.52 h (95% CI, –14.74 to –4.79 h); p < 0.001), and oral tolerance (–12.00 h (95% CI, –18.01 to –5.99 h); p < 0.001). Morphine consumption was reduced in the active groups of 4 studies (average reduction, 12.9–30.0 mg), and 1 study demonstrated significantly reduced measures of systemic inflammation. Nonsteroidal anti-inflammatory drugs were not associated with adverse events, but 1 study was temporarily suspended for safety. LIMITATIONS: The data presented are relatively outdated but represent the best available evidence. CONCLUSIONS: Nonsteroidal anti-inflammatory drugs may represent an effective and accessible intervention to improve GI recovery, but hesitancy over their use after colorectal surgery persists. Additional preclinical research to characterize their mechanisms of action, followed by well-designed clinical studies to test safety and patient-reported efficacy, should be considered

Determination of generator groupings for an islanding scheme in the Manitoba Hydro system using the method of normal forms

This paper deals with the application of the method of normal forms in the analysis of a specific aspect of system dynamic behavior in the Manitoba Hydro system. Following a major loss of transmission capacity on the Manitoba Hydro HVDC system (Nelson River system), and the subsequent operation of protection systems, there is a major deficit of generation in the remaining system, comprising Manitoba and Saskatchewan. The method of normal forms is applied to determine the natural groupings which are formed by the machines in Manitoba Hydro due to nonlinear interaction. This grouping then provides a basis for developing a systematic procedure to island the remaining system.published_or_final_versio

Global academic response to COVID ‐19: Cross‐sectional study

This study explores the response to COVID‐19 from investigators, editors, and publishers and seeks to define challenges during the early stages of the pandemic. A cross‐sectional bibliometric review of COVID‐19 literature was undertaken between 1 November 2019 and 24 March 2020, along with a comparative review of Middle East respiratory syndrome (MERS) literature. Investigator responsiveness was assessed by measuring the volume and type of research published. Editorial responsiveness was assessed by measuring the submission‐to‐acceptance time and availability of original data. Publisher‐responsiveness was assessed by measuring the acceptance‐to‐publication time and the provision of open access. Three hundred and ninety‐eight of 2,835 COVID‐19 and 55 of 1,513 MERS search results were eligible. Most COVID‐19 studies were clinical reports (n = 242; 60.8%). The submission‐to‐acceptance [median: 5 days (IQR: 3–11) versus 71.5 days (38–106); P < .001] and acceptance‐to‐publication [median: 5 days (IQR: 2–8) versus 22.5 days (4–48·5‐; P < .001] times were strikingly shorter for COVID‐19. Almost all COVID‐19 (n = 396; 99.5%) and MERS (n = 55; 100%) studies were open‐access. Data sharing was infrequent, with original data available for 104 (26.1%) COVID‐19 and 10 (18.2%) MERS studies (P = .203). The early academic response was characterized by investigators aiming to define the disease. Studies were made rapidly and openly available. Only one‐in‐four were published alongside original data, which is a key target for improvement

Airway smooth muscle cells from severe asthma patients with fixed airflow obstruction are responsive to steroid and bronchodilator treatment in vitro

Asthma is characterised by recurrent symptoms associated with variable airflow obstruction and airway hyperresponsiveness, all of which are improved with combination inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) treatment in mild-to-moderate asthma [1]. A proportion of patients however develop fixed airflow obstruction (FAO), despite optimised treatment. FAO is prevalent in up to 60% of patients with severe asthma and is associated with a more rapid decline in lung function and increased symptoms [2]. The underlying mechanisms of FAO in asthma are poorly understood; therefore, development of novel treatment strategies remains a challenge. Airway smooth muscle cells (ASMCs) are the major effector cells of bronchoconstriction in asthma and also contribute to the inflammatory process by secreting pro-inflammatory cytokines and chemokines. Therefore, ASMCs are a major target of both β2-agonist and ICS treatment [3]. Although several studies have suggested that steroid signalling [4] or β2-adrenoceptor (β2AR) signalling may be abnormally regulated in severe asthma [5], it remains unknown whether impaired airway smooth muscle corticosteroid and/or β2-agonist response may contribute to the development of FAO. The aim of this study was to investigate whether primary human ASMCs obtained from severe asthma patients with FAO differ in their response to β2-agonists and corticosteroids compared with asthma patients without FAO and healthy controls. We hypothesised that ASMCs from asthma patients with FAO are less responsive to corticosteroid and β2-agonist treatment than those from patients without FA